Preventing vertical virus infections: the role of serologic screening of pregnant women
Several virus infections affect the pregnancy itself as well as the foetal development (rubella, PVB19, VZV, HSV, HCMV, HBV, HIV). Prevention can be established by vaccination or an assessment of the immunity status as well as by chemotherapy. The following review provides an update to current aspects focusing on the role of serologic screening.
KeywordsPregnancy Vertical virus infections Serologic screening
During pregnancy, foetal development as well as the health of the mother-to-be is threatened by several virus infections. Rubella is the most dangerous, not for the pregnant woman, but for the foetus itself, since it is easily vertically transmitted. When rubella is passed on during the first 4 months of pregnancy, the non-cytolytic vertically transmitted virus may stop cell division and organ development in the embryo resulting in malformations of the new-born. Children with congenital rubella syndrome (CRS) can suffer from hearing impairments, eye and heart defects and other permanent handicaps such as autism, diabetes mellitus and thyroid dysfunction. Before the introduction of the vaccine up to 4 in 1000 live births were diagnosed with CRS. Due to general vaccination, rubella in pregnancy has become a rare incident in many developed and in some developing countries. In fact, the western hemisphere and several European countries have eliminated rubella and CRS . The immune status can be easily assessed by serum IgG antibody detection. Simple tests (mainly ELISAs) are available and have been proven to be most effective through proficiency trials. Although these tests may not determine virus neutralizing antibodies and the IgG antibody quantification in terms of IU/mL is not yet completely satisfying , a clear-cut positive (non-equivocal) test result indicates a previously passed wild or vaccine virus infection which usually provides long lasting immunity. The tests are not considered to be mandatory in Germany, if the complete (first and booster) vaccination is being well documented [3, 4]. A positive virus-specific serum IgM test indicates an acute rubella infection which should be confirmed by other methods (for example RNA detection, rubella IgG avidity determination, western blot) .
Parvovirus B19 (PV B19) may cause a rubella-like disease (erythema infectiosum, slapped cheek syndrome) and can also be vertically transmitted to the foetus during the entire pregnancy with a probability of about 1:3. In contrast to rubella, this virus infection is cytopathogenic. The foetus is severely affected, especially regarding its blood production in the liver. Erythroblasts are the main target of PV B19. In seronegative pregnant women, acute parvovirus B19 infections can result in foetal death (about 9% of the infections) and/or hydrops foetalis (about 20% of the infections). After erythema infectiosum in the first trimenon of the pregnancy, the abortion rate is about 5% higher than without PV B19 infection [5, 6, 7]. Fortunately, the self-recovery rate of foetal infections is high. Most new-borns are not suffering from permanent damage. However, a smaller percentage is born presenting a severe aplastic anaemia, which may even be fatal.
PV B19 is a typical, frequent and air-droplet-borne infection of children. Hence, most of adolescents and adults have already went through the infection before they even reach the age of child bearing . Nevertheless, there are infections during pregnancy, which do not show the typical exanthema . In a non-immunocompromised individual, a PV B19 infection is usually restricted to specific immune reactions, although a viremia might persist for a longer period. After the virus has been eliminated from the blood, a life-long immunity is established due to the production of antibodies which can be easily determined by ordinary tests (ELISA and others) such as rubella . Until now, only a passive vaccination (IgG application), but no viral vaccine, is available.
Is serologic screening of pregnant women recommendable to prevent a vertical PV B19 infection? Yes, for women who are being potentially exposed in their day to day work environment such as in medical and child caring professions. A positive IgG detection indicates a passed infection and immunity could be supposed. An active PV B19 infection should be preferentially diagnosed by virus-DNA detection in serum or plasma samples. In addition, IgG seroconversion or the detection of IgM could also prove an acute infection . A previously acquired infection may persist even though specific IgM serum antibodies have been replaced by IgG. A chronic or recurrent viremia should be detected or excluded by virus-DNA detection methods in blood, serum or plasma samples . Repeatedly low positive PV B19 DNA detection (< 500–1000 copies/mL) in combination with IgG detection are a hint that the infection happened a longer time ago and holds, at the current state of knowledge, no risk for the unborn child . If a PV B19 infection is diagnosed during the first 28 weeks of the pregnancy, the presence of a vertical transmission should be checked weekly by ultrasound and Doppler sonography and when indicated by investigating an amniotic fluid specimen by viral DNA-PCR. Foetal damages are evaluated by medical ultrasound and hematologic markers (determination of haemoglobin and reticulocytes). The recovery can be supported by intrauterine blood transfusion . While viremia of the unborn is stopped, viral DNA persists in the bone marrow. There is no specific antiviral drug against parvovirus B19 infection. Although some cases indicate that the application of gamma globulins seem to be successful against hydrops foetalis, which is not recommended in German Guidelines [4, 12].
