Инфекция вирусом гепатита С и беременность
Бюллетень WHEC Практика и клинической управления для медицинских работников. Образовательный грант предоставляемых Здоровье женщин и центр образования (WHEC).
Hepatitis C virus (HCV) infection has been called a silent epidemic, because after infection, many individuals are unrecognized and untreated until years later. Advanced HCV leads to significant morbidities such as cirrhosis, hepatocellular carcinoma and the need for liver transplant (1). Acute hepatitis C is a rare event in pregnancy. The most common scenario is chronic HCV infection in pregnancy. The World Health Organization (WHO) has called for efforts to combat HCV to eliminate the disease by 2030 (2). Identification of HCV infection is essential to achieve that goal, and special populations, such as pregnant women and their newborns, are of significant interest. Using well-publicized Center for Disease Control and Prevention (CDC) and National Institutes of Health (NIH) recommendations for risk-based screening, appropriately 50% of patients with HCV infections are detected by risk-factor based testing and are aware of their disease status (3). Because risk-factor screening has obvious limitations, universal screening in pregnancy has been suggested to allow for linkage to postpartum care and identification of children for future testing and treatment. Universal screening additionally has the advantage of identifying women who may not have contact with health care or health insurance were it not for their pregnant state.
The purpose of this document is to describe the prevalence of hepatitis C virus (HCV) infection and pregnancy, evaluate current risk factors associated with HCV antibody positivity, and identify novel composite risk factors for identification of groups most likely to demonstrate HCV antibody seropositivity in an obstetric population. In this review, we have also provided an up-to-date overview of the existing evidence on the pediatric use of direct-acting antivirals (DAAs), summarizing indications for treatment and recommendations for monitoring.
Universal Screening for HCV during pregnancy
The American College of Obstetricians and Gynecologists (ACOG) and the Society of Maternal-Fetal Medicine have not advocated universal screening for pregnant women for several reasons: this strategy invites the possibility and sequelae of false-positive test results (4), mother-to-child transmission of HCV occurs at a relatively low rate, and there are no effective interventions during pregnancy that would modify mother-to-child transmission of HCV. Additionally, there are no current antiviral treatments approved for use in pregnant women (5). With current systems of care and absence of safety evidence of antivirals during pregnancy, identification of a pregnant woman with HCV does not necessarily expedite treatment. The mother is not eligible for treatment until she is postpartum, which may be weeks to months, and her child would not definitely be identified as having HCV infection until at least 18 months of life.
The argument for universal HCV screening in pregnancy is strengthening in the setting of readily available and effective treatment options for the nonpregnant individuals. This will be strengthened further once direct-active antiviral agent regimens are found that are safe and effective during pregnancy and other interventions are identified to decrease vertical transmission risks. Although early cost-effective analyses showed variable results, a recent model incorporating direct-acting antiviral agents with greater than 90% sustained virologic response, a one-time HCV screen, and contemporary seroprevalence rates showed that universal prenatal HCV screening improved health outcomes of women with HCV infection and identification of neonates with infection and was cost effective to an HCV infection prevalence as low as 0.16% (13).
The decision as to how often to screen pregnant women has yet to be determined - there is concern that there will be a higher false-positive rate in the setting of increased screening frequency in an overall low-risk population. It is time to reevaluate universal screening for HCV infection during pregnancy. Women's Health and Education Center (WHEC) supports one-time screening during the index pregnancy, with repeat screening during subsequent pregnancies if new risk factors are identified.
Prevalence of HCV Infection
With global prevalence of 2.5% (6), HCV infection is a chronic disease, have affected 2.4 million Americans in 2016 (7). Reported cases of acute HCV infection increased 3.5-fold from 2010 to 2016 (from 850 to 2,967 reported cases, respectively), and the number of cases has been rising annually (8). The increase in acute HCV case reports reflects new infections associated with rising rates of injection-drug use, and to a lesser extent, improved case detection. Several early investigations of newly acquired HCV infections reveal that most occur among young, white individuals who inject drugs and live in non-urban areas (particularly in states within the Appalachian, Midwestern, and New England regions of the United States). Trends in these regions suggest an overall increase in HCV incidence throughout the country (9). The increased in acute HCV infection was greater among young women than among men. This has led to an increase in the number of neonates born to mothers who are HCV positive. In the United States, mother-to-child transmission is the primary cause of HCV infection in children, with a rate in women with HCV monoinfection of 2 - 8% (10). At least 40,000 children are exposed annually to HCV during pregnancy, resulting in an estimated 2,700 to 4,000 new cases of pediatric HCV infection each year (11).
