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Epidemiology of Human Herpes Virus 8 in Pregnant Women and their Newborns - A cross-sectional delivery survey in Central Gabon

  • Mesküre Capan-Melser
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany
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  • Ghyslain Mombo-Ngoma
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany

    Département de Parasitologie, Université des Sciences de la Santé, Libreville, Gabon
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  • Daisy Akerey-Diop
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany
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  • Arti Basra
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany
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  • Rella Manego-Zoleko
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany
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  • Heike Würbel
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany
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  • Felix Lötsch
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria
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  • Mirjam Groger
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria
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  • Michael Skoll
    Affiliations
    Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria
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  • Julia Schwing
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany
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  • Ulla Schipulle
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany
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  • Pierre-Blaise Matsiegui
    Affiliations
    Centre de Recherches Médicales de la Ngounié, Fougamou, Gabon
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  • Raquel González
    Affiliations
    Barcelona Centre for International Health Research Hospital Clinic (CRESIB, Hospital Clínic-Universitat de Barcelona), IS Global, Barcelona, Spain
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  • Clara Menendez
    Affiliations
    Barcelona Centre for International Health Research Hospital Clinic (CRESIB, Hospital Clínic-Universitat de Barcelona), IS Global, Barcelona, Spain
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  • Peter G. Kremsner
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany
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  • Ayôla A. Adegnika
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany
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  • Selidji T. Agnandji
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany
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  • Michael Ramharter
    Correspondence
    Corresponding author. Institut für Tropenmedizin, University of Tübingen, 72074 Tübingen, Germany. Tel.: +49-7071-2987179; fax: +49-7071-295189.
    Affiliations
    Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon

    Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany

    Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria
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Open AccessPublished:August 10, 2015DOI:https://doi.org/10.1016/j.ijid.2015.08.004

      Highlights

      • This study investigates whether in utero transmission of human herpes virus-8 is an important mode of transmission in Central Africa
      • Seropositivity was 35% in pregnant women and passive transfer of specific IgG occurred in 31% of newborns.
      • Viraemia was detected in only one pregnant woman at delivery and none of the tested cord blood samples showed evidence for active HHV-8 infection. This indicates that other routes of transmission account for the early increase in seroprevalence during childhood in Central African communities.
      • No association between HHV-8 seropositivity and adverse birth outcomes was observed.

      Summary

      Objectives

      On the background of a high prevalence of HHV-8 infection in pre-pubertal Central African children, this study investigated the potential for in utero transmission of HHV-8.

      Patients

      Gabonese pregnant women were invited to provide peripheral and cord blood samples for serological and PCR diagnostics of HHV-8 infection at delivery for this cross-sectional survey.

      Results

      Out of 344 participants 120 (35%, 95% CI: 30-40%) were serologically positive for HHV-8. 31% (95% CI: 22-40%) of cord blood samples of seropositive women had detectable IgG antibodies. Among all seropositive participants HHV-8 was detected by PCR in one maternal peripheral blood sample at delivery (1%, 95% CI: 0.2-7%) and in none of cord blood samples. There was no association between demographic characteristics and infection status. Similarly, there was no difference in risk for premature delivery, low birth weight, and maternal anaemia in HHV-8 seropositive women.

      Discussion

      These data suggest a high seroprevalence of HHV-8 infection in pregnant women, however viraemia at delivery does not commonly occur in Central Africa. Based on these observations it may be speculated that infection of children may occur more commonly either antepartum or later on in infancy and childhood.

