Herpes simplex virus in pregnancy: new concepts in prevention and management

Genital herpes simplex virus (HSV) infection is one of the most common viral sexually transmitted diseases in the United States. It is estimated that 45 million adolescents and adults are infected with genital HSV. Most genital herpes infections in the United States are caused by HSV type 2 (HSV-2), and 25% to 30% of women of reproductive age have HSV-2 antibodies. What is more striking is that genital herpes is frequently under-recognized, and that only 5% to 10% of these women have a history of genital herpes. Because such a small percentage of women are aware of being infected with HSV, the risk of maternal transmission of this virus to the fetus or newborn is a significant health issue.     

人细小病毒B19感染与自然流产关系的研究

目的：探讨人细小病毒Ｂ１９感染与自然流产之间的关系。方法：用巢式聚合酶链反应技术检测１０５例（病例组）自然流产胚胎组织标本中的Ｂ１９病毒ＤＮＡ，并取２０例胚胎组织和２０例胎肝作对照，Ｂ１９病毒阳性标本作合并ＴＯＲＣＨ感染的诊断。结果：病例组检出２６例阳性（２４．８％），对照组检出２例阳性（５．０％），（Ｐ＜０．０５）。２６例阳性标本中，５例合并巨细胞病毒（ＣＭＶ）感染，２例合并ＣＭＶ、单纯疱疹病毒感染。结论：Ｂ１９病毒感染可能是引起自然流产的重要原因。     

Seroprevalence of varicella zoster virus, parvovirus B19 and Toxoplasma gondii in a Melbourne obstetric population: implications for management

At an antenatal clinic at a Melbourne obstetric hospital, 308 women were questioned about a known past history of infection with varicella zoster virus (VZV), human parvovirus B19 and Toxoplasma gondii. Immunoglobulin G (IgG) concentrations were determined for the 3 infectious agents and a recalled history of infection was compared with the presence of specific antibody. Exactly 66% of women recalled being infected with chickenpox (VZV) and 94% showed serological evidence of past exposure. Although 64% of women had parvovirus specific IgG, only one gave a definite history of past parvovirus infection. None of the 23% of women with evidence of previous exposure to Toxoplasma gondii recalled a past infection. The proportion of antenatal women at risk in this study was used to estimate the potential burden of disease from congenital infections in Australia and to examine implications for management of pregnancies complicated by these 3 infections.     

Effect of maternal herpes simplex virus (HSV) serostatus and HSV type on risk of neonatal herpes

BACKGROUND: Neonatal herpes simplex virus (HSV) is a rare but devastating disease. We have conducted pooled analyses of data from 3 cohorts to evaluate the effects of maternal HSV serostatus and HSV type on risk of neonatal HSV acquisition and severity. METHODS: Data from cohorts in Seattle, WA, and Stanford, CA, USA, and Stockholm, Sweden were pooled using Mantel-Haenszel methods. RESULTS: Seventy-eight infants with documented neonatal HSV and known maternal HSV serostatus were included. The risk of neonatal HSV-2 infection was similar in infants born to HSV seronegative women compared with HSV-1 seropositive women (pooled OR: 1.6; 95% CI: 0.6-4.0). The odds of neonatal HSV infection was increased in the presence of exposure to maternal HSV-1 versus HSV-2 (adjusted pooled OR: 19.2; 95% CI: 5.8-63.6). An elevated odds of disseminated HSV in infants born to women with newly acquired genital herpes was observed in Stockholm (OR=13.5; 95% CI: 1.4-630), but not in Seattle or Stanford. CONCLUSION: Our results suggest that maternal HSV-1 antibody offers little, if any, protection against neonatal HSV-2 infection. During reactivation, HSV-1 appears more readily transmissible to the neonate than HSV-2, a concerning finding given the rising frequency of genital HSV-1 infection.     

