M. Arshad; S. S. El-Kamary; R. Jhaveri
From
Journal of Viral Hepatitis
Hepatitis C Virus Infection During Pregnancy and the Newborn Period
Are They Opportunities for Treatment?
Posted: 05/26/2011; J Viral Hepat. 2011;18(4):229-236. © 2011 Blackwell Publishing
Abstract
The worldwide prevalence of hepatitis C virus (HCV) infection in pregnant women is estimated to be between 1 and 8% and in children between 0.05% and 5%. While parenteral transmission is still common in children living in developing countries, perinatal transmission is now the leading cause of HCV transmission in developed countries. The absence of an HCV vaccine or approved therapy during pregnancy means that prevention of vertical transmission is still not possible. However, a low vertical transmission rate of 3–5%, a high rate of spontaneous clearance (25–50%) and delayed morbidity have resulted in HCV being overlooked in pregnant women and their infants. Yet a study of the natural history in mothers and children demonstrates that the prognosis of HCV can vary greatly and should be taken seriously. Factors known to increase the risk of perinatal transmission include HIV coinfection and higher maternal viral loads, while elective C-section and withholding breastfeeding have not been demonstrated to reduce vertical transmission. Current guidelines for the diagnosis of persistent perinatal infection require a positive anti-HCV test in infants born to infected mothers after 12 months or two positive HCV RNA tests at least 6 months apart. Current HCV treatment options using pegylated interferon and ribavirin are both unsuitable for use in pregnancy and infancy. However, new agents currently in preclinical phases of development, along with the recently identified association between single-nucleotide polymorphisms within the IL28 gene and treatment response, may serve to create a therapeutic window for these patients.
Introduction
It is well known that hepatitis C virus (HCV) chronic infection is a major cause of liver disease among adults worldwide
[1] and is the leading indication for adult liver transplantation in the United States.
[2] There are over 170 million people infected with the virus worldwide, and only half of patients treated with the current standard therapies achieve a sustained viral response.
[3] Among the groups less often discussed when considering the burden of HCV infection are pregnant women and their infants. Much remains unknown about the dynamics of chronic HCV infection during and after pregnancy, as well as in the neonatal period. It is clear, however, that chronic HCV infection does have a modified course during these times of tremendous physiological changes. This review will summarize what is known about HCV infection during pregnancy and infancy and offer some perspectives on possible treatment opportunities that may arise during these times as new therapies for HCV become available
Epidemiology
Worldwide, the seroprevalance of HCV in pregnant women is thought to be anywhere from 0.15% to 2.4% in the United States and European countries and much higher in countries like Egypt where it is estimated to be as high as 8.6%.
[4–8]
The prevalence of HCV infection in children ranges from 0.05% to 0.36% in studies carried out in the United States and Europe
[9–11] and is much higher in developing countries where it can range from 1.8% to 5%.
[12,13] Insufficient screening of transfused blood and blood products and parenteral exposure continue to be the major causes of HCV transmission in developing countries.
[14] In the United States and other developed countries, vertical transmission is the major route of HCV infection. In the United States, an estimated 240 000 children have antibodies to HCV, with seroprevalences of 0.1–0.2%.
[11,15,16] A tenfold higher seroprevalence of 2% was reported in incarcerated juveniles, and rates of 10–20% have been reported among children with a variety of other potential exposures such as malignancy, haemodialysis, extracorporeal membrane oxygenation or surgery for congenital heart disease.
[17–19] Almost all children who remain viremic after several years have chronic hepatitis,
[20] and decompensated HCV-associated cirrhosis in children as young as 4 years has been reported.
[21] Given that most perinatal HCV infections are silent with long-term complications that present later in adulthood, it is a considerably underestimated childhood disease with a predicted significant economic and health burden on society. At the current rate of HCV infection in children, it is estimated that in the next decade, 26 million dollars will be spent in screening, 117–206 million dollars in monitoring and 56–104 millions dollars in treatment. The total cost was calculated to be between 199 and 335 million.
[22]
Natural History of HCV in Pregnancy
The intensity of HCV infection varies during pregnancy as demonstrated by the varying level of viral loads and HCV-specific T-cell responses that correspond with the progression of pregnancy. Some studies have shown that there is a decrease in serum alanine transferase levels (ALT) in the 2nd and 3rd trimesters of pregnancy,
[23,24] along with a corresponding increase in HCV RNA during these trimesters. It is hypothesized that this may be seen because of a relative suppression of immunity as pregnancy proceeds. Oestrogen has shown to suppress intrathymic T-cell differentiation while activating the extrathymic pathways,
[25] a phenomenon that has also been noted during pregnancy.
