Helping achieve optimal pregnancy outcomes through proper infectious disease testing

For centuries, scientists and clinicians have known that pregnant women are susceptible to many infectious diseases that can cause harm to both the pregnant woman and the developing fetus.¹ Healthy mothers and infants are fundamental goals of all societies. Prenatal and newborn laboratory screening and diagnostics are vital to the early detection and management of infectious diseases. Updates on diagnostic testing for four important infectious diseases impacting mothers and babies are reviewed in this article.

Congenital syphilis

The transmission of Treponema pallidum, the spirochete bacterium responsible for syphilis, can have a devastating impact on pregnancy outcomes. Congenital syphilis can cause:²

• Miscarriage
• Stillbirth
• Prematurity, low birth weight
• Death shortly after birth

Past data demonstrates that untreated syphilis in pregnant women can lead to infection of the fetus in up to 80 percent of cases, and may result in stillbirth or death of the infant in up to 40 percent of cases.³ Infants born with congenital syphilis develop issues such as deformed bones, severe anemia, enlarged spleen and liver, and meningitis.²

After decreasing rates of congenital syphilis during 2008-2012, the number of cases has increased each year since 2012. In 2017, there were a total of 918 reported cases of congenital syphilis, including 64 stillbirths and 13 infant deaths, and the national rate was 23.3 cases per 100,000 live births. This rate represents a 43.8 percent increase relative to 2016 and a 153.3 percent increase relative to 2013.³

The effective prevention and detection of congenital syphilis depends on the routine serologic screening of pregnant women during the first prenatal visit. Centers for Disease Control and Prevention (CDC) recommends additional testing at 28 weeks gestation, and again at delivery for women who are at increased risk of syphilis infection.

There are two types of antibody tests for syphilis detection. Treponemal tests detect antibody to T pallidum proteins. Nontreponemal tests detect antibodies directed against lipoidal antigens, which originate from damaged host cells. Both are used to confirm the infection and determine whether the disease is active. In the traditional screening, algorithm testing is initiated with the nontreponemal test—a manual, labor intensive test. If confirmed, it is followed by a treponemal test. The drawbacks of the traditional algorithm are associated with high false-positive rates, with non-treponemal tests which lead to unnecessary treponemal testing. Nontreponemal tests can also miss early primary and treated infections.⁴

With the availability of automated treponemal tests there has been a shift in testing in laboratories. Called the reverse-screening algorithm, the first test for screening specimens employs a treponemal test and if confirmed, is reflexed to a nontreponemal test. This can identify persons previously treated for syphilis, those with untreated or incompletely treated syphilis, and persons with false-positive results that can occur with a low likelihood of infection.⁵ Since the majority of persons screened are negative, only a small percentage of samples require the manual nontreponemal test in this approach. Evidence suggests an increased detection rate of late-stage syphilis with a reverse-screening algorithm. Treponemal antibody is found in the majority of syphilis-infected individuals (~85 percent remain positive for life). In contrast, up to 30 percent of untreated, late-stage infected individuals become undetectable for nontreponemal antibody, but remain positive for treponemal antibody. Increased late-stage identification allows for treatment intervention and minimizes potential for disease progression.⁶ Both algorithms are supported by CDC.⁷

Perinatal transmission of hepatitis B

The risk of transmission of hepatitis B (HBV) from an infected mother to infant is a global problem. Mother to child transmission of hepatitis B accounts for over a third of chronic HBV infections worldwide.⁸ In the United States, approximately 25,000 infants are born to mothers infected with HBV.⁹ Without postexposure immunoprophylaxis, approximately 40 percent of infants born to HBV-infected mothers in the U.S. will develop chronic HBV infection, approximately one-fourth of whom will eventually die from chronic liver disease. For a newborn infant whose mother is positive for both HBsAg and HBeAg, in the absence of post-exposure immunoprophylaxis, the risk for chronic HBV infection is 70 to 90 percent by six months of age.

Theoretically, there are three possible routes for transmission of HBV from an infected mother to her infant: transplacental transmission of HBV in utero, natal transmission during delivery, and postnatal transmission through breast milk.¹⁰

By identifying HBV infections in pregnant women, perinatal HBV transmission can be reduced or prevented. Hepatitis B surface antigen (HBsAg) is the recommended screening test for all pregnant women. A reactive HBsAg test indicates acute or chronic infection.¹¹

National guidelines are an integral part of the overall strategy to prevent perinatal HBV transmission and eliminate hepatitis B in the U.S. They include the following:¹¹

• Universal screening of pregnant women for HBsAg during each pregnancy
• Screening all HBsAg-positive pregnant women for HBV DNA to guide the use of maternal antiviral therapy during pregnancy. The American Association for the Study of Liver Diseases (AASLD) suggests maternal antiviral therapy when HBV DNA is >200,000 IU/mL.
• Case management of HBsAg-positive mothers and their infants
• Provision of immunoprophylaxis for infants born to infected mothers, including hepatitis B vaccine and hepatitis B immune globulin within 12 hours of birth
• Routine vaccination of all infants with the hepatitis B vaccine series, with the first dose administered within 24 hours of birth.