Maternal human parvovirus B19 infection and the risk of fetal death and low birthweight: a case–control study within 35 940 pregnant women

Objectives  To assess the association between maternal parvovirus B19 infection and fetal death, birthweight and length of gestation.
Design  Case–control study.
Setting  Population based.
Population  Cases were all 281 women with fetal death within a cohort of 35 940 pregnant woxmen in Norway. The control group consisted of a random sample of 957 women with a live born child.
Method  Information on pregnancy outcome was obtained from the Medical Birth Registry of Norway. First trimester serum samples were tested for antibodies against parvovirus B19 (IgM and IgG). In seronegative women, further serum was analysed to detect seroconversion during pregnancy.
Main outcome measures  Fetal death, length of gestation and birthweight.
Results  Two of 281 (0.7%) of the women who experienced fetal death and nine of 957 (0.9%) of the controls had presence of IgM antibodies, crude odds ratio 0.8; 95% CI (0.2–3.5). In initially, seronegative women, 3.1% (2/65) with fetal death and 2.6% (8/307) with a live birth seroconverted, crude odds ratio 1.2; 95% CI (0.2–5.7). Presence of maternal parvovirus-specific IgG or IgM antibodies in the first trimester, or seroconversion during pregnancy were not associated with lower birthweight or reduced length of gestation in live born children, but was associated with low birthweight in stillborn offspring.
Conclusion  Maternal parvovirus B19 infection was not associated with fetal death in our study. Very few cases of fetal death may be attributed to maternal parvovirus B19 infection.     

Incidence of parvovirus B19 infection among an unselected population of pregnant women in the Netherlands: A prospective study

OBJECTIVE: To evaluate seroprevalence of anti-parvovirus B19 IgG immunoglobulins and the rate of seroconversion in seronegative pregnant women. DESIGN: Prospective assessment of anti-parvovirus B19 IgG immunoglobulins in an unselected population of pregnant women booked for antenatal care from 1998 to 2000. SETTING: Maternity departments of an academic hospital and four affiliated teaching hospitals in the Netherlands. SUBJECTS: Two thousand five hundred and sixty seven pregnant women. MAIN OUTCOME MEASURES: Seroprevalence of anti-parvovirus B19 IgG immunoglobulin in the first trimester of pregnancy and subsequent seroconversion in those women who were tested negative for parvovirus B19 antibodies in the first trimester of pregnancy. RESULTS: The estimated seroprevalence of anti-parvovirus B19 IgG immunoglobulins among the study population is 70% (95% CI: 68-71) in the first trimester of pregnancy. Seven hundred and seventy nine women tested negative for parvovirus B19 antibodies in the first trimester of pregnancy. Paired testing in these women confirmed 18 seroconversions. Based on these findings the estimated incidence of maternal parvovirus B19 infection in this population among seronegative Dutch women is 2.4% (95% CI: 1.4-3.7). CONCLUSION: Maternal infection with parvovirus B19 is relatively common. However, it is argued that in the Netherlands routine assessment of parvovirus antibodies in pregnant women is not warranted as there is a low risk of adverse fetal outcome and measures to prevent the parvovirus B19 infection and its consequences are very limited.     

Understanding herpes simplex virus: transmission, diagnosis, and considerations in pregnancy management

Genital herpes simplex virus (HSV) infections are frequently asymptomatic or undiagnosed, but more than half the US population is seropositive for HSV, and about one-fifth are positive for HSV-2. These two factors contribute to the risk for sexual transmission and therefore to the risk of late-pregnancy acquisition of HSV. Most neonatal herpes infections are the result of undiagnosed, new-onset HSV infection in the mother. This article reviews the epidemiology of HSV, risks of transmission, and testing and management of HSV during pregnancy. Options for evaluation and management are presented.     