      Keywords

      1. Introduction

      Human herpes virus-8 (HHV-8) – also known as Kaposi's sarcoma associated herpes virus – is an infectious agent causing Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease.
      • Gao S.J.
      • Kingsley L.
      • Li M.
      • Zheng W.
      • Parravicini C.
      • Ziegler J.
      • et al.
      KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma.
      • Martin J.N.
      • Ganem D.E.
      • Osmond D.H.
      • Page-Shafer K.A.
      • Macrae D.
      • Kedes D.H.
      Sexual transmission and the natural history of human herpesvirus 8 infection.
      • O’Brien T.R.
      • Kedes D.
      • Ganem D.
      • Macrae D.R.
      • Rosenberg P.S.
      • Molden J.
      • et al.
      Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma.
      • Whitby D.
      • Howard M.R.
      • Tenant-Flowers M.
      • Brink N.S.
      • Copas A.
      • Boshoff C.
      • et al.
      Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma.
      • Cesarman E.
      • Chang Y.
      • Moore P.S.
      • Said J.W.
      • Knowles D.M.
      Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas.
      • Soulier J.
      • Grollet L.
      • Oksenhendler E.
      • Cacoub P.
      • Cazals-Hatem D.
      • Babinet P.
      • et al.
      Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease.
      HHV-8 infection is thought to be primarily transmitted by sexual contact.
      • Martin J.N.
      • Ganem D.E.
      • Osmond D.H.
      • Page-Shafer K.A.
      • Macrae D.
      • Kedes D.H.
      Sexual transmission and the natural history of human herpesvirus 8 infection.
      • Kedes D.H.
      • Ganem D.
      • Ameli N.
      • Bacchetti P.
      • Greenblatt R.
      The prevalence of serum antibody to human herpesvirus 8 (Kaposi sarcoma-associated herpesvirus) among HIV-seropositive and high-risk HIV-seronegative women.
      • Simpson G.R.
      • Schulz T.F.
      • Whitby D.
      • Cook P.M.
      • Boshoff C.
      • Rainbow L.
      • et al.
      Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
      However, the observation of high seroprevalence in pre-pubertal children residing in Africa and the Western and Eastern Mediterranean region
      • Gessain A.
      • Mauclere P.
      • van Beveren M.
      • Plancoulaine S.
      • Ayouba A.
      • Essame-Oyono J.L.
      • et al.
      Human herpesvirus 8 primary infection occurs during childhood in Cameroon, Central Africa.
      • Mayama S.
      • Cuevas L.E.
      • Sheldon J.
      • Omar O.H.
      • Smith D.H.
      • Okong P.
      • et al.
      Prevalence and transmission of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in Ugandan children and adolescents.
      • Pica F.
      • Volpi A.
      Transmission of human herpesvirus 8: an update.
      • Sarmati L.
      HHV-8 infection in African children.
      suggests other epidemiologically relevant routes of transmission. However, little is known about the potential for vertical transmission of HHV-8.
      Active infection during pregnancy with several herpes viruses may affect the human placenta, including herpes simplex virus-1, varicella-zoster virus, and cytomegalovirus, potentially leading to placental insufficiency, premature delivery, miscarriage, or major congenital abnormalities.
      • Avgil M.
      • Ornoy A.
      Herpes simplex virus and Epstein-Barr virus infections in pregnancy: consequences of neonatal or intrauterine infection.
      • Enright A.M.
      • Prober C.G.
      Herpesviridae infections in newborns: varicella zoster virus, herpes simplex virus, and cytomegalovirus.
      • Schleiss M.R.
      Vertically transmitted herpesvirus infections.
      To date, only limited data are available about the impact of maternal HHV-8 infection on birth outcomes and about the potential for vertical transmission of HHV-8. Previous studies report that seropositivity in newborns was mostly caused by transplacental passage of maternal antibodies.
      • Gessain A.
      • Mauclere P.
      • van Beveren M.
      • Plancoulaine S.
      • Ayouba A.
      • Essame-Oyono J.L.
      • et al.
      Human herpesvirus 8 primary infection occurs during childhood in Cameroon, Central Africa.
      • Calabro M.L.
      • Gasperini P.
      • Barbierato M.
      • Ometto L.
      • Zanchetta M.
      • De Rossi A.
      • et al.
      A search for human herpesvirus 8 (HHV-8) in HIV-1 infected mothers and their infants does not suggest vertical transmission of HHV-8.
      However, HHV-8 DNA was detected in newborns in Zambia in peripheral mononuclear cells (PBMCs)
      • Brayfield B.P.
      • Phiri S.
      • Kankasa C.
      • Muyanga J.
      • Mantina H.
      • Kwenda G.
      • et al.
      Postnatal human herpesvirus 8 and human immunodeficiency virus type 1 infection in mothers and infants from Zambia.
      indicating vertical transmission during pregnancy. To further investigate the potential for vertical transmission and the impact of HHV-8 infection on birth outcomes this study assessed the prevalence of HHV-8 infection in pregnant women at delivery and in cord blood samples of their offspring in the Central African country Gabon.