HSV and VZV
Herpes simplex virus (HSV) and varicella zoster virus (VZV) are feared when they infect the new-born sub partu causing the life-threatening herpes neonatorum generalisatus. Symptoms of the new-born vary from infection of defined areas of the skin, eyes and mucous membranes, central nervous system (CNS) infection or disseminated systemic infection. Like all herpes viruses, HSV and VZV infections persist life-long in a latent state with frequent (HSV) or infrequent reactivations (VZV). Varicella, due to the primary VZV infection, is very dangerous for pregnant women. They are at risk of developing a life-threatening pneumonia needing immediate antiviral therapy. Intravenously administered acyclovir is the drug of choice. There is a hypothetical danger for the foetal development, although it has not yet been proven . VZV can be vertically transmitted to the foetus, mostly without pathological consequences. A congenital varicella syndrome is rare. However, some months after birth the infant may fall ill with a herpes zoster when the prenatally acquired infection is reactivated. Its prognosis is good . During life, VZV is spread by air droplets preferentially in the early childhood or by smear contacts to patients suffering from herpes zoster. Before the introduction of general vaccination for infants and children, the distribution was so fast that > 95% of the population had been infected long before the age of pregnancy . Herpes zoster (due to VZV reactivation) happens when cell-mediated immunity decreases, usually after many years in the senior citizens, but occasionally also during the (slightly immunosuppressing) pregnancy . In this case, the new-born is protected by maternal anti-VZV antibodies . Many routine tests are available to detect VZV serum antibodies which persist life-long post infection . A screening of pregnant women may become reasonable when the VZV distribution decreases due to a common, but not complete vaccination of the population. Currently this danger does not exist. However, German guidelines recommend VZV-IgG screening of all women who could potentially get pregnant without known previous VZV infection. Especially, adult individuals, exposed to the virus by (medical) work or contact to children, should be screened . The test may not be needed, if the complete (first and booster) vaccination is well documented. The diagnosis of acute primary VZV infection is usually done clinically. The sole detection of VZV-IgM is not sufficient due to its potential cross-reactivity and should be controlled by a virologic/molecular biologic test (e.g. DNA-PCR) [4, 19].
In vitro neutralizing antibodies against HSV-1 or HSV-2 have not proven to protect in vivo. HSV-2 seropositive people should always be regarded as potential virus transmitter . Both primary and secondary (recurrent) perinatal HSV infections may harm the new-born ascending or sub partu during a herpes genitalis of the mother-to-be. Viral transmission to the child via the mother’s genital tract during labour is regarded as the most common reason for neonatal HSV infection. Through a longer and more intensive virus shedding, HSV-2 is more dangerous than HSV-1, the primary infection is more dangerous than the recurrence. Two-third of herpes genitalis cases are caused by HSV-2, one-third by HSV-1 [20, 21]. However, neonatal herpes is rare, the risk of neonatal infection is higher among pregnant women who are seronegative for HSV-1 or HSV-2 and who acquire their first (primary) HSV infection close to delivery . Antenatal antiviral prophylaxis reduces viral shedding and recurrences at delivery and reduces the need for cesarean delivery for genital herpes . Prenatally HSV infection is rarely transmitted to the foetus, but possible . Despite many approaches a vaccine could not be developed up to date . A serologic screening is not necessary, since every clinical suspect can be easily and rapidly assessed or excluded by well-established virologic test methods such as PCR or virus isolation by cell culture. A HSV-type-specific serologic screening informs whether the pregnant woman is carrier or might be concerned by a primary infection of the more dangerous HSV-2. This aspect is similar to the HCMV-serologic screening (see below) [19, 20]. Infants born to mothers with active genital lesions and no prior history of HSV should be screened more vigorously.
