| Introduction |
Hepatitis C virus (HCV) is the most common blood-borne infection in the United States, affecting an estimated 2.4 million people today.1 Reports of new HCV infections are on the rise, especially among rural young adults, particularly white youth with a history of injection drug use.2,3
As new HCV infections have emerged among young adults in the United States, rates of HCV infections have also increased among pregnant women.
From 2009 to 2014, HCV infections in women with live births nearly doubled in the United States, reaching 3.4 per 1000 births.4 The rate of vertical transmission of HCV is estimated at ∼3% to 6% but It can be as high as 11% if the mother is co-infected with the human immunodeficiency virus (HIV).5,6
Given that vertical transmission is the most common route of infection for children,7,8 the rapid increase in HCV infections among pregnant women in the United States is an emerging public health concern for the pediatric population. Current estimates suggest that perinatal exposure to HCV affects approximately 40,000 children born annually in the United States, resulting in ∼2700 to 4000 new HCV infections.7,9
Despite the rapid increase in HCV infections among pregnant women and data demonstrating the cost-effectiveness of universal HCV screening during pregnancy,10 there are limited data on the evaluation of testing in HCV-exposed infants. National guidelines recommend that infants exposed to HCV be tested with an HCV antibody at 18 months of age or with an HCV RNA polymerase chain reaction (PCR) from 1 to 2 months of age. .
The few published studies on this topic suggest that infants exposed to HCV are not commonly tested for HCV, with testing rates ranging from 16% to 68%.11–15 However, these data are limited by the small numbers generated. from studies of a single city11 or a single tertiary care center.14,15 Other studies are limited by the relatively short study period,11,15 or by following a specific maternal population, such as infants of women with opioid use disorder.13
To address gaps in the existing literature, the objectives of this study were to (1) determine what proportion of HCV-exposed infants were tested in a large population-based cohort, (2) evaluate whether testing was appropriate according to national guidelines, and (3) determine whether hospital- and patient-level factors were associated with testing performance.
| Methods |
This retrospective cohort study included mother-child dyads for infants born in Tennessee from January 1, 2005 to December 31, 2014 and who were enrolled in TennCare (Tennessee’s Medicaid program). The children were followed until 2 years of age, until December 31, 2016.
Data were obtained from TennCare and birth certificate records.16,17 This study was approved by the Institutional Review Boards of Vanderbilt University Medical Center and the Tennessee Department of Health.
> Cohort
Mother-infant dyads were included if the mother was between 15 and 44 years of age at the time of delivery and was enrolled in TennCare at least 30 days before delivery, and if the infant was enrolled in TennCare within 30 days of birth. and maintained such enrollment until 2 years of age with no more than 30 days of discontinuation during this time. Infants who died during the 2-year follow-up period were excluded.
Maternal HCV status was obtained from birth certificates and the following codes
of maternal hospitalization for childbirth of the International Classification of Diseases, Ninth Revision, Clinical Modification : 070.41, 070.44, 070.51, 070.54, 070.70 and 070.71.
> Outcome measures
The primary outcome of interest was HCV assessment in perinatally exposed infants during the first 24 months. HCV screening was determined using Current Procedural Terminology codes for HCV antibody testing (86803 and 86804), HCV RNA (87520, 87521, and 87522), and HCV genotype (87902).
The secondary outcome was adequate HCV testing according to current national screening guidelines, defined as HCV antibody testing at or after 18 months of age or HCV RNA testing at or after 2 months of age. age.18–20
> Covariates
Covariates associated with HCV testing were chosen a priori based on literature and clinical relevance. It was hypothesized that mothers who were younger and less educated would be less likely to have tested babies. It was also considered that infants with
birth defects or admitted to the neonatal intensive care unit (NICU) would be more likely to have additional follow-up visits and therefore have higher rates of HCV screening. Similarly, it was hypothesized that higher rates of both maternal and child health system use would translate into a higher likelihood of HCV screening.
Maternal covariates included: maternal age, race, ethnicity, educational level, maternal pregnancy and parity, tobacco use, maternal ICU admission, and maternal co-infections with hepatitis B or HIV.