      2. Material and Methods

      This study was conducted at the Centre de Recherches Médicales de Lambaréné at the Albert Schweitzer Hospital in Lambaréné, and the Ngounié Medical Research Centre in Fougamou, Gabon.
      • Ramharter M.
      • Adegnika A.A.
      • Agnandji S.T.
      • Matsiegui P.B.
      • Grobusch M.P.
      • Winkler S.
      • et al.
      History and perspectives of medical research at the Albert Schweitzer Hospital in Lambarene, Gabon.
      Pregnant women participating in a multicentre study evaluating alternative drugs for intermittent preventive treatment of malaria in pregnancy (MIPPAD study: “Evaluation of the safety and efficacy of mefloquine as intermittent preventive treatment of malaria in pregnancy (IPTp; NCT 00811421).”) were invited to participate in this cross-sectional study by providing written informed consent.
      • Gonzalez R.
      • Mombo-Ngoma G.
      • Ouedraogo S.
      • Kakolwa M.A.
      • Abdulla S.
      • Accrombessi M.
      • et al.
      Intermittent Preventive Treatment of Malaria in Pregnancy with Mefloquine in HIV-Negative Women: A Multicentre Randomized Controlled Trial.
      • Basra A.
      • Mombo-Ngoma G.
      • Melser M.C.
      • Diop D.A.
      • Wurbel H.
      • Mackanga J.R.
      • et al.
      Efficacy of mefloquine intermittent preventive treatment in pregnancy against Schistosoma haematobium infection in Gabon: a nested randomized controlled assessor-blinded clinical trial.
      In accordance with inclusion criteria of MIPPAD only HIV-negative women were recruited. Other major inclusion criteria were gestational age ≤28 weeks, no history of allergy to sulfa drugs or mefloquine (MQ), no history of severe renal, hepatic, psychiatric, or neurological disease and no recent MQ or halofantrine treatment. No further inclusion or exclusion criteria other than specific informed consent for this study were applied.
      Peripheral maternal and cord blood samples were obtained at delivery. Blood samples were centrifuged at 2500 rpm for 10 minutes to obtain plasma for the detection of specific antibodies directed against latent nuclear antigen of HHV-8. Whole blood was used for the detection of virus specific DNA by PCR. Plasma samples were tested at a 1/20 dilution for the presence of HHV-8-specific IgG by an indirect immunofluorescence assay (HHV-8 IFA; ABI, Columbia, MD) following instructions by the manufacturer. No quantification of antibody titres was performed. In this assay specific HHV-8 antibodies binding to the antigen of infected cells were visualized after incubation with Fluorescein Isothiocyanate under a fluorescence microscope.
      • Chatlynne L.G.
      • Lapps W.
      • Handy M.
      • Huang Y.Q.
      • Masood R.
      • Hamilton A.S.
      • et al.
      Detection and titration of human herpesvirus-8-specific antibodies in sera from blood donors, acquired immunodeficiency syndrome patients, and Kaposi's sarcoma patients using a whole virus enzyme-linked immunosorbent assay.
      Based on the high sensitivity of the serologic test, only seropositive samples were further analysed by PCR.
      DNA was extracted from maternal and cord blood using QIAamp tissue kit (Qiagen, Bechman Instruments Inc, US). DNA extracts were further assayed by RT-PCR using the LightCycler® carousel-based system. Amplification was carried out in a 15 μl PCR master mix containing 10 pmol/μl of each primer,
      • Boshoff C.
      • Talbot S.
      • Kennedy M.
      • O’Leary J.
      • Schulz T.
      • Chang Y.
      HHV8 and skin cancers in immunosuppressed patients.
      • Chang Y.
      • Cesarman E.
      • Pessin M.S.
      • Lee F.
      • Culpepper J.
      • Knowles D.M.
      • et al.
      Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.
      3 mM of MgCl2, 1x Lightcycler® LightCycler® FastStart DNA Master SYBR Green I (Roche Diagnostic GmbH, Mannheim, Germany) and 1.5 μl of DNA. To detect HHV-8, two sets of primers were used. The first set of primers amplified a 233-bp region of open-reading frame 26 (ORF26);
      • Chang Y.
      • Cesarman E.
      • Pessin M.S.
      • Lee F.
      • Culpepper J.
      • Knowles D.M.
      • et al.
      Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.
      the second set of primers was specific for the ORF25 region.
      • Boshoff C.
      • Talbot S.
      • Kennedy M.
      • O’Leary J.
      • Schulz T.
      • Chang Y.
      HHV8 and skin cancers in immunosuppressed patients.
      Birth weight was measured within 24 h after birth in all newborns. For estimation of gestational age, the Ballard score was used.
      Data were recorded on paper record forms, transcribed into an electronic database, and further analysed (JMP 7.0, SAS Institute Inc., NC). Ethics clearance of this study was obtained by the Comité d’Ethique du Centre de Rercherches Médicales de Lambaréné, at the Albert Schweitzer Hospital in Gabon.