HCMV, another member of the herpesvirus family, in pregnancy is an old unsolved problem. In developed countries, about half of the population has acquired this persistent infection, which is frequently reactivated, especially during pregnancy because of a slight immunosuppression [26, 27]. The rate of HCMV seroprevalence is about 50% in Germany . The seroprevalence is a lot higher in other parts of the world (up to 100%). Besides primary infection and reactivation, exogenous secondary infections with another HCMV strain are possible, especially in people suffering from a disease- or therapy-mediated immunosuppression . While HCMV infections usually produce no or sparse symptoms, in affected individuals a cytomegalic inclusion (CID) disease can probably be clinically diagnosed or suspected. However, CID is polysymptomatic and, therefore, clinical diagnosis could be difficult, so that laboratory investigations are needed, which are well established. During the proceeding of the pregnancy, both primary and recurrent HCMV infections can lead to vertical virus transmission to the foetus. 0.5–5% of new-borns are prenatally infected—perinatally up to ten times more. These infants shed high levels of the virus via saliva and urine (> 1000 infectious particles/mL). Nearly every tenth of them is affected. A large spectrum of diseases has been described. Especially the central nerve system is affected by prenatal infection. In addition, mental retardation has been associated . As a rule of thumb, the primary infection is being considered a lot more dangerous than the secondary, resp. recurrent one due to a bigger and longer viremia . However, foetus-damaging vertical infections have been linked to HCMV recurrence. Hence, this rule has been questioned . A serologic screening of young women appears reasonable , although neutralizing serum antibodies does not provide sufficient protection, since the virus spread is also leukocyte-associated . This might explain the high rate of perinatal infections when the placenta is damaged sub partu and materno-foetal blood micro transfusion happens. A negative test result of serologic screening warns that a primary HCMV infection is possible. Concerning pregnancy, such women should avoid close contact to people, who might spread the virus via sputum, urine or sexual activity. The urine or saliva of viral-shedding infants up to 3 years of age and the genital secretions of adolescents and adults are the main source of maternal infection . This means restriction from some professions (e.g. paediatric nursery, kindergarten, medical laboratory). Moreover, strict hygiene and measures of disinfection must be attended. A positive test result warns about recurrences which may increasingly happen during proceeding pregnancy. Additionally, it should be considered that breastfeeding is a common route for CMV transmission and new-borns with low level birth weight or born < 32 weeks gestational age has a higher risk of developing symptomatic postnatal CMV disease .
If an acute or reactivated infection is diagnosed during pregnancy (i.e. detection of CMV IgM antibodies), serologic methods can identify the primary infection by determining low CMV IgG antibody avidity [32, 35] or Western blot analysis showing lacking CMV glycoprotein G antibody reaction [4, 29]. Via investigation of amniotic fluid after week 21 of the pregnancy (at least 13 weeks after the infection), the vertical infection can be detected, and an antiviral treatment can be applied using hyper-immune globulins (HIG) or (val)ganciclovir [36, 37]. The usage of HIG is discussed controversially and has only been recommended within clinical studies . However, new data show that a 2-weekly protocol resulted in a highly efficient prevention of materno-fetal CMV transmission . Unfortunately, HCMV vaccines are still not available. New approaches aim to induce protecting humoral and cellular immune reactions [40, 41, 42].
HIV and HBV
The important routes of HBV and HIV transmission are by sexual contacts, resp. blood (micro)transfusion. The rate of mother-to-child transmission ranges from 1 to 28% for HBV and 3–15% for HCV . The probability of a child with an HIV-positive mother being born with HIV has now been reduced to approximately 1–2% in Western Europe, due to effective preventative interventions including universal antenatal testing, caesarean sections, formula feeding and particularly using anti-retroviral therapy (ART) .
Serologic screening of pregnant women is commonly well established (antigen and antibody tests). Generally, HBV screening (i.e. testing for HBs-antigen) is recommended in Germany for each pregnant woman after week 32 of gestation. If an infection is diagnosed, efficient measures can be applied to prevent the vertical transmission to the foetus by administering active/passive vaccination (HBV) or antiretroviral treatment. Recently, also an antiviral treatment of a HBV infection during pregnancy is recommended to decrease a very high plasma HBV-DNA load (> 200,000 IU/mL) [45, 46, 47, 48]. For this purpose, screening for HBV early in pregnancy especially for women who have a higher risk for infection should be considered . The screening for HBV infection (serum anti-HBc, HBsAg), resp. immunity (anti-HBs) can be considered useful, although the vaccination or a previously passed infection is well documented. There are non-responders (up to 5% of vaccinees), and (rare) break-through infections have been reported . Therefore, the HBV vaccines should be optimised [49, 50].
A lot of mother-to-child transmissions (MCT) are due to insufficient antenatal antiretroviral therapy for the women, especially because of late diagnosis of HIV infection at the end of pregnancy. Since treatment of the mother and post exposition prophylaxis of the new-born prevents nearly all MCTs, HIV screening of pregnant women is essentially and should be offered to each pregnant woman. Screening should be performed as soon as possible during pregnancy and probably repeated testing in cases of higher risk (HIV-positive partner) should be performed . Because of long lasting persistence of maternal antibodies the proof of an infection in the first year of life should be done by HIV-RNA testing .
We greatly thank Andrea Doerr for editing the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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