Transmission of HCV Infection
HCV belongs to the Flaviviridae family, whose genetic material is composed of a positive-sense single strand RNA, and its genetic variation allows recognizing seven different genotypes. Its transmission takes place through percutaneous, sexual, and vertical exposure. The occurrence frequency for each of such categories varies according to the studied population and associated factors concomitance. However, it should be highlighted that the parenteral route is more efficient and prevalent in HCV transmission than sexual and vertical transmission. The highest number of new infections has been observed among injectable drug users and through syringe and needle sharing (20).
Persons for Whom Hepatitis C Virus Testing is Recommended (12)
- Adults born from 1945 through 1965;
- HCV testing is recommended for those who:
- Currently inject drugs;
- Ever injected drugs, including those who injected once or a few times many years ago;
- Have certain medical conditions
- Who received clotting factor concentrates produced before 1987,
- Who were ever on long-term hemodialysis,
- With persistently abnormal alanine aminotransferase levels,
- Who have HIV infections
- Were prior recipients of transfusions or organ transplants:
- Were notified that they received blood from a donor who later tested positive for HCV infection,
- Received a transfusion of blood, blood components, or an organ transplant before July 1992.
- Health care, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures to HCV-positive blood;
- Children born to women who are HCV positive.
Persons for Whom Routine HCV Testing is of Uncertain Need (12)
- Recipients of transplanted tissue (e.g., corneal, musculoskeletal, skin, ova, sperm);
- Intranasal cocaine and other non-injecting illegal drug users;
- Persons with a history of multiple sex partners or sexually transmitted diseases;
- Long-term steady sex partners of persons who are HCV positive.
Acute Hepatitis C Viral Infection
Acute hepatitis C during pregnancy has been rarely reported in pregnancy, and limited to high-risk groups, such as intravenous drug users, whereas the risk in general population is negligible. From the epidemiological point of view, however, acute hepatitis C is not a relevant problem in pregnancy (14). The differential diagnosis of acute hepatitis C requires us to rule out hepatitis caused by other hepatotropic viruses (hepatitis A, B, D and E) and liver disorders unique to pregnancy. Sporadic cases in immigrants from developing countries might be seen in developed countries. Generally, symptoms of acute illness including jaundice develop in 80% of cases. The reported risk for fulminant hepatic failure in pregnancy was up to 20% in previous studies. The result from recent studies in India and elsewhere indicate that the severity of viral hepatitis during pregnancy is similar to that in non-pregnant women (15).
Acute viral hepatitis in pregnancy requires differential diagnosis from liver disorders unique to pregnancy, in particular the HELLP syndrome, intrahepatic cholestasis of pregnancy (ICP), and acute fatty liver of pregnancy. The HELLP syndrome is a variant of pre-eclampsia/eclampsia and is characterized by elevated liver enzymes, low platelet count and hemolysis. Its onset is generally in the second trimester of pregnancy, and patients may show initially elevated blood pressure, edema and proteinuria (16).
The ICP most frequently occurs in the third trimester of pregnancy with pruritis and elevated serum transaminases and bile salts; jaundice is rare and synthetic function of the liver is conserved (17). Acute fatty liver of pregnancy is a severe condition that usually occurs in the third trimester with symptoms of encephalopathy and liver failure (18). Early diagnosis is essential because treatment of acute hepatitis is generally conservative, whereas acute fatty liver of pregnancy and often HELLP syndrome require immediate treatment.