      3. Results

      Between May 2010 and October 2011, 344 pregnant women delivering at the two health care centres were recruited for his study. Mean age at recruitment was 24 years ranging from 14 to 49 years, and mean birth weight was 2,954 g (SD: 581 g).
      A total of 120 pregnant women (35%, 95% CI: 30-40%) tested positive for HHV-8 specific antibodies in the serological assay. Proportions of seropositivity in primigravidae, secundigravidae and multigravidae were 33%, 47%, and 32%, respectively. No difference in the distribution of baseline and demographic characteristics including age and parity were observed in HHV-8 positive versus negative individuals (Table 1). HHV-8 prevalence was comparable in syphilis positive (40%, 95% CI: 11.8-76.9%) and negative individuals (35%, 95% CI: 30.3-40.5%; Table 1), respectively. No association between HHV-8 seropositivity and adverse birth outcomes was found (Table 2).
      Table 1Analysis of baseline characteristics as potential factors associated with HHV-8 seropositivity in pregnant women in Gabon
      ParametersTotal number of participantsHHV-8 seropositive n(%)p-Value
      Chi-squared test.
      Age group
       14-174516 (36%)0.944
       18-209234 (37%)
       21-3013948 (35%)
       31-496822 (32%)
      Literacy
       Literate283102 (36)0.331
       Illiterate6118 (30%)
      Gravidity
       Primigravid8628 (33%)0.070
       Secundigravid7133 (46%)
       Multigravid18759 (32%)
      Syphilis
      Syphilis infection was assessed by Rapid Plasma Reagin testing.
       Positive52 (40%)0.825
       Negative332117 (35%)
      a Syphilis infection was assessed by Rapid Plasma Reagin testing.
      b Chi-squared test.
      Table 2Birth outcome and HHV-8 infection in pregnant women in Gabon
      ParametersnHHV-8 seropositive n(%)p-Value
      Delivery
       Livebirth336119 (35%)0.179
       Stillbirth81 (13%)
      Delivery characteristics
      Data not available for all 344 individuals.
       Vaginal325113 (35%)0.965
       Caesarean176 (35%)
      Delivery anaemia
      Data not available for all 344 individuals.
       No anaemia19266 (34%)0.818
       Anaemia
      anaemia: haemoglobin < 11.0g/dl.
      14953 (36%)
      Term delivery
      Data not available for all 344 individuals.
       Normal314114 (36%)0.197
       Preterm
      preterm delivery: < 37 weeks of gestation.
      153 (20%)
      Birth weight
      Data not available for all 344 individuals.
       Normal27697 (35%)0.724
       Low
      low birth weight: defined as < 2500g at delivery.
      6421 (33%)
      a HHV-8 infection classified based on serology.
      b anaemia: haemoglobin < 11.0 g/dl.
      c preterm delivery: < 37 weeks of gestation.
      d low birth weight: defined as < 2500 g at delivery.
      * Data not available for all 344 individuals.
      Ninety-eight cord blood samples from seropositive women were collected for further serological analysis. Among those, 30 cord blood samples (31%, 95% CI: 22-40%) tested positive for the presence of HHV-8 specific IgG. 76 paired samples from maternal and cord blood were available for further PCR analysis (inadequate DNA extraction in 22 samples). One maternal blood sample (1%, 95% CI: 0-7%) yielded a positive result for HHV-8 DNA. All other maternal samples and all cord blood samples were negative in PCR analysis.