Infant covariates included: gestational age at birth, birth weight, classification as small for gestational age (birth weight < 10th percentile), sex, breastfeeding at discharge, NICU admission, infant seizures, head injuries. birth, and congenital disorders (cleft lip, cleft palate, confirmed trisomy 21, congenital hernia, gastroschisis, heart disease, hypospadias, limb reduction, omphalocele, and spina bifida).
Hospital and provider-level factors included: hospital, county of residence, and health system use, defined as the number of maternal prenatal visits and the number of well-child visits. Maternal county of residence was classified according to the 2013 Code of Rural-Urban Continuity (CCRU)21 as urban (CCRU 1, 2, or 3), adjacent rural (CCRU 4, 6, or 8), or remote rural (CCRU 5 , 7 or 9).
> Data analysis
Descriptive statistics were used to compare HCV-exposed infants with unexposed infants and HCV-tested populations with untested populations. These were presented as frequency (percentage) for categorical variables and median (interquartile range) for continuous variables. χ tests and Wilcoxon rank tests were used to compare categorical and continuous variables, respectively.
The primary model was a multivariable, multilevel logistic regression model constructed to assess whether the following factors were associated with infant HCV screening: maternal age, maternal race, rurality, maternal education, maternal parity, number of maternal prenatal visits, maternal tobacco use, maternal co-infection with hepatitis B or HIV, NICU admission, gestational age, small for gestational age, sex of infant, presence of a congenital birth defect or neonatal disorder identified at birth (such as seizures or birth injuries), and number of well-child controls.
This regression model took into account random effects at the delivery hospital level. The intra-class correlation coefficient was calculated to determine how much of the variability in the tests was accounted for to be grouped at the hospital level. A similar model was then constructed to assess the secondary outcome of appropriate HCV screening, as previously defined.
A series of supplementary analyzes were carried out to test the robustness of the study assumptions. First, the level of missing data was assessed. Overall, 11.3% of observations had missing data. For each of the covariates, 0.5% of the observations were missing, except for the number of prenatal visits, where 10.1% of the observations were missing.
Supplementary analysis using multiple imputation with 11 iterations was performed to account for these missing data. Then, because prenatal visits had higher levels of missing data, a supplemental analysis was performed excluding prenatal visits as a covariate.
Statistical significance was set at P < 0.05 for all tests. Statistical analysis was performed using R version 3.5.1 (R Foundation for Computing Statistics, Vienna, Austria) and Stata version 15.1 (Stata Corp, College Station, TX).
| Results |
Among 384,837 mother-child dyads of infants born in Tennessee and enrolled in TennCare from 2005 to 2014, a total of 4072 (1.1%) mothers had HCV infection during pregnancy. HCV-positive mothers, compared to HCV-negative mothers, were more likely (P < 0.001) to be white than African American (92.9% vs. 6.4%), to have more pregnancies (2 vs. 1), to have consume tobacco (72% vs 29%), and were more likely to be hepatitis B positive (2.5% vs 0.2%), and HIV positive (0.6% vs 0.2%).
HCV-exposed infants, compared with unexposed infants, were more likely (P < 0.001) to have a lower birth weight (median 3027 vs. 3204 g), to be small for their gestational age (21% vs. 14 %), and to be admitted to the NICU (11.5% vs 6.9%). HCV-negative mother-child dyads were more likely to have more prenatal visits (median 11 vs. 10; P < 0.001), and to have infants breastfed (54% vs. 33%; P < 0.001).
The prevalence of infants exposed to HCV increased each year, from 5.1 per 1000 live births in 2005 to 22.7 per 1000 live births in 2014 (P < 0.001). Overall, 92.9% of HCV-positive mothers were white, compared with 6.4% African-American and 0.6% other races. Although HCV rates remained relatively constant for mothers who were African American or other races, HCV rates rose sharply for white mothers.
There was significant variation by county in HCV exposure rates, with the highest rates of perinatal HCV exposure observed in the eastern, predominantly Appalachian, region of Tennessee.
Overall, 946 (23%) HCV-exposed infants underwent any HCV testing in the first 24 months of life, with a slight year-on-year variation of 18% to 26%. The majority (57.3%) of tests performed were HCV antibody tests, compared to 39% HCV RNA PCR tests and 3.7% HCV genotyping tests.