[26] The modulation of cytokines as a result of this is important in maintaining tolerance of the paternal antigens in the foetus. This may also increase the proliferation of HCV resulting in higher HCV RNA titres in the 2nd and 3rd trimesters. The seemingly paradoxical decrease in liver enzymes and hepatic inflammation is explained by the decrease in immune-mediated hepatocellular destruction seen in chronic HCV.
[23]
Conversely, HCV RNA titres tend to decrease in the postpartum period.
[27,28] A study from Japan on 22 pregnant HCV RNA-positive women noted that some women may have spontaneous resolution of viremia following parturition.
[28] They also noted significantly greater rates of clearance compared to the nonpregnant control group. In addition, the HCV core protein levels at 3 months postpartum were much lower among patients who cleared their viremia versus those who had persistent HCV elevation. It is thought that the loss of physiological pregnancy-induced immunosuppression after birth leads to a surge in maternal cellular immune activation that results in viral clearance.
[27,29] Interestingly, pregnancy is associated with a decrease in Th-1 activity and a corresponding increase in Th-2 activity leading to a greater humoral immunity.
[30] One advantage of the weakened Th-1 responses is the reduction in the number of viral quasispecies that usually develop by the rapidly mutating HCV to escape host immunity.
[31] The postpartum reversal of this phenomenon with a decrease in Th-2 activity and a surge in Th-1 postpartum, combined with fewer viral quasispecies, may explain the increased ability of some mothers to clear persistent viremia. Some authors have also recommended that this may be an optimal time to initiate antiviral treatment, which can augment the natural defence mechanism.
Recent studies have confirmed that a tremendous surge in HCV-specific T cells in the third trimester and postpartum period is accompanied by a corresponding drop in HCV RNA. Honegger
et al. demonstrated that in nine chronically infected women, a 1.4 log drop in HCV RNA titres occurred when the HCV-specific interferon-γ responses increased by more than 100% as measured by ELISpot. Depletion studies confirmed that this surge consisted of both CD4+ and CD8+ T cells, indicating a broad and potent response.
[32]
Risks of obstetrical complications in HCV-infected pregnant women are varied. A study on 506 patients in the United States showed that the infants born to such mothers were more likely to be low in birth weight, small for gestational age, be admitted to the intensive care nursery or require assisted ventilation of some sort.
[33] However, a smaller study carried out on mothers who were infected by contaminated anti-D immunoglobulin in Ireland did not show any adverse outcomes in the study group versus the control group.
[34]
In a five-year study on 208 women, Locatelli
et al. [35] showed that the risk of cholestasis increased in pregnant women who are also HCV antibody positive, and this tends to occur earlier in the gestation compared to HCV-negative mothers. This has also been noted in other studies.
[36] While gestational cholestasis is a common complication of pregnancy, it has been suggested that HCV alters the epithelial cells in a way that predisposes women to cholestasis.
[35] Berkley
et al. [37] noted that neonates born to HCV antibody-positive mothers were more likely to have neonatal abstinence syndrome when adjusted for the dose of methadone used. The authors speculate that this may be because of poor metabolism of methadone in an HCV-infected liver; hence, a considerably higher dose is transferred transplacentally compared to women who are not infected.
The Pathogenesis of HCV Vertical Transmission
Studies on the pathogenesis of HCV have been numerous, diverse and, in many cases, yielded conflicting results. Studies to examine the timing of transmission indicate that many infants who are infected with HCV have PCR tests that are positive at or soon after delivery, suggesting
in utero transmission.
[38] Testing of amniotic fluid for HCV did not demonstrate evidence of detectable virus, which suggests that transmission may occur directly through the placenta.
[39] This is supported by numerous studies that have demonstrated no significant differences with mode of delivery.
[40,41] Case reports of divergent outcomes in monochorionic, diamniotic twins suggest that this placental infection is likely a sporadic event.
[42] Studies of the hypervariable regions of HCV from infants demonstrated limited diversity, which indicates that transmission is likely restricted to a few virions.
[43–46] Maternal factors that have been cited as playing a significant role in HCV vertical transmission are certain HLA types, as well as the presence of HCV RNA in maternal peripheral blood mononuclear cells.
[47,48] The presence of maternal neutralizing antibodies was studied and found to have no role in promoting or protecting against HCV vertical transmission.