Chronic Hepatitis C Viral Infection
The most important studies of HCV infection in pregnancy have dealt with chronically infected women, and the natural history of the liver disease in pregnant mothers and their offspring is not fully understood. HCV infection has a high chronification rate, and around 50% to 85% of people evolve to the chronic infection form. Symptoms are present in a minority of cases (20 to 30%), and are mainly unspecific manifestations such as tiredness, changes in sleeping, nausea, diarrhea, abdominal pain, anorexia, myalgia, arthralgia, weakness, behavior changes, and weight loss (20). Extrahepatic manifestations include cryoglobulinemia, membranoproliferative glomerulonephritis, autoimmune thyroiditis, porphyria cutanea tarda, among others. In case of lack of spontaneous viral elimination or treatment, an average of 20% HCV infection evolve to cirrhosis of liver (20).
Interpretation of Results of Tests for HCV Infection and Further Actions (21)
|Test Outcome||Interpretation||Further Actions|
HCV antibody non-reactive
No HCV antibody detected
Sample can be reported as non-reactive for HCV antibody. NO further action required. If recent exposure in person tested is suspected, test for HCV RNA*
HCV antibody reactive
Presumptive HCV infection
A repeatedly reactive result is consistent with current HCV infection, or past HCV infection that has resolved, or biologic false positivity for HCV antibody. Test for HCV RNA to identify current infection.
HCV antibody reactive, HCV RNA detected
Current HCV infection
Provide person tested with appropriate counseling and link person tested to care and treatment. †
HCV antibody reactive, HCV RNA not detected.
No current HCV infection
No further action required in most cases. If distinction between true positivity and biologic false positivity for HCV antibody is desired, and if sample is repeatedly reactive in the initial test, test with another HCV antibody assay. In certain situations††, follow up with HCV RNA testing and appropriate counseling.
Effect of Pregnancy on HCV
During pregnancy in chronic HCV infection a significant reduction in the mean alanine aminotransferase (ATL) levels are reported, with rebound during the postpartum period (19). However, when we consider a cohort of pregnant women with HCV infection and persistently high aspartate aminotransferase (AST)/ALT levels, this trend is not confirmed. The release of endogenous interferon from the placenta during pregnancy might partly explain changes in liver enzymes, but does not interfere with viral clearance (22). Other factors, such as hemodilution or immune tolerance, may account for the decrease in serum transaminases during pregnancy. Sex hormones, and possibly immunosuppressive cytokines synthesized during pregnancy, might result in modulation of the immune response against HCV.
Observation regarding serum HCV-RNA concentration have been variable. Monitoring of viral load by monthly testing showed that HCV RNA is relatively stable over time in HCV chronic carriers without biochemical activity of the disease, whereas a low number of viremic flares can occur over a year in patients with biochemical activity of liver disease (23).
Effect of HCV on Course of Pregnancy
There is no unfavorable effect of HCV on pregnancy. It has been shown that infants born to HCV-positive women are more likely to have low birth-weight, be small for gestational age, be admitted to the intensive care unit, or require assisted ventilation (24). In a more recent study using birth certificate records of 1,670,369 pregnancies, it was found that women with HCV were more likely to have infants born preterm, with low birth weight and congenital anomalies (25). However, this study had several limitations, in particular, its retrospective design and lack of association with several variables, such as use of tobacco, alcohol or drugs. Indeed, there is no explanation for prematurity and low birth weight in HCV-negative mothers, although increased cytotoxicity of placental natural killer T cells could be hypothesized possibility.
It has been reported that in pregnant women involved in a methadone treatment program, HCV reactivity was associated with an increased risk of neonatal withdrawal regardless of maternal methadone use (26). The link between ICP and HCV has not been completely explained so far, although several hypotheses can be suggested, including a defect in the transport of sulfated pregnancy hormones in the liver. It has been suggested that HCV down-regulates the expression of the ABC transporter multi-drug resistance protein 2 (MRP2) in the liver, thus inducing failure in the transport of various toxic substances. Furthermore, another link may be with a defect in the ABCB11 gene encoding the bile salt export pump (27).
Vertical Transmission of HCV Infection
The biology of perinatal transmission of HCV to the infection of maternal peripheral blood mononuclear cells (PBMCs) by the virus and to the presence of the negative strand of HCV inside the PBMC, which is a sign of viral replicative activity. It was noted that HLA antigen class II diversity between the mother and the baby induces rapid clearance of infected maternal cells through the newborn alloimmune anti-major histocompatibility complex response; this was demonstrated to be protective for perinatal transmission of HCV. High-levels of NK cells in the placenta of HCV-positive mothers were detected by some researchers. These cells had greater cytotoxicity in the HCV-positive mothers. This may be explanation for the relatively low rates of vertical transmission, though the increased cytotoxicity of the NK cells may also lead to a higher risk of preterm delivery (28).