Prevalence of HSV-2 antibody in a Melbourne antenatal population attending a tertiary obstetric hospital

Objective: To determine the herpes simplex virus 2 (HSV-2) seroprevalence rate in a Melbourne antenatal cohort.
Design: Prospective collection of serum and questionnaires in 1371 women attending an outpatient antenatal clinic.
Setting: A tertiary obstetric hospital in metropolitan Melbourne.
Participants: Women aged 18 years or older attending an antenatal clinic appointment.
Main outcome measure: Seroprevalence rate of HSV-2 using an ELISA-based- type-specific serological assay.
Results: The overall HSV-2 seroprevalence rate in women was 13.6%. Only 0.4% of assays were equivocal and required confirmation by Western blot analysis. By multivariate analysis, HSV-2 seroprevalence was found to be associated with increasing age (odds ratio (OR) 4.63; confidence interval (CI) 1.86, 11.52 for age greater than 40 years), increasing number of sexual partners (OR 4.07, CI 2.13, 7.7 for five or more) and a past history of genital herpes in the index case (OR 5.48, CI 2.77, 10.87) or in a current or previous partner (OR 8.29, CI 4.15 to 16.56).
Conclusions: HSV-2 seroprevalence rates in Melbourne are comparable to other similar populations in Australia. Routine antenatal screening for HSV-2 is probably not warranted but targeted screening based on numbers of sexual partners or a history of genital herpes in partners may be justified.     

Viral invasion of the amniotic cavity (VIAC) in the midtrimester of pregnancy

Introduction: The prevalence of viral infections in the amniotic fluid (AF) has not yet been ascertained. The aim of this study was to determine the prevalence of specific viral nucleic acids in the AF and its relationship to pregnancy outcome. Study design: From a cohort of 847 consecutive women undergoing midtrimester amniocentesis, 729 cases were included in this study after exclusion of documented fetal anomalies, chromosomal abnormalities, unavailability of AF specimens and clinical outcomes. AF specimens were tested by quantitative real-time PCR for the presence of genome sequences of the following viruses: adenoviruses, herpes simplex virus (HSV), varicella zoster virus (VZV), human herpesvirus 6 (HHV6), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), parvovirus B19 and enteroviruses. Viral nucleic acid testing was also performed in maternal blood and cord blood in the population of women in whom AF was positive for viruses and in a control group of 29 women with AF negative for viral nucleic acids. The relationship between the presence of viruses and pregnancy and neonatal outcome was examined. The correlation between the presence of nucleic acids of viruses in the AF and the concentration of the cytokine interleukin-6 (IL-6) and the T cell chemokine CXCL-10 (or IP-10) in AF and maternal blood were analyzed. Results: Viral genome sequences were found in 16 of 729 (2.2%) AF samples. HHV6 was the most commonly detected virus (7 cases, 1.0%), followed by HCMV (6 cases, 0.8%), parvovirus B19 (2 cases, 0.3%) and EBV (1 case, 0.1%), while HSV, VZV, enteroviruses and adenoviruses were not found in this cohort. Corresponding viral DNA was also detected in maternal blood of six out of seven women with HHV6-positive AF and in the umbilical cord plasma, which was available in one case. In contrast, viral DNA was not detected in maternal blood of women with AF positive for parvovirus B19, HCMV, EBV or of women with AF negative for viruses. HHV6 genome copy number in AF and maternal blood was consistent with genomic integration of viral DNA and genetic infection in all women. There was no significant difference in the AF concentration of IL-6 and IP-10 between patients with and without VIAC. However, for HCMV, there was a significant relationship between viral copy number and IP-10 concentration in maternal blood and AF. The group of women with AF positive for viral DNA delivered at term healthy neonates without complications in 14 out of 16 cases. In one case of HHV6 infection in the AF, the patient developed gestational hypertension at term, and in another case of HHV6 infection in the AF, the patient delivered at 33 weeks after preterm premature rupture of membranes (PPROM). Conclusion: Viral nucleic acids are detectable in 2.2% of AF samples obtained from asymptomatic women in the midtrimester. HHV6 was the most frequently detected virus in AF. Adenoviruses were not detected. Vertical transmission of HHV6 was demonstrated in one case.     