[49]
One can make some general conclusions from the results of these disparate studies. In cases where vertical transmission occurs, it is likely that HCV is transmitted
in utero at an early or middle stage of pregnancy. The event likely consists of a few virions with limited or no diversity crossing the placenta through direct infection in an inefficient manner given the low rate of transmission. This may be influenced by maternal genetic or immune factors.
Modifiers of and Risk Factors for HCV Vertical Transmission
Perinatal transmission is thought to be the leading cause of mother to baby transmission.
[50] Both intrauterine and intrapartum transmission are possible. It is estimated that up to one-third of the infected children acquire the infection
in utero, as evidenced by the positive PCR testing within the first 3 days of life, and up to one-half as late intrauterine or intrapartum and are PCR positive after 3 days of life.
[38] Other studies have shown that HCV RNA reaches detectable levels several weeks after birth in infants born to infected mothers, raising the likelihood that HCV can also be transmitted perinatally and postnatally.
[46,51,52]
Several factors have been studied as potential modifiers of the frequency of HCV vertical transmission. Multiple obstetric, immunological and virologic factors may influence perinatal transmission of HCV. These include maternal HCV RNA levels (at viral titres beyond 10
5 to 10
6 copies/mL), HIV coinfection, HCV genotype, neutralizing antibodies, cytokine modulation, amniocentesis, foetal blood monitoring, prolonged membrane rupture and type of delivery.
[53,54]
HIV Coinfection
Maternal HCV and HIV coinfection has consistently been shown to be associated with higher transmission rates. Studies have shown that vertical transmission is 3- to 4-fold higher compared to maternal HCV alone [40,55–57]. Polis
et al. in a meta-analysis of 10 articles showed that HIV and HCV coinfection increase the odds of vertical transmission by 90%. The incidence of HCV vertical transmission is approximately 3–5% in HCV RNA-positive-monoinfected mothers, but can be as high as 19% in HIV-coinfected mothers. Even when controlling for HIV, presence of HCV viremia increases the odds of vertical transmission by 2.82-fold.
[55] Studies have shown a 0% transmission, when maternal HCV RNA is negative.
[40,58]
Prolonged Rupture of Membranes
Rupture of membranes for more than 6 h has been significantly associated with viral transmission.
[40,59] However, there is lack of any statistically significant data on the impact of obstetrical procedures on intrapartum HCV exposure. There is some suggestion that use of scalp electrodes may lead to HCV exposure.
[40] Another study demonstrated a potential increase in HCV infection in infants following amniocentesis.
[60] Benefits of doing elective C-section in mothers with HCV viremia are controversial. Gibb
et al. [51] in a study on 441 mother–infant pairs in United Kingdom and Ireland reported a transmission rate of 7.7% among infants delivered vaginally, 5.9% among those delivered via an emergent C-section and 0% among those delivered by elective C-section (i.e. prior to membrane rupture). Paccagnini
et al. [61] in a study on 70 high-risk mother–infant pairs (HIV positive and/or a history of drug use) showed a 32% rate of vertical transmission in infants born vaginally compared to 6% in those who were born by C-section. There were only two infants who were HIV positive, and both were born by caesarean section. However, most studies have not found any association between route of delivery and a decrease in transmission rates.
[56,62,63] The European Paediatric Hepatitis C Virus Network showed in a study carried out on 1758 mother–infant pairs that there was no significant difference (
P = 0.16) in vertical transmission between elective C-section, vaginal delivery or emergent C-section.
[64]
Severity of Maternal HCV Disease
The effects of maternal HCV disease activity on vertical transmission are not completely understood. Two recent studies showed that mothers with HCV infection of the peripheral blood monocytes have a higher rate of transmission to their infants.
[48,65] This is similar to what is noticed in the vertical transmission of other viruses, e.g. HIV. It has also been noted that persistently high ALT levels in the year preceding pregnancy or during pregnancy are associated with higher rates of vertical transmission.
[66] This is likely related to the higher viral loads that may cause the more extensive hepatic damage and subsequent elevated ALT. Elevated ALT is also associated with certain HCV genotypes that are more likely to be transmitted like 1a or 1b.
[67]
A small study carried out on 12 HCV seropositive mothers and their infants and a control group of 16 healthy mothers and their infants showed an increase in the natural killer (NK) cells in the placenta of HCV-positive mothers compared to the control group.
[68] It also showed that these cells had greater cytotoxicity in the HCV-positive mothers. This may be an 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 in HCV-positive mothers.
Breastmilk/Breastfeeding Transmission
HCV RNA has been detected in breast milk and colostrum.
[69,70] However, there are only isolated studies that show some indication of HCV infection of the infant secondary to breastfeeding in mothers with a high viral load.
