Case History 2: A couple with male factor infertility of 3 years duration are referred for ICSI. The female partner is found to be positive for hepatitis C infection.
Background
Hepatitis B
Hepatitis B virus (HBV), a DNA virus, is the most common chronic viral infection in the world, having infected approximately 2 billion people [1]. It is estimated that there are more than 350 million people who are chronic carriers of HBV and that the virus causes approximately 786,000 deaths per year. HBV‐related death is caused by chronic hepatic inflammation leading to chronic liver failure, cirrhosis and hepatocellular cancer. HBV vaccination programs are safe and effective. However, global prevalence of HBV is highly variable due to differences in the uptake of universal HBV vaccination programs [2].
HBV is transmitted through contact with infected blood or semen. Where HBV prevalence is high, the most common route of transmission is vertical, from infected mother to neonates. Where HBV prevalence is low, the commonest mode of transmission is through sexual contact. HBV can also be transmitted by blood transfusion, renal dialysis or unsafe use of needles for drug injection [3].
The risk of developing chronic infection is age dependent. In neonatal transmission, the risk of chronic liver disease is 95%. If transmitted in childhood, the chance of chronic liver disease is 80%. If infected in adulthood, the chance of chronic liver disease is 5% [4].
The diagnosis of HBV infection is made by serological testing. HBV surface antigen (HBsAg) is diagnostic of acute and chronic infection. Positive HBsAg indicates that the patient is infective. Two weeks after acute infection, hepatitis B core antibody (anti‐HBc) IgG becomes positive by serological testing, and the infected patient will have raised liver transaminase activity and also become symptomatic (flu‐like symptoms, loss of appetite, diarrhea, vomiting and jaundice). During recovery from acute infection or after successful vaccination, hepatitis B surface antibodies (anti‐HBs) appear. Clinical interpretation of the serological markers of HBV infection should be made with all available serological test results (table 5.1) [1].
Hepatitis C
Hepatitis C virus (HCV) is an RNA virus thought to affect approximately 143 million people worldwide. Although the incidence is not well understood, as most infected people are asymptomatic, it is estimated that 1.75 million people are infected each year. Prevalence is highest in Central and East Asia, North Africa and the Middle East. Of those infected, 70–85% develop chronic liver disease, of which 20% develop cirrhosis and 5–7% die of HCV sequelae [5].
HCV is transmitted primarily by blood to blood contact, from blood transfusions and unsafe drug injections. Less frequently, HCV can be transmitted perinatally or through sexual transmission. Acute HCV symptoms develop in 20–30% of those infected, 4–12 weeks after transmission. Symptoms include flu like illness, nausea, vomiting and jaundice. Diagnosis of HCV infection is made by serological testing for anti‐HCV antibody, which becomes positive 6–8 weeks after transmission or by HCV RNA PCR testing [6].
Table 5.1 Clinical interpretation of serological markers of hepatitis B virus infection [1].
| HBV serological test | Results | Clinical interpretation |
|---|---|---|
| HBsAgAnti‐HBcAnti‐HBs | NegativeNegativeNegative | Susceptible |
| HBsAgAnti‐HBcAnti‐HBs | NegativePositivePositive | Immune due to previous HBV infection |
| HBsAgAnti‐HBcAnti‐HBs | NegativeNegativePositive | Immune due to HBV vaccination |
| HBsAgAnti‐HBcAnti‐HBsIgM anti‐HBc | PositivePositiveNegativePositive | Acutely infected |
| HBsAgAnti‐HBcAnti‐HBsIgM anti‐HBc | PositivePositiveNegativeNegative | Chronically infected/ carrier |
| HBsAgAnti‐HBcAnti‐HBs | NegativePositiveNegative | Unclear interpretation. Possibly:Resolved HBV infection (most common)Low‐level chronic infectionResolving acute infection |
There is no vaccine against HCV; prevention is focused around harm reduction by encouraging safe needle use and screening blood products. Antiviral medications have been developed to cure chronic liver disease resulting from HCV. However, left untreated, chronic HCV infection can also lead to cirrhosis and liver cancer [5].
The European Society of Human Reproduction and Embryology (ESHRE) recommends that HBV and HCV screening should be undertaken in both partners before performing assisted reproductive techniques (ART). This is to reduce the risk of transmission to the partner and neonate whilst also ensuring that the gametes and embryos can be handled with precaution.
Management of patients
Hepatitis B
Infertility patients known to have chronic carrier status of HBV should be managed in a fertility unit with appropriate expertise. In cases where partners have discordant HBV serological status, it is recommended that the unaffected partner receives HBV vaccination.
In women who are HBV chronic carriers, there has been conflicting evidence regarding the effect of HBV on pregnancy. Overall, pregnancy does not seem to affect the disease course of chronic HBV infection. If pregnancy is achieved naturally, the risk of neonatal infection from a chronically infected mother is 2–15% [7]. If the mother is acutely infected with positive HBsAg and anti‐HBc then the risk of vertical transmission rises to 80–90%. In either case, the neonate should be vaccinated at birth. Hepatitis B vaccination and a dose of HBV immunoglobulin administered to the neonate within the first 24 hours of life reduces the risk of HBV infection and carrier status by up to 90% [8].
In ART, previously published studies assessing the fertility treatment outcomes in couples with at least one partner who is HBV seropositive have yielded conflicting results [9]. Some observational studies have shown lower pregnancy rates in couples undergoing ART with HBV whilst others have not shown this [10,11]. It has been suggested that the lower pregnancy rates amongst couples with HBV undergoing ART may be due to extra precautions in handling gametes and embryos [9]. Overall, it appears that in couples where one or both of the partners have HBV, the pregnancy outcomes are similar to unaffected couples.
Male partners with HBV have been shown to have poorer sperm results and lower oocyte fertilization rates; however, this does not seem to impact on ART outcomes [12]. In male HBV carriers, the female partner should have HBV vaccination to reduce the risk of sexual transmission. Sperm washing during ART is a common practice in this situation but is now not thought to be of clear benefit. Previously, it was considered unsafe to perform intra‐cytoplasmic sperm injection (ICSI) treatment for male HBV carriers due to the risk of HBV integration into the fetal genome. However, newer evidence has proven that this is not a risk.
In ART treatments involving HBV‐positive female partners, there has been evidence to show that HBV can affect the follicular fluid, oocytes and ovaries. However, women with HBV infected follicular fluid or oocytes do not appear to have worse ART outcomes [13]. Overall, ART is considered safe in both male and female carriers, and the risk of vertical transmission is similar to pregnancies conceived naturally. Therefore, the couple in Case History 1 should be reassured.