Immediate and long term outcome of human parvovirus B19 infection in pregnancy

Objective To estimate more precisely the risk of fetal loss and congenital abnormalities after maternal parvovirus B19 infection, and to assess the long term outcome for surviving infants.
Design Prospective cohort study of pregnant women with confirmed B19 infection with follow up of the surviving infants. The rate of fetal loss in the study cohort was compared with that in pregnant women with varicella.
Setting Cases reported by laboratories in England and Wales between 1985-1988 and 1992–1995.
Sample Four hundred and twenty-seven pregnant women with B19 infection and 367 surviving infants of whom 129 were followed up at 7–10 years of age.
Methods Questionnaires to obstetricians and general practitioners on outcome of pregnancy and health of surviving infants. Maternal infection confirmed by B19-specific IgM assay and/or IgG seroconversion.
Results The excess rate of fetal loss in women with B19 infection was confined to the first 20 weeks of gestation and averaged 9%. Seven cases of fetal hydrops followed maternal infections between 9 and 20 weeks of gestation (observed risk 2.9%, 95% CI 1.2–5.9). No abnormalities attributable to B19 infection were found at birth in surviving infants (observed risk 0%, upper 95% CI 0.86%). No late effects were found at 7–10 years.
Conclusions Around 1 in 10 women infected before 20 weeks of gestation will suffer a fetal loss due to B19. The risk of an adverse outcome of pregnancy after this stage is remote. Infected women can be reassured that the maximum possible risk of a congenital abnormality due to B19 is under 1% and that long term development will be normal.     

Cytomegalovirus and Epstein–Barr virus may be associated with some cases of cerebral palsy

Objective: Intrauterine infection is a risk factor for cerebral palsy. Previous work reported a high frequency of viral DNA in newborn screening cards from cerebral palsy cases and controls possibly due to contamination. Methods: Retrospective case-control study using improved methodologies to minimize contamination during PCR-based detection of viral DNA sequences. Newborn screening cards of 339 Caucasian children with cerebral palsy and 594 controls were examined. Viruses tested were herpes simplex viruses 1 and 2 (HSV1 and 2), varicella zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), human herpes viruses 6, 7 and 8 (HHV6, HHV7 and HHV8), and parvovirus B19. Genotyping was performed on DNA extracted from dried blood spots. Results: CMV and EBV were detected in 5 (1.5%) and 3 (0.9%) of 339 cases, respectively, but not in controls (p?=?0.047 and 0.006). Frequencies of detection of the other viruses examined were similar for cases and controls. DNA from at least one of the nine viruses tested was found in 4.4% of cases and 3.1% of controls [OR 1.4 95% CI (0.71–2.76)]. Conclusion: Evidence of congenital viral infection was uncommon in cases of cerebral palsy and controls. However, CMV and EBV were significantly associated with cerebral palsy.     

Occurrence of genital herpes simplex and cytomegalovirus infections in pregnancy.

A total of 244 pregnant women, 172 in the first and 72 in the third trimester, were screened for genital herpes simplex (HSV) and cytomegalovirus (CMV) infections using virus isolation, cytological examination and serological studies. In addition, immuno-fluorescence staining of exfoliated cervical cells was used for the detection of HSV infections. Herpes simplex virus (HSV) could not be isolated and no characteristic HSV altered cells were found in cytological (PAPA) smears. Cytomegalovirus was isolated four times but PAPA smears obtained from these patients were also normal. In 34 (14%) patients HSV antiserum detected immunofluorescence positive exfoliated cervical cells. Overall, 14% of patients had HSV-2 antibodies and 71% CMV antibodies. No differences between the first or third trimesters in these respects were noted.     