[69] Most studies indicate that even though theoretical transmission may be possible, the viral count in breast milk is extremely low and likely becomes inactivated in the digestive tract of the infant [51,54,70–72]. Infants in several of the aforementioned studies had a single positive HCV RNA, which could be explained by vertical transmission and not necessarily breastfeeding itself. The European Paediatric Hepatitis C Virus Network noted no difference in infection rates in breast-
vs formula-fed infants in a study carried out on 1758 infants.
[64] The risk of transmission is higher if the mother has cracked or bleeding nipples. Mothers who are coinfected with HIV and HCV are recommended to follow the current guidelines for the prevention of HIV transmission
HCV Infection in Children: Short- and Long-term
As noted earlier, the most common cause of chronic hepatitis in children is HCV infection. With the improvements in HCV detection in transfused blood products and the prevention of other modes of parenteral transmission, the most common method of transmission in children is maternal–infant perinatal transmission. Conservative estimates suggest that 10 000–60 000 infants can be infected with HCV per year worldwide because of vertical transmission.
[54] Current CDC guidelines recommend testing for anti-HCV in infants born to infected mothers after 12 months.
[73] Passively acquired antibodies from the mother fall below detectable levels at this time. If earlier testing is required, CDC recommends RT-PCR for HCV RNA 1–2 months after birth.
The European Pediatric HCV network prospectively studied 357 HCV-exposed infants and found that the sensitivity of PCR for HCV RNA was 22% at birth and increased dramatically to 70–85% after 1 month of age.
[74] This study also showed that the PPV of the PCR test was 33% at birth and increased to 78% at 9 months of age, while NPV ranged from 96% to 99%. While these results could be attributed to very low and undetectable viral loads in the first month of life, they could also be explained by the widely variable incubation period of HCV that can range from 2 weeks to 6 months. These results suggest that negative testing at birth using PCR is not an adequate predictor of the infant's HCV infection status at a later date. Conversely, a negative PCR test after 12 months of age should be confirmed with the 'gold' standard of anti-HCV to detect children who were previously infected and successfully cleared their viremia.
Spontaneous clearance of HCV can occur in up to 25–30% of children.
[75,76] Rates of clearance are not different among those who are infected via vertical transmission or parenteral transmission. However, a younger age at follow-up and normal ALT levels favour HCV clearance.
[76] Another prospective study with seven infants was carried out in Italy and showed constant viremia in all of the subjects at least in the first few years of life.
[77] They all had initial elevation of ALT, with some subsequently recovering from it. Liver biopsies showed varying degrees of chronic persistent hepatitis. Most other studies reviewed showed similar low rates of HCV RNA clearance and a high rate of chronicity in the paediatric population.
[78–80] Although most patients continued to have only mild elevations of their liver enzymes, liver biopsies showed evidence of mild to moderate hepatitis. Data from the adult population suggest that approximately 10–20% of patients with HCV can go on to develop cirrhosis and hepatocellular carcinoma.
[81] Currently, there are no long-term studies to show the rates of cirrhosis or hepatocellular carcinoma in adults who acquired HCV through vertical transmission.
What Potential Treatment Opportunities Exist?
The current standard of care in HCV therapy is the combination of pegylated interferon and ribavirin. These medications have several drawbacks that are magnified during pregnancy and in the neonatal period. Pegylated interferon would be problematic given its psychiatric side effects in these women given the high background rate of postpartum depression. Addition of an agent that could promote these symptoms would not be tolerated. Similarly, ribavirin is a known teratogen and could not be used during pregnancy. Likewise, in the neonatal period, given the low rates of vertical transmission, relatively high rate of spontaneous resolution and lack of symptoms, one ought to be highly selective in who would be treated. Given the concern for growth suppression seen with pegylated-interferon treatment in older children, using it in any infant during a period of intense growth could have devastating effects. Thus, any consideration of treatment during this period could only occur once new anti-HCV agents are approved and have a demonstrated long-term safety profile.
A first strategy would be to select who would most benefit from therapy. The recent association of single-nucleotide polymorphisms within the IL28B gene being significantly associated with treatment response is highly provocative.
[82] Obviously, these data are based on interferon being the primary agent used in treatment, which has already been discussed as problematic. However, perhaps IL28B profiling could be used in a broader campaign to treat those young women infected with HCV who intend to become pregnant, thus resolving their infection prior to conception. This could be carried out immediately now that IL28B testing is commercially available.