      4. Discussion

      This study demonstrates a high prevalence of HHV-8 seropositive HIV negative pregnant women indicating that HHV-8 infection is highly prevalent in this rural Central African population. Interestingly, the proportion of illiterate and very young pregnant women – an important surrogate marker for socioeconomic status – was not different between infected and uninfected individuals.
      • Kurth F.
      • Belard S.
      • Mombo-Ngoma G.
      • Schuster K.
      • Adegnika A.A.
      • Bouyou-Akotet M.K.
      • et al.
      Adolescence as risk factor for adverse pregnancy outcome in Central Africa--a cross-sectional study.
      This finding indicates that HHV-8 is rather uniformly distributed in this African population without evidence for particular risk factors for HHV-8 infection. Importantly, there was no difference in prevalence of HHV-8 seroprevalence depending on the age and parity of pregnant women. Interestingly, prevalence of syphilis was low in both groups. The low rate of syphilis in our cohort might be explained by the fact that HIV was defined as an exclusion criterion and thus women with high risk sexual behaviour were excluded. In Europe and North America unprotected sexual contacts are considered to be the major route of transmission for HHV-8.
      • Martin J.N.
      • Ganem D.E.
      • Osmond D.H.
      • Page-Shafer K.A.
      • Macrae D.
      • Kedes D.H.
      Sexual transmission and the natural history of human herpesvirus 8 infection.
      • Blauvelt A.
      • Sei S.
      • Cook P.M.
      • Schulz T.F.
      • Jeang K.T.
      Human herpesvirus 8 infection occurs following adolescence in the United States.
      However, in Central Africa there is epidemiological evidence for early increase of HHV-8 seroprevalence during childhood. A sero-epidemiological survey in a highly endemic region in Uganda showed that HHV-8 transmission occurs during childhood increasing progressively up to 50% in adults. Similarly, a Cameroonian study reported a gradual increase of seropositivity from 13% in 7-24 month olds to 39% in 12-14 year old children, reaching 45% in adult women.
      • Gessain A.
      • Mauclere P.
      • van Beveren M.
      • Plancoulaine S.
      • Ayouba A.
      • Essame-Oyono J.L.
      • et al.
      Human herpesvirus 8 primary infection occurs during childhood in Cameroon, Central Africa.
      • Mayama S.
      • Cuevas L.E.
      • Sheldon J.
      • Omar O.H.
      • Smith D.H.
      • Okong P.
      • et al.
      Prevalence and transmission of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in Ugandan children and adolescents.
      These data from the Central African region demonstrate that routes of transmission other than by sexual contact play the most important role for transmission of HHV-8 in this pre-pubertal population. Importantly, other modes of transmission including exposure to saliva are increasingly incriminated for the transmission of HHV-8 and may potentially explain the epidemiological pattern of HHV-8 transmission in Central Africa.
      • Phipps W.
      • Saracino M.
      • Selke S.
      • Huang M.L.
      • Jaoko W.
      • Mandaliya K.
      • et al.
      Oral HHV-8 replication among women in Mombasa, Kenya.
      In our study, seropositivity was detected in 31% of cord blood samples of seropositive women. This finding may be explained by passive transfer of maternal IgG antibodies and is per se no conclusive proof for vertical transmission. Importantly, all cord blood samples were tested negative for the presence of HHV-8 DNA in PCR analysis. This finding indicates that infection and subsequent viraemia in the newborn does not occur commonly. However, this study did not investigate the potential for intra-partum transmission of HHV-8. In addition longitudinal sampling of pregnant women was not performed during pregnancy due to the cross section study design, which constitutes a limitation of our study. Further follow up and blood sampling during the first year of life would have been necessary to address this research question but was beyond the scope of this work.
      Whereas active infections with other herpes viruses during pregnancy are reportedly associated with adverse pregnancy outcome including spontaneous abortion, premature delivery, and miscarriage,
      • Avgil M.
      • Ornoy A.
      Herpes simplex virus and Epstein-Barr virus infections in pregnancy: consequences of neonatal or intrauterine infection.
      • Enright A.M.
      • Prober C.G.
      Herpesviridae infections in newborns: varicella zoster virus, herpes simplex virus, and cytomegalovirus.
      • Schleiss M.R.
      Vertically transmitted herpesvirus infections.
      this survey did not show such an association for HHV-8 seropositive pregnant women. However, viraemia was not detected in all but one woman and therefore the sample size of this study was not large enough to reliably detect more subtle risk differences between viraemic and non-infected individuals.
      In summary these data confirm a uniformly high prevalence of HHV-8 seropositivity in Gabon. No evidence for in utero transmission of HHV-8 and viraemia in cord blood was found in this study. Future investigations should further characterize transmission characteristics in infancy and childhood in Central Africa potentially focussing on oro-oral transmission patterns.