Is there an association between fetal viral infection and fetal malformation? I. Detection of specific IgM antibodies in the serum of malformed fetuses

Determinations of IgG and IgM antibodies specific for cytomegalovirus (CMV), herpes simplex virus (HSV1), herpes simplex virus (HSV2), varicella-zoster virus (VZV), rubella, echo, Coxsackie and morbilli viruses were performed in 20 sera from malformed fetuses. Demonstration of a fetal infection by increased fetal serum IgM permits linkage to a detected fetal malformation. In parallel, 14 maternal sera and 17 amniotic fluid samples were examined. Laser nephelometry (a quantitative method) was used for the determination of IgM and IgG class immunoglobulins. None of the fetal sera were found to contain IgM class antibodies specific for the viral antigens studies. While IgM CMV-specific antibodies were present in one maternal serum, the specific IgM was absent in the fetus. The absence of specific IgM antibodies appears to warrant the conclusion that the malformed fetuses were uninfected by any of the above viruses. IgM antibodies were detected in two fetal sera by quantitative methods. The IgM antibodies present in two fetuses probably were generated in response to some other introduced antigen.     

Neutralizing antibody to herpes simplex in pregnant women and their neonates

The neutralizing antibody (NAb) titer against herpes simplex virus (HSV) was determined in blood obtained at term delivery in 76 women with documented genital HSV infection. Maternal and cord blood NAb titers against HSV-1 and HSV-2 displayed significant correlation (r = .88 and r = 0.89, respectively). In 33% of the paired samples, the neonatal NAb titer against HSV-1 exceeded the concomitant maternal titer, and in 59% the maternal and neonatal NAb titers against HSV-1 were equal. In 28% of the pairs, neonatal NAb titer against HSV-2 exceeded the concomitant maternal NAb titer against HSV-2, and in 59% the neonatal and maternal titers against HSV-2 were equal. Since maternal NAb titers against HSV accurately predict a minimum neonatal NAb titer against HSV-1 and HSV-2 in 92% and 87% of cases, respectively, such measurements may be useful in the management of delivery in women with recurrent genital HSV infection.     

Fetale Virusinfektionen

Infections during pregnancy may adversely affect pregnancy outcome and child health. They may be associated with fetal death, preterm delivery, congenital defects, and an increased risk of perinatal morbidity and mortality. The risk of intrauterine transmission and fetal disease depends on the nature of the pathogen, type of maternal infection (primary, recurrent, or chronic infection), and gestational age at time of fetal infection. The most important viruses that may cause symptomatic fetal infections are human cytomegalovirus (CMV), human parvovirus B19 (B19V), varicella-zoster virus (VZV), and rubella virus (RV). Available preventive measures (e.g., active or passive immunization, exposure or postexposure prophylaxis) and treatment options as well as modern serological and virological diagnostics should be thoroughly used to minimize the risk of sequelae associated with prenatal viral infections..     

Detection of parvovirus B19, cytomegalovirus and enterovirus infections in cases of intrauterine fetal death

AIMS: Maternal infections with parvovirus B19, cytomegalovirus (CMV) and enterovirus have been associated with intrauterine fetal death (IUFD), but the incidence of these infections is not clear. This prospective study was conducted to estimate this incidence. METHODS: A prospective study of 38 months was conducted on cases of IUFD referred to Huddinge University Hospital, Stockholm, Sweden. Placental biopsies, fetal blood and amniotic fluid were collected from cases of IUFD (n=52). Placental biopsies from normal pregnancies at term (n=53) were used as controls. These tissues were examined for parvovirus B19 DNA, CMV DNA and enterovirus RNA using polymerase chain reaction (PCR). Maternal viral serology was measured in 46 cases and virus isolation for enterovirus in maternal stool samples was performed in 31 cases. RESULTS: Viral nucleic acid was recovered in at least one tissue sample from six cases of fetal death (parvovirus B19 in two cases, CMV in three and enterovirus in one), while all placental biopsies from controls were found negative. Serological signs of primary maternal infection were found in two of the cases, and virus isolation for enterovirus was negative in all samples examined. CONCLUSION: Parvovirus B19, CMV and enterovirus may be considered as etiologic agents in cases of fetal death. PCR on placental and/or fetal tissue improves diagnostic accuracy for these infections.     

