HERPES SIMPLEX VIRUS (HSV) is transmitted by intimate contact with someone who is shedding the virus. HSV type 1 (HSV-1), which is excreted mainly orally, is usually acquired during childhood from a parent but may also be acquired later in life from a partner through intimate, e.g., sexual contact. HSV type 2 (HSV-2) is excreted mainly genitally and is predominantly acquired through sexual activity. 1,2 Both viruses can cause neonatal herpes, a severe and often life-threatening disease. 3–7 In many countries neonatal herpes is caused by HSV-2, and it is generally accepted that passage through an infected birth canal is the most probable route of transmission. 8,9 Recently, we retrospectively investigated the incidence of neonatal herpes in the Netherlands. 10 In this study an incidence of 2.4 cases per 100,000 newborn infants was found. Seventy-three percent of cases were caused by HSV-1. Similar study findings have been reported from other countries, 11,12 but these findings contrast strongly with those from the USA, where the majority of cases are caused by HSV-2. 8,9,13,14 To better understand this difference, we studied the seroprevalence of HSV-1 and HSV-2 in pregnant women in different parts of the Netherlands.
Materials and Methods
Serum samples drawn in the first trimester for pregnancy screening were collected during the period of April to December 1998. Four hundred ninety-six samples were from women who were living in the agglomeration of Amsterdam, 498 were from women living in the agglomeration of Rotterdam, and 513 were from women living in the agglomeration of Nijmegen (in the southeastern part of the Netherlands). The latter consists of both rural and urban regions. These samples were collected for routine screening (for rubella antibody, rhesus blood group, hepatitis B antigen, and syphilis) and were stored afterward. For our purposes, the samples were made anonymous, and the only available information was age, city, and ethnic origin.
The median age of the women was 31.2 years (range, 16–48). There was no difference in age between native and nonnative women.
Demographics of the Netherlands
About 83% of the total Dutch population of 15.6 million (according to statistics from January 1, 1998) is of native origin and 17% is nonnative. Twenty-five percent of the total population lives in the agglomerations of the three largest cities (Amsterdam, Rotterdam, and The Hague), called the Randstad. Thirty-one percent of this population is of nonnative origin. In Amsterdam and Rotterdam, half of the population is nonnative (Table 1). 15–21 Outside the Randstad the proportion of nonnatives is 12%, and a similar percentage of nonnatives (13%) lives in the region of Nijmegen (Table 1). 15,16 Consequently, the population of Nijmegen is considered to be representative of the Randstad, and the population of Amsterdam and Rotterdam are considered representative of the Randstad.
All sera were tested for HSV-1 and HSV-2 type-specific IgG antibodies by enzyme-linked immunosorbent assay (ELISA), with use of recombinant type-specific gG1 and gG2 proteins (MRL Diagnostics, Cypress, CA). This method has been approved by the Food and Drug Administration.
Statistical analyses, by means of chi-square tests, were performed with Epi Info (version 6.01, 1994; Centers for Disease Control and Prevention, Atlanta, GA). P levels of 0.05 or less were considered significant.
The seroprevalences of HSV-1 and HSV-2 antibodies in pregnant women are presented in Table 2. As the shows, differences in seroprevalence were found between different regions and between different ethnic groups. With regard to HSV-1, the seroprevalences in Amsterdam (73%) and Rotterdam (75%) were similar, but they were significantly higher than in Nijmegen (61%). The seroprevalence of HSV-1 among nonnatives was significantly higher than that among natives, and the regional differences were caused mainly by the differences in the composition of the populations in the regions that were investigated. The largest minority groups in the Netherlands are from the Mediterranean countries of Turkey and Morocco and the Caribbean countries Surinam and Dutch Antilles. The highest seroprevalence of HSV-1 was found among women from Turkey (96%) and Morocco (90%), higher than among women from Surinam (77%) and the Dutch Antilles (72%) and among native women (61%).
With regard to HSV-2, the seroprevalences in Amsterdam (35%) and Rotterdam (27%) were also significantly higher than in Nijmegen (11%). Among the native population of Amsterdam and Rotterdam a quarter had antibodies against HSV-2, whereas in Nijmegen only 8% had such antibodies. Among nonnatives the seroprevalence was highest in Amsterdam (48%), intermediate in Rotterdam (32%), and, again, low in Nijmegen (13%). The difference between Amsterdam and Rotterdam was attributed to the high number of women of Caribbean origin who are living in Amsterdam and who have a high seroprevalence of HSV-2. Among women from Surinam, 40% had HSV-2 antibody, and among women from the Dutch Antilles, 60% had such antibody. Much lower percentages were found among women from Turkey and Morocco (20%) and among native women (24–26%), percentages which are nevertheless higher than those found in Nijmegen.
In Nijmegen 41% of the native women and 17% of the nonnative women and in the Randstad, approximately 37% of the native women and 15% of the nonnative women are HSV-1 antibody–negative and thus susceptible to a primary, or first, episode of HSV-1 infection.
In order to better understand why HSV-1 is the main cause of neonatal herpes in our country, we performed a seroepidemiological survey of the prevalence of HSV-1 and HSV-2 among pregnant women in the Netherlands. Because of the multiethnic composition of the Dutch population, women were included from three different regions. The main finding of the study is that significant geographical differences do exist in the prevalence of HSV-1 and HSV-2, which can be attributed to a variation in composition of the population. Women from Morocco and Turkey showed the highest seroprevalence of HSV-1 but a relatively low prevalence of HSV-2, whereas women from Surinam and the Dutch Antilles had high seroprevalences of HSV-1 as well as HSV-2. Dutch women living outside the big cities of Amsterdam and Rotterdam had relatively low seroprevalences of both HSV-1 and HSV-2. Native women living in Amsterdam and Rotterdam had similar seroprevalences of HSV-1 but much higher seroprevalences of HSV-2.