      Acknowledgements

      We are grateful for the participation of the pregnant women in this study. We acknowledge the support of Christian Kleine, Florian Thol, Malte Witte, and Moritz Fürstenau for the conduct of this study. We are indebted for the technical assistance and continued support of Heide-Maria Winkler.
      Ethical approval: Ethics clearance of this study was obtained by the Comité d’Ethique du Centre de Rercherches Médicales de Lambaréné, at the Albert Schweitzer Hospital in Gabon.
      Funding: This work was funded by a grant of the Hochschuljubiläumsstiftung der Stadt Wien (H-2412/2009). The main clinical trial (MIPPAD) was funded by a grant from EDCTP (EDCTPIP.07.31080.002), BMBF (FKZ: 01KA0803) and the Malaria in Pregnancy Consortium, which is funded through a grant from the Bill and Melinda Gates Foundation to the Liverpool School of Tropical Medicine. This work was supported by Deutsche Forschungsgemeinschaft (DFG-Projekt KR 1150/6-1) and Open Access Publishing fund of the University of Tübingen.
      Conflicts of Interest: MR is serving as Corresponding Editor in the International Journal of Infectious Diseases. The authors declare no other potential conflicts of interest.

      References

        • Gao S.J.
        • Kingsley L.
        • Li M.
        • Zheng W.
        • Parravicini C.
        • Ziegler J.
        • et al.
        KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma.
        Nature medicine. 1996; 2: 925-928
        • Martin J.N.
        • Ganem D.E.
        • Osmond D.H.
        • Page-Shafer K.A.
        • Macrae D.
        • Kedes D.H.
        Sexual transmission and the natural history of human herpesvirus 8 infection.
        The New England journal of medicine. 1998; 338: 948-954
        • O’Brien T.R.
        • Kedes D.
        • Ganem D.
        • Macrae D.R.
        • Rosenberg P.S.
        • Molden J.
        • et al.
        Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma.
        The Journal of infectious diseases. 1999; 180: 1010-1017
        • Whitby D.
        • Howard M.R.
        • Tenant-Flowers M.
        • Brink N.S.
        • Copas A.
        • Boshoff C.
        • et al.
        Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma.
        Lancet. 1995; 346: 799-802
        • Cesarman E.
        • Chang Y.
        • Moore P.S.
        • Said J.W.
        • Knowles D.M.
        Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas.
        The New England journal of medicine. 1995; 332: 1186-1191
        • Soulier J.
        • Grollet L.
        • Oksenhendler E.
        • Cacoub P.
        • Cazals-Hatem D.
        • Babinet P.
        • et al.
        Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease.
        Blood. 1995; 86: 1276-1280
        • Kedes D.H.
        • Ganem D.
        • Ameli N.
        • Bacchetti P.
        • Greenblatt R.
        The prevalence of serum antibody to human herpesvirus 8 (Kaposi sarcoma-associated herpesvirus) among HIV-seropositive and high-risk HIV-seronegative women.
        JAMA: the journal of the American Medical Association. 1997; 277: 478-481
        • Simpson G.R.
        • Schulz T.F.
        • Whitby D.
        • Cook P.M.
        • Boshoff C.
        • Rainbow L.
        • et al.
        Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
        Lancet. 1996; 348: 1133-1138
        • Gessain A.
        • Mauclere P.
        • van Beveren M.
        • Plancoulaine S.
        • Ayouba A.
        • Essame-Oyono J.L.
        • et al.
        Human herpesvirus 8 primary infection occurs during childhood in Cameroon, Central Africa.
        International journal of cancer Journal international du cancer. 1999; 81: 189-192
        • Mayama S.
        • Cuevas L.E.
        • Sheldon J.
        • Omar O.H.
        • Smith D.H.
        • Okong P.
        • et al.
        Prevalence and transmission of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in Ugandan children and adolescents.
        International journal of cancer Journal international du cancer. 1998; 77: 817-820
        • Pica F.
        • Volpi A.
        Transmission of human herpesvirus 8: an update.