Risk factors of HCV Perinatal Transmission
Factors affecting the risk of HCV perinatal transmission that may cause more extensive hepatic damage and subsequently elevated ALT, are (28):
- High maternal serum viral load at the time of delivery as it indicates active viremia. The risk is proportionate to the increase in levels of viral load above 105 IU/ml and reaches a maximum at levels above 107 IU/ml.
- High maternal serum ALT levels in the 12 months before pregnancy and/or at the time of delivery as it is considered a reflection of higher viral replication rate that may cause more extensive hepatic damage and subsequently elevated ALT.
- Rupture of membranes >6 hours.
- Prolonged and/or difficult deliveries.
- Fetal sex remained the only risk factor significantly associated with HCV perinatal transmission, with girls as twice as likely to be infected as boys in one study and 8 to 3 in another study. This finding likely reflects hormonal or genetic differences in susceptibility or response to infection. Maternal infections increase fetal cortisol and dehydro-epiandrosterone synthesis. Androgens may influence the immune response; estradiol protects stimulated feline lymphocytes from apoptosis, and human male and female fetuses exhibit differences in regulation of the cytokine network.
- Twin pregnancies discordant for transmission of HCV are another supporting factor.
- Use of invasive procedures during pregnancy such as amniocentesis, although its impact is still debatable.
- Studies reported conflicting findings on the effect of invasive fetal monitoring. Some authors have suggested that there is higher risk of HCV exposure with the use of scalp electrode.
- Concomitant HIV infection:
- Increases risk by 3- to 4-fold;
- A meta-analysis showed that HIV and HCV co-infection increases the odds of HCV perinatal transmission by 90%.
- The incidence of HCV vertical transmission is approximately 3-5% in HCV RNA-positive mono-infected mothers, but can be as high as 19% in HIV-co-infected.
- Even when controlling HIV, presence of HCV viremia increases the odds of vertical transmission 2.82-fold. This is thought to be attributed to the higher HCV load in immunosuppressed HCV/HIV-infected women than in women with HCV-infection only.
Factors decreasing the risk of HCV perinatal transmission
- Specific HLA markers such as HLA D13 and HCV-specific CD4 reactivity decrease transmission, highlighting the potential importance of immune-mediated mechanisms in HCV spread.
- High NK cells in the placenta. These cells had greater cytotoxicity in the HCV-positive mothers. This may be an explanation for the relatively low rates of vertical transmission; however, the increased cytotoxicity of the NK cells may also lead to higher risk of preterm delivery in HCV-positive mothers.
Monitoring of HCV-Positive Patients during Pregnancy
Recommendations for monitoring HCV-infected women during pregnancy are (29):
- HCV RNA and routine liver function tests are recommended at initiation of prenatal care for HCV-antibody-positive pregnant women to assess the risk of mother-to-child transmission (MTCT) and severity of liver disease.
- All pregnant women with HCV infection should receive prenatal and intrapartum care that is appropriate for their individual obstetric risk(s) as there is no currently known intervention to reduce MTCT.
- In HCV-infected pregnant women with pruritis or jaundice, there should be a high index of suspicion for intrahepatic cholestasis of pregnancy (ICP) with subsequent assessment of ALT, AST, and serum bile acids.
- HCV-infected women with cirrhosis should be counseled about the increased risk of adverse maternal and perinatal outcomes. Antenatal and perinatal care should be coordinated with a maternal-fetal medicine (i.e. high-risk pregnancy) obstetrician.
Mode of Delivery to reduce HCV Perinatal Transmission
Theoretically, elective cesarean section might reduce the HCV MTCT risk by preventing contact of the newborn with maternal blood during labor and infected genital secretions during the passage through the birth canal. Some studies observed that lower risk of infection in children by cesarean section (30). However, the majority of targeted investigations, including the largest observational studies, consistently concluded that mode of delivery dose not influence the HCV vertical transmission rate and such findings have been confirmed by a targeted metanalysis (31).