The majority of infants tested (70%) underwent a single test to evaluate HCV infection. The number of tests, however, varied, with an outlier of 1 child undergoing 13 HCV tests. There was significant county variation in testing rates, with lower rates of HCV testing in West Tennessee.
Of the HCV-exposed infants who were tested, 733 (18%) met the authors’ definition of appropriate evaluation. Three hundred fifty-four (48%) of these appropriately screened children had HCV antibody testing at or after 18 months of age, 298 (41%) underwent HCV RNA PCR testing at or after 2 months of age, and 81 (11%) underwent both tests.
Among HCV-exposed infants, maternal educational attainment, parity, and number of prenatal visits were similar between infants who were screened and those who were not screened.
However, HCV-exposed infants who were tested were more likely to be born to mothers who used tobacco (78% vs. 70%; P < 0.001) or who had coinfection with HIV (1.3% vs. 0.4% ; P < 0.001). Additionally, HCV-exposed infants who were born at a lower gestational age (38 vs. 39 weeks), with a lower birth weight (2960 vs. 3040 g), who were admitted to a NICU (14% vs. 11%), or who had More healthy child controls (median 7 vs. 6) were also more likely to be tested (P < 0.001). Among infants
exposed to HCV, adequate HCV evaluation was significantly more likely with the following covariates: white race (96.5% vs 3.1% vs 0.4%; P < 0.001), urban residence (73% vs 22.1 % vs 4.9%; P = 0.02), maternal tobacco use (78% vs 70%; P < 0.001), maternal HIV co-infection (1.2% vs 0.5%; P = 0 .01), lower birth weight (2954 vs 3037 g; P < 0.001), small for gestational age (24% vs 21%; P = 0.048), NICU admission (15% vs 11%; P = 0.001) and more healthy child controls (median 7 vs 6; P < 0.001), similar to factors associated with any HCV test.
After accounting for maternal and infant characteristics, health system use patterns, and hospital of birth, HCV-exposed African American infants were less likely to be tested compared with exposed White infants (adjusted odds ratio [aOR] 0.32; 95% confidence interval [CI], 0.13-0.78).
HCV-exposed infants residing in rural counties adjacent to metropolitan areas were also less likely to be tested (aOR, 0.73; 95% CI, 0.58–0.92). HCV-exposed infants who attended a greater number of well-child visits (aOR 1.29; 95% CI, 1.24–1.33), whose mothers used tobacco (aOR 1.41; 95% CI, 1 .14–1.74), or who were exposed to HIV (aOR, 7.85; 95% CI, 2.82–21.84) were more likely to be tested for HCV.
Furthermore, babies exposed to HCV with a higher gestational age (aOR 0.95; 95% CI, 0.91–0.99) and whose mothers had a greater number of previous pregnancies (aOR 0.93; 95% CI, 0.86–0.99) were less likely to be screened for HCV. Results were similar for appropriate HCV screening and in supplemental analyses.
| Discussion |
In a state disproportionately affected by the rise of HCV among women with live births, testing of HCV-exposed infants occurred in <1 in 4 at-risk infants overall and in only 1 in 10 African American children.
Additionally, HCV-exposed infants residing in rural counties adjacent to metropolitan areas were also less likely to undergo testing, which is concerning given the rapid increase in HCV rates among young adults in rural communities.
Assuming a vertical transmission rate of 3% to 6% among the 4,072 women with live births who were identified with HCV,5,6 an estimated 122 to 244 children in the state of Tennessee were presumed to have been infected with the virus during the study period, with 94 to 187 children not identified due to lack of evaluation.
The greater likelihood of screening with perinatal HIV exposure, lower gestational age, and more well-child visits could be due to greater exposure to the health system and potentially greater access to specialized care.
The decreased likelihood of testing of babies whose mothers resided in rural areas could represent problems with transportation, a lack of professional information on screening recommendations, or less overall availability of testing.
Greater parity could have resulted in a low probability of testing because mothers may have a false sense of security due to the relatively low rate of vertical transmission and potentially having other children who were not perinatally infected.