        Curr Opin Infect Dis. 2007; 20: 152-156
        • Sarmati L.
        HHV-8 infection in African children.
        Herpes. 2004; 11: 50-53
        • Avgil M.
        • Ornoy A.
        Herpes simplex virus and Epstein-Barr virus infections in pregnancy: consequences of neonatal or intrauterine infection.
        Reprod Toxicol. 2006; 21: 436-445
        • Enright A.M.
        • Prober C.G.
        Herpesviridae infections in newborns: varicella zoster virus, herpes simplex virus, and cytomegalovirus.
        Pediatr Clin North Am. 2004; 51 (viii): 889-908
        • Schleiss M.R.
        Vertically transmitted herpesvirus infections.
        Herpes. 2003; 10: 4-11
        • Calabro M.L.
        • Gasperini P.
        • Barbierato M.
        • Ometto L.
        • Zanchetta M.
        • De Rossi A.
        • et al.
        A search for human herpesvirus 8 (HHV-8) in HIV-1 infected mothers and their infants does not suggest vertical transmission of HHV-8.
        International journal of cancer Journal international du cancer. 2000; 85: 296-297
        • Brayfield B.P.
        • Phiri S.
        • Kankasa C.
        • Muyanga J.
        • Mantina H.
        • Kwenda G.
        • et al.
        Postnatal human herpesvirus 8 and human immunodeficiency virus type 1 infection in mothers and infants from Zambia.
        The Journal of infectious diseases. 2003; 187: 559-568
        • Ramharter M.
        • Adegnika A.A.
        • Agnandji S.T.
        • Matsiegui P.B.
        • Grobusch M.P.
        • Winkler S.
        • et al.
        History and perspectives of medical research at the Albert Schweitzer Hospital in Lambarene, Gabon.
        Wiener klinische Wochenschrift. 2007; 119: 8-12
        • Gonzalez R.
        • Mombo-Ngoma G.
        • Ouedraogo S.
        • Kakolwa M.A.
        • Abdulla S.
        • Accrombessi M.
        • et al.
        Intermittent Preventive Treatment of Malaria in Pregnancy with Mefloquine in HIV-Negative Women: A Multicentre Randomized Controlled Trial.
        PLoS medicine. 2014; 11: e1001733
        • Basra A.
        • Mombo-Ngoma G.
        • Melser M.C.
        • Diop D.A.
        • Wurbel H.
        • Mackanga J.R.
        • et al.
        Efficacy of mefloquine intermittent preventive treatment in pregnancy against Schistosoma haematobium infection in Gabon: a nested randomized controlled assessor-blinded clinical trial.
        Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2013; 56: e68-e75
        • Chatlynne L.G.
        • Lapps W.
        • Handy M.
        • Huang Y.Q.
        • Masood R.
        • Hamilton A.S.
        • et al.
        Detection and titration of human herpesvirus-8-specific antibodies in sera from blood donors, acquired immunodeficiency syndrome patients, and Kaposi's sarcoma patients using a whole virus enzyme-linked immunosorbent assay.
        Blood. 1998; 92: 53-58
        • Boshoff C.
        • Talbot S.
        • Kennedy M.
        • O’Leary J.
        • Schulz T.
        • Chang Y.
        HHV8 and skin cancers in immunosuppressed patients.
        Lancet. 1996; 348: 138
        • Chang Y.
        • Cesarman E.
        • Pessin M.S.
        • Lee F.
        • Culpepper J.
        • Knowles D.M.
        • et al.
        Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.
        Science. 1994; 266: 1865-1869
        • Kurth F.
        • Belard S.
        • Mombo-Ngoma G.
        • Schuster K.
        • Adegnika A.A.
        • Bouyou-Akotet M.K.
        • et al.
        Adolescence as risk factor for adverse pregnancy outcome in Central Africa--a cross-sectional study.
        PloS one. 2010; 5: e14367
        • Blauvelt A.
        • Sei S.
        • Cook P.M.
        • Schulz T.F.
        • Jeang K.T.
        Human herpesvirus 8 infection occurs following adolescence in the United States.
        The Journal of infectious diseases. 1997; 176: 771-774
        • Phipps W.
        • Saracino M.
        • Selke S.
        • Huang M.L.
        • Jaoko W.
        • Mandaliya K.
        • et al.
        Oral HHV-8 replication among women in Mombasa, Kenya.
        Journal of medical virology. 2014; 86: 1759-1765