Diagnosis of fetal parvovirus B19 infection: value of virological assays in fetal specimens

Objective  The purpose of our work was to examine the most reliable laboratory diagnosis of fetal parvovirus B19 infection in hydropic fetuses by evaluating the most appropriate clinical sample and laboratory test.
Design  B19 DNA detection in fetal samples and serological signs of B19 infection in the respective mothers. Samples collected between January 2000 and July 2008.
Setting  Microbiology, University of Bologna, Bologna, Italy.
Samples One hundred thirty-five fetal samples (58 fetal cord blood and 77 amniotic fluid samples) and 109 serum samples collected from 109 pregnant women.
Methods  Validated and certified in situ hybridisation assay (ISH) and polymerase chain reaction–enzyme-linked immunosorbent assay (PCR-ELISA) were performed on fetal samples to detect B19 DNA. B19-specific antibodies were investigated in maternal serum samples by a commercial enzyme immunoassay.
Main outcome measures  Parvovirus B19 DNA detection in fetal specimens was analysed in relation to maternal serological signs of infection.
Results  Parvovirus B19 DNA was detected in 22.41% of fetal cord blood and 36.36% of amniotic fluid samples. A statistically significant difference was found between DNA detection by ISH (23.70%) and PCR-ELISA (14.81%) ( P = 0.004). Only 11.76% of fetuses with virological diagnosis of B19 infection were from women with serological signs of acute/recent B19 infection.
Conclusions  Diagnosis of fetal parvovirus B19 infection cannot always rely on maternal serological investigations but rather on the virological analysis of fetal samples. Both fetal cord blood and amniotic fluid samples are suitable for diagnosis, but the detection of B19 DNA in the cells of amniotic fluid samples by ISH proved to be the most reliable diagnostic system.     

Fetal demise due to herpes simplex virus: an illustrated case report.

We report and illustrate a case of fetal demise at 31 weeks caused by fulminant herpes simplex virus (HSV) infection. The 15-year-old mother reported no past history or symptoms of an HSV infection during pregnancy. Autopsy revealed extensively ulcerated skin and necrosis of the liver, adrenal glands, brain, and placental membranes. Fluorescent in situ hybridization studies of the lungs, liver, adrenal glands and placenta were positive for HSV, but did not distinguish between HSV-1 and HSV-2. A maternal postpartum blood sample was positive for HSV-2 by immunoblot assay.     

自然流产孕妇巨细胞病毒与单纯疱疹病毒感染的研究

目的:探讨自然流产孕妇中巨细胞病毒与单纯疱疹病毒感染的状况。方法:留取132例自然流产孕妇及113例因计划外妊娠行人工流产者(对照组)的绒毛组织,用荧光定量多聚酶链反应技术检测绒毛组织标本中巨细胞病毒和单纯疱疹病毒的基因数量。结果:自然流产组孕妇中巨细胞病毒阳性率为16.67％(22/132),对照组阳性率为1.91％(2/113),差异有显著性(P<0.005)。自然流产组孕妇单纯疱疹病毒阳性率为17.42％(23/132),对照组阳性率为2.65％(3/113),差异有显著性(P<0.005)。两者皆为阳性者自然流产组孕妇有12例,占9.09％,对照组均为阴性。治疗后复查巨细胞病毒和单纯疱疹病毒阴性的妇女再次妊娠成功。结论:巨细胞病毒和单纯疱疹病毒均可导致孕妇发生自然流产,且巨细胞病毒及单纯疱疹病毒易合并存在,因此,对自然流产孕妇应同时检测巨细胞病毒及单纯疱疹病毒,针对病因进行治疗,提高下一次妊娠成功率。