Zika virus

The World Health Organization (WHO) prioritizes diseases and pathogens for research and development in public health emergency contexts utilizing a tool developed by WHO. The aim is to identify diseases that carry a public health risk due to their epidemic potential, but do not have sufficient countermeasures. WHO then publishes the R&D Blueprint for the list of identified pathogens. Zika is included in the list of nine diseases released by WHO in the 2018 R&D Blueprint of the diseases requiring accelerated research and development.¹²

The Zika virus (ZIKV) is a mosquito-borne flavivirus first discovered in 1947 in monkeys during routine surveillance for Yellow fever in Uganda and later discovered in humans in 1952. Although there were documented outbreaks of ZIKV infection over the years, it was not until the unprecedented epidemic during 2015-2016 in the Americas that Zika made headlines. The size of the epidemic, the newly discovered birth defects, and other health risks associated with the virus mobilized the public health and research communities. The threat of international spread of the virus, lack of immunity in the affected regions, and the absence of rapid diagnostic tests, vaccines, or treatments created a serious epidemic.¹³

Scientists have reported severe health problems in infants born to Zika-positive mothers including birth defects, problems with vision and hearing, seizures, and developmental delays. More than 4,800 pregnancies in the U.S. territories had a lab result showing confirmed or possible Zika from 2016-2018. From these pregnancies, 1,450 babies were at least one year of age and had some follow-up care reported for this analysis. About 1 in 7 (or 14 percent) of the 1,450 babies had one or more health problems possibly caused by Zika reported to the U.S. Zika Pregnancy and Infant Registry. Some of these problems were not apparent at birth and were identified as the babies grew older. The full range of long-term health problems caused by Zika will remain unknown until these babies mature. Throughout early childhood, healthcare providers should closely monitor the health and development of all babies born to mothers with Zika during pregnancy.¹⁴

CDC advises pregnant women not to travel to areas where Zika is being transmitted. Partners of pregnant women and couples considering pregnancy should know the risks to pregnancy and take prevention steps.¹⁵ ZIKV disease is a nationally notifiable condition and clinicians should take a thorough travel history and consider testing when indicated. Cases are reported to CDC by state, territorial, and local health departments using standard case definitions.¹⁶

Zika diagnostics

On February 26, 2016, the Secretary of Health and Human Services declared that circumstances existed to justify the authorization of the emergency use of in vitro diagnostics (IVD) for detection of ZIKV and/or diagnosis of ZIKV infection.

The Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for a number of molecular- and serological-based assays for Zika. In the case of the molecular-based assays, IVD developers as part of their EUA conditions were required to test an FDA Reference Material Panel that includes two different ZIKV strains from the Asian lineage (S1 and S2), using an FDA protocol that included a sensitivity evaluation.¹⁷
Other performance characteristics are evaluated prior to the granting of an EUA. In addition to sensitivity and specificity, the currently authorized tests offer unique characteristics with respect to sample throughput, testing environment, claimed sample types and performance, that are taken into account when considering whether to issue an EUA for an assay.¹⁸

Multiple assays and sample types are often needed to establish a definitive laboratory diagnosis of ZIKV infection due to the temporal nature of biologic analytes in the infected person. Viral ribonucleic acid (RNA) is the first analyte that can be detected in an infected person in multiple specimen types. As the immune response develops, immunoglobulin M (IgM) titers rise in peripheral blood and the level of viral RNA generally declines.

However, viral RNA may be detectable in some infected people for longer periods in certain specimen types. Nucleic acid testing (NAT) is most informative in the first six weeks after symptom onset. IgM antibodies are most likely to be detected in the first 12 weeks after symptom onset, but may persist longer.

Paired serum and urine are the primary diagnostic specimens for ZIKV infection. Other specimen types such as plasma, whole blood, cerebrospinal fluid (CSF), and amniotic fluid are authorized for use with some assays that have received an EUA from the FDA.

Due to the temporal nature of ZIKV RNA in serum and urine, a negative NAT does not exclude recent Zika infection. Serologic detection of ZIKV infection may help confirm exposure to Zika in settings where people have not previously been exposed to the virus. Antibodies (IgM) directed against ZIKV are typically first detected as viral RNA begins to wane. The decline in reported cases of ZIKV infection increases the proportion of false positive test results for ZIKV. Although IgM is most likely to be detected in the first 12 weeks after infection, emerging data indicate that ZIKV IgM may persist beyond 12 weeks in a subset of infected individuals, limiting the ability of testing to determine whether an infection occurred during or prior to pregnancy.¹⁹

HIV prevention

Similar to HBV, mother to child HIV transmissions can occur during pregnancy, labor and delivery, or breastfeeding. It accounts for the majority of childhood HIV infections. However, since the implementation of HIV testing and preventive interventions in the early 1990s there has been more than a 90 percent decrease in the number of children perinatally infected with HIV in the U.S. Between 1994 and 2010, an estimated 21,956 cases of perinatally acquired HIV infections were prevented.²⁰

HIV testing is recommended by the CDC for all women who are pregnant, or planning to become pregnant, as early as possible. The earlier HIV is diagnosed and treated, the more effective the HIV antiretroviral treatment will be at preventing transmission and improving the health outcomes of both mother and child.²⁰

Conclusion

Understanding the risks of infectious disease in pregnancy and following the current guidelines for diagnostic testing can aid in achieving better pregnancy outcomes with health benefits for both the mother and baby.

REFERENCES

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