Another strategy would be to follow the model used for the interruption of HIV vertical transmission. Initial strategies centred around use of an antiviral agent, in this case zidovudine, for the last 6 weeks of pregnancy, as an infusion intrapartum and then for the first 6 weeks of the infants life. This strategy when it was first applied reduced the transmission rate of HIV from 25% to 8%.
[83] Over the years, other agents have been added so that antiviral use has reduced transmission to <2% in developed nations. Obviously, HCV vertical transmission does not have the immediate consequences that HIV does, so the need to be so aggressive in prevention is not there. However, if it was possible to use short-term treatment with a combination of an HCV protease and polymerase inhibitor to coincide with the natural drop in HCV RNA in the pregnant woman postpartum, combined with treatment in those infants that demonstrated viremia soon after birth, this could be a viable strategy. Obviously, the costs associated with this kind of regimen would have to be considered.
To most effectively design treatment strategies, more research on HCV infection during pregnancy and infancy needs to be conducted. Further understanding of the influence of pregnancy on the immune response to HCV within the liver as well as how HCV infects the foetal liver as it matures is needed. This knowledge would allow better selection of treatment candidates as well as agents used for therapy.
Conclusions
HCV infection during pregnancy and the post-partum period appears to be a highly unique period in the interaction between virus and host. These periods of intense physiological change appear to force some adaptation of the virus that may offer a therapeutic window when more suitable agents come into use. Further studies of how and when the virus is transmitted from mother to child will only enhance the ability for prevention and treatment in the future.
Update June 20 2011
Pregnancy After Liver Transplant Raises Risk of Graft Loss
PHILADELPHIA – Women who become pregnant after receiving a transplanted liver face an elevated risk of graft rejection, especially during or immediately following the pregnancy, based on a review of 161 U.S. cases.
"The data suggest poorer outcomes for both mothers and their newborns in female liver recipients with risk factors for graft loss within 5 years post pregnancy," Dr. Carlo B. Ramirez said at the American Transplant Congress. "The findings highlight the high-risk nature of this group, warranting closer follow-up of both mother and child," said Dr. Ramirez, a transplant surgeon at Thomas Jefferson University, Philadelphia.
Of the 161 women who became pregnant following a liver transplant and were enrolled in the
National Transplantation Pregnancy Registry (in place since 1991), 16 (10%) lost their graft within 5 years following their first posttransplant pregnancy. The pregnancy and the 3 months following pregnancy posed a particular risk, with half of the women who eventually lost their graft experiencing rejection during that time. In a multivariate model that took into account baseline risk factors, women with a liver transplant faced a 14-fold increased risk for graft loss during the pregnancy, Dr. Ramirez said.
"A lot of patients who have a stable equilibrium with their graft may destabilize under stress. It is possible that there is low-grade, clinically insignificant rejection in some of these patients prior to pregnancy" that then becomes exacerbated by the stress of pregnancy, commented Dr. Jean C. Emond, professor of surgery and director of transplantation at Columbia University in New York. Dr. Emond suggested that a liver biopsy prior to pregnancy might be warranted to assess the stability of the transplant.
Other risk factors for graft loss included younger age of the mother and low gestational age at the time of delivery. In the multivariate analysis, the risk for graft loss fell by a statistically significant 26% for each additional year of age for the mother. Graft loss fell by a statistically significant 5% for each additional week of gestational age when delivery occurred.
Among the 16 women who lost their graft during pregnancy or the following 5 years, their average age when they conceived was 22 years old, compared with an average age of 28 years old among the 145 women who did not lose their graft. Average gestational age at delivery was 33 weeks among the women who lost their graft, and 37 weeks among the women who did not lose their graft.
The average age of the women at the time they received their liver transplant was 18 years among those who later lost their grafts, and 23 years among those who retained their grafts. However, the average time between transplantation and conception was an identical 4.3 years in both groups.
The only other risk factor for graft loss that approached statistical significance in the multivariate model was viral hepatitis as the etiologic agent for the liver failure that led to the transplants. Viral hepatitis was the cause of liver failure for six (38%) of the women who lost their grafts following pregnancy, and for 23 (16%) of the women who did not lose their grafts. In the multivariate model, viral hepatitis as the cause of liver failure was linked with a nearly fourfold increased risk for women losing their graft during or after pregnancy, but this relationship failed to meet the standard criterion for statistical significance, Dr. Ramirez said.
The congress was sponsored by the American Society of Transplant Surgeons. Dr. Ramirez said he had no disclosures. The National Transplantation Pregnancy Registry has been supported by grants from Novartis, Astellas, Genentech, Pfizer, Teva, and Sandoz.