Unfortunately, there are currently no recommended medical interventions to reduce the risk of vertical transmission during pregnancy.7,22
Of infants who acquire HCV, 20% will have resolution of their acute infection, 50% will develop an asymptomatic chronic infection, and 30% will develop an active chronic infection.23 Given these risks and the possibility of treatment before age As an adult, infants infected with HCV need to be identified, tested and managed so that effective treatment can be implemented as soon as possible.
There are several recommendations from national organizations regarding the evaluation of exposed children. All organizations recommend HCV antibody screening as a first-line screening starting at 18 months of age. Antibody testing before 18 months of age is unreliable due to transplacental or passive acquisition of maternal antibody, which may persist up to 18 months; this can lead to false positive results.
Opinions regarding the timing of initiation and repeat HCV RNA testing vary.18-20,24 Before 1 to 2 months of age, HCV RNA testing is not recommended given the low sensitivity early in the life of a child and the potential for false negatives due to intermittent viremia.25
There are some studies that also found inadequate testing in infants exposed to HCV in the United States.11–15 Taken together, these findings suggest that there is an urgent need to ensure adequate evaluation of infants exposed to HCV. Universal HCV screening in pregnant women could improve detection of exposed infants.
Additionally, build data systems that ensure maternal laboratory results are included in the child’s medical record and increase provider and patient education on national recommendations for HCV screening in infants, particularly in risk groups such as African Americans and residents of rural areas, could improve the evaluation of exposed children.
Given that there has been substantial improvement in treatment options for HCV,26 pregnancy should serve as an opportunity to identify women who are HCV-positive and treat them after delivery. This strategy facilitates the timely identification of infants exposed to HCV, and also potentially eliminates the risk of vertical transmission in subsequent pregnancies.
Current strategies to identify women who are HCV positive during pregnancy using a risk-based screening approach have been evaluated in the literature and have suggested failures in HCV identification.27–29 Additionally, there is evidence in the literature which indicates that universal screening in pregnancy may be feasible and at an acceptable cost.10,30
The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America currently recommends that all pregnant women be tested for HCV, preferably when prenatal care is initiated.31
Additionally, some states, such as Kentucky, have adopted universal HCV screening during pregnancy, which may be preferable to risk-based screening, particularly in communities with a high prevalence of HCV infections.
Despite recognition among public health officials and adult physicians that HCV has become epidemic, there appears to be less awareness among those who care for children. For example, infant screening remained low throughout the study period despite increased identification of maternal cases.
Importantly, infants exposed to HCV typically do not show clinical signs of exposure, and maternal risk factors for HCV may not be identified or reported. Furthermore, even among clinicians who consider the possibility of childhood HCV infection, the lack of changes in policies and guidelines for the approach to mothers and infants affected by HCV may impede evaluation.
Centers, particularly those in high HCV prevalence settings, should consider standardizing their approaches for pregnant and lactating women to ensure HCV identification and treatment.
There are limitations to this study, as with any study involving secondary analysis of administrative data. First, because HCV testing among pregnant women in Tennessee is not universal but risk-based, it is possible that infants exposed to HCV were not identified.22
In this case, the study’s prevalence estimates could be underestimated. Additionally, reliance on administrative and vital records data may have resulted in misclassification bias due to errors of omission or commission.
Inclusion criteria requiring pregnant women to enroll in TennCare at least 30 days before delivery may have excluded women who did not receive prenatal care, a population that may also be at risk for HCV infection and poor follow-up.
The rate of HCV infection in a given county in Tennessee may not necessarily represent the burden of the disease, but rather the initiative in that county to identify the disease. Furthermore, given that maternal HCV positivity
was obtained from birth certificates and billing data and not laboratory data, HCV positivity could be indicative of past infection or a false positive and not necessarily active infection during pregnancy.
This study only included Medicaid-funded births, representing approximately half of all births in Tennessee; therefore, this study may not be generalizable to other populations.
| Conclusions |
- HCV infection is a growing public health problem that affects maternal and child health.
- HCV screening among infants with knowledge of HCV exposure was poor, with fewer than 1 in 4 children tested, and was worse among African American infants and those with rural residences.
- Furthermore, even among the babies tested, the tests were often inadequate.
- Strategies to improve education of professionals and patients about HCV and targeting at-risk populations could improve the care of those affected by or exposed to HCV.32–34