Indeed, it is worth considering that elective cesarean section might have protective effects in women with high viral load, a situation that has not been sufficiently analyzed. In fact, most expert recommendations or guidelines conclude that there is no reason to offer elective cesarean section to HCV infected pregnant women (32).
Breastfeeding and HCV Perinatal Transmission
Most researchers found that the HCV viral count in breast milk is extremely low and that it likely becomes inactivated in the digestive tract of the infants. As there is no proof of any increase in the risk of HCV transmission with breastfeeding, discouraging breastfeeding is not recommended.
Breastfeeding is not contraindicated in women with HCV infection, except when the mother has cracked, damaged, or bleeding nipples, or in the context of HIV co-infection. Women with HCV-infection should have their HCV RNA reevaluated after delivery to assess for spontaneous clearance. Spontaneous clearance of HCV can occur in the postpartum period. Previous studies with small numbers of patients demonstrated that up to 10% of postpartum women became HCV RNA undetectable (33). A recent study from Egypt demonstrated that a 25% rate of spontaneous resolution that was strongly associated with the favorable IL28B allele (34).
Given these findings, women should have their HCV RNA reevaluated after delivery. In that time, HCV RNA could become undetectable or rebound to pre-pregnancy levels. The possibility of spontaneous viral clearance should be considered for any woman who is assessed for DAA treatment in the postpartum period.
Diagnosis of HCV Infection in the Newborn
Infants born to women with chronic hepatitis C have maternal anti-HCV antibodies that can be detected until 12 to 15 months of life. Chronic hepatitis C infection in infancy is diagnosed by the presence of HCV RNA by PCR testing at 3 to 6 months of age or by detectable HCV antibody at 18 months. Therefore, appropriate infant follow-up after birth for testing is needed to detect HCV MTCT. It is believed that maternal HCV infection can affect the babies in different ways (35):
- It can lead to increased incidence of intrauterine growth retardation, low birth weight, a higher neonatal intensive care admission rate and more frequent need for ventilatory support (35).
- Neonatal abstinence syndrome: In the New Mexico study, 84 of 95 neonates (88.4%) born to HCV antibody-positive mothers on methadone had neonatal abstinence syndrome that required weaning, whereas only 12 of 33 neonates (36.4%) born to HCV antibody-negative mothers on similar methadone doses required weaning (26). Pediatricians should be aware of the high risk of methadone withdrawal for infants born to HCV antibody-positive mothers on methadone.
- Perinatal infection may happen as the presence of reactive neutralizing antibodies in the mother does not prevent perinatal HCV transmission or progression to chronicity in infants and children. The timing of perinatal transmission of HCV is based on the appearance of HCV RNA positivity in the newborn.
- Perinatal infection can lead to:
- Chronicity in 80% of cases, moreover, the appearance of cross-reactive neutralizing antibodies during the chronic phase dose not correlate with better control of viremia or with the clearance of HCV,
- A wide range of variability of ALT levels in the first year of life, when high values may be found, indicating acute hepatitis.
- Third trimester assessment of fetal growth may be performed, but antenatal testing is not indicated in the setting of hepatitis C virus diagnosis alone.
- Screening for viral hepatitis in patients with a diagnosis of intrahepatic cholestasis of pregnancy at an early gestational age or with high levels of bile acids.
- Obstetrical providers screen all pregnant patients for hepatitis C virus by testing for anti-hepatitis C virus antibodies in every pregnancy.
- Obstetrical care providers screen hepatitis C virus-positive pregnant patients for other sexually transmitted diseases (if not done previously), including HIV, syphilis, gonorrhea, chlamydia and hepatitis B Virus.
- Vaccination against hepatitis A and B virus (if not immune) for patients with hepatitis C virus.
- Direct-acting antiviral regimens (DAAs) only be initiated in the setting of a clinical trial during pregnancy and that people who become pregnant while taking a DAA should be counseled in a shared decision-making framework about the risks and benefits of continuation.
- If prenatal diagnostic testing is requested, patients are counseled that data regarding the risk of vertical transmission are reassuring but limited.
- SMFM recommends against cesarean section delivery for the indication of hepatitis C virus alone.
- Obstetric care providers avoid internal fetal scalp monitoring and early artificial rupture of membranes when managing labor in patients with hepatitis C virus, unless necessary in the course of management, (i.e., when unable to trace the fetal heart rate with external monitors and the alternative is proceeding with cesarean delivery).
- Hepatitis C virus status does not alter standard breastfeeding counseling and recommendations unless nipples are cracked or bleeding.
- Viral Hepatitis in Pregnancy;
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Postnatal Follow-up of mothers
Currently, all new therapy regimens are contraindicated in pregnant/breastfeeding settings, because of lack of sufficient safety information and adequate measures of contraception are still routinely recommended for female patients of childbearing potential. HCV RNA levels can fluctuate during pregnancy and the postpartum period, most likely as a result of the release of tolerance in HCV-specific T-lymphocyte responses that develop during pregnancy. HCV-infected patients should be treated with antiviral therapy, with the goal of achieving a sustained virologic response (SVR), preferably early in the course of chronic HCV infection, prior to the development of severe liver disease and other complications.
Achievement of SVR prevents additional HCV-related liver damage and is associated with >70% reduction of the risk of hepatocellular carcinoma, and 90% reduction of the risk of mortality and liver transplant (36). SVR is positively associated with quality of life, as indicated by physical, emotional, and social health status.
The safety of direct-acting antivirals (DAAs) administration during pregnancy, including possible effects of fertility, is yet not-known. If women become pregnant while receiving DAAs therapy (with or without ribavirin), their physicians should discuss with them the risks and benefits of continuing treatment.
Recommendations of The Society for Maternal-Fetal Medicine (SMFM) (37):
Children and Adolescents with Chronic Hepatitis C Infection
In 2017, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved fixed-dose direct-acting antiviral (DAA) combination sofosbuvir and ledipasvir and the combination of sofosbuvir plus ribavirin for the treatment of adolescents (aged 12 - 17 years) with chronic hepatitis C. Preliminary results on the use of DAAs in pediatric patients are available for the fixed-dose combination sofosbuvir and ledipasvir in children aged 6 - 17 years for genotype 1 or 4 infection; for combination sofosbuvir plus ribavirin for adolescents aged 12 - 17 years for genotype 2 or 3 infection; for the fixed-dose combination ombitasvir, paritaprevir, and ritonavir with or without dasabuvir and with or without ribavirin for adolescents aged 12 - 17 years with genotype 1 or 4 infections.
All the results available indicated positive efficacy and favorable safety profiles of the different combinations of DAAs. With the approval of the new drugs, indications for treatment of children with chronic hepatitis C have changed. DAA therapy is recommended for all adolescents aged 12 - 17 years with chronic hepatitis C infection independent of treatment history and disease severity. If and when DAAs are approved for younger age cohorts, all children older than 3 years infected with hepatitis C will benefit from antiviral therapy (38).
In general, pregnancy does not have a negative effect on hepatitis C Virus infection. conversely, chronic hepatitis does not appear to have an increase effect on the course of pregnancy, or the birth weight of newborn infant. The overall rate of mother-to-child transmission for HCV is 3% to 5 % if the mother is known to be anti-HCV positive. Co-infection with HIV increases the rate of mother-to-child transmission up to 19.4%. Both interferon and ribavirin are contraindicated during pregnancy. Viral clearance prior to the pregnancy increases likelihood that a woman remains non-viremic in pregnancy with a consequent reduced risk of vertical transmission.
The HCV perinatal infection is an underestimated health problem which can lead to major chronic complications in life. This necessitates intimate follow-up of all infants born to HCV-infected mothers by anti-HCV serology and PCR to apply timely management when needed. In areas with high HCV prevalence, a national screening program for HCV in females before marriage is warranted so as to start DAA treatment before marriage, which in turn can eradicate HCV vertical infection.
Understanding the modularity effects of pregnancy on the immune response to HCV within the mother's liver as well as how HCV infects the fetal liver as it matures is necessary to allow better therapy. The recently appointed DAAs may open a new era of treatment of HCV infection during pregnancy in the near future. Universal HCV screening during the pregnancy is a fair, realistic, strategy which should be implemented in healthcare systems worldwide.
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