Infection with HSV-2 is associated with risk behavior for STD. 22,23 Accordingly, the higher seroprevalence among women in Amsterdam and Rotterdam as compared with Nijmegen may be due to a difference in factors that affect acquisition of STD, such as past sexual behavior (the number of sex partners and the number of years of sexual activity). 24,25 However, risk behavior for STD has not systematically been investigated for the country outside Amsterdam and Rotterdam. Alternatively, a high prevalence of HSV-2 indicates that the risk to become exposed to the virus is increased, which promotes viral spreading apart from sexual behavior. The high prevalence of HSV-2 in Amsterdam and Rotterdam is probably the result of the different ethnic composition of the population in these cities, where half of the population is of nonnative origin. The highest prevalence of HSV-2 antibodies was found among women of Caribbean origin (40% for women from Surinam and 60% for those from the Dutch Antilles), of whom the majority live in the Randstad, particularly in Amsterdam. A high seroprevalence of HSV-2 among women of Caribbean origin was earlier reported following a study of visitors to the STD clinic in Amsterdam, where a seroprevalence of 52% was found among women of Caribbean origin. 24 However, visitors to STD clinics are not representative of the general population, whereas pregnant women can be considered to be. 26 The results of our study are in concordance with those of earlier European investigations of pregnant women, which have shown overall prevalences of HSV-2 to range between 9% and 33%. 27–30 Ades et al. reported a seroprevalence of 37% among black women of African origin and 33% among black women of Caribbean origin. 30 The other European studies did not provide information on differences in seroprevalence in relation to ethnicity.
Extrapolation of the outcome of our study implies that the Randstad region, where a quarter of the entire population lives, has a distinctly different epidemiology for HSV-2, compared with the rest of the country. In the Randstad the prevalence of HSV-2 is rather similar to that in many regions of the USA. 9 In spite of that, the incidence of neonatal herpes in the Randstad was not different from that in the rest of the Netherlands and approximately 10 times lower than has been reported from the USA. 10,31 This difference is not well understood. Moreover, the incidence of neonatal herpes in the Netherlands did primarily correlate with the population size as such, and not with the epidemiology of HSV-1, HSV-2, or both (data not shown).
The risk of transmitting HSV to the neonate is highest during a primary genital infection with either HSV-1 or HSV-2 in the last month of pregnancy. 32,33 According to Brown et al., maternal antibodies to HSV-2 but not those to HSV-1 reduce the risk of transmission of HSV-2 to the neonate. None of the infants born to mothers with reactivation of HSV-2 in early labor subsequently had neonatal herpes, but neonatal HSV-2 infection was found in 31% of the neonates when the mother did shed HSV-2 at delivery but did not have HSV-2-specific antibodies. The rates of transmission of neonatal herpes were similar among seronegative women who had a primary HSV-2 infection (25%) and women who already had HSV-1 antibodies and had a nonprimary first episode of genital HSV-2 infection (31%). In Nijmegen 34% of the women and in the Randstad 19% of the women were HSV antibody–negative and thus susceptible to both HSV-1 and HSV-2 infection. Overall, 38% of the native women were still susceptible for HSV-1 and might acquire the infection during pregnancy.
HSV-1 is transmitted to the newborn more readily than HSV-2, irrespective of the type of maternal disease, 34 which may partly explain a preponderance of HSV-1 detected in neonates.
With half of the cases being caused by HSV-1, this virus type is also a frequent cause of neonatal herpes in Great Britain. 11,12,14,35 By contrast, 70% of cases of neonatal herpes in the USA are due to HSV-2, although a recent study indicated a possible shift in favor of HSV-1. 13,36,37
An unchanged incidence of neonatal herpes, as observed in our country over a period of 17 years, supports that factors other than genital herpes must be involved. 10 Otherwise, an increase in incidence would have been observed, because the incidence of HSV-2 did strongly increase during the past few decades. 38 Underreporting is not a likely explanation, since the number of virus diagnostic laboratories in the Netherlands has almost doubled during that period. Furthermore, attention was focused on neonatal herpes and its prevention by establishing a preventive protocol. 39 We therefore assume that primary HSV-1 infection near delivery and possibly also postnatal infection of the infant are major risk factors causing neonatal herpes in the Netherlands. Documented sources of postnatal HSV-1 infection include infected breast milk, the mother or father having an oral lesion, and cold sores in other family members or medical staff. 40,41 However, we are not well informed on the contribution of postnatal infection to the total number of cases of neonatal herpes in the Netherlands.
A possible way to prevent neonatal herpes may be serological screening to identify HSV-discordant couples, who can subsequently be counseled on how to avoid infection. 33 A prospective study of highly motivated couples, however, showed that knowledge of HSV discordance did not eliminate the risk of acquisition of genital herpes during pregnancy. 42 Considering the low incidence in the Netherlands of 1/40,000 neonates, it can be debated whether extensive preventive measures are cost-effective.
This study report is the first to describe the prevalence of HSV-1 and HSV-2 among a sentinel population of pregnant women in the Netherlands. For this study, first-trimester sera were used, which did not address the actual status at the time of delivery. Overall, however, the expected rate of acquisition of HSV during pregnancy is less than 2%, 43 a figure that does not affect the outcome. Our study shows that ethnical or cultural differences influence the epidemiology. However, the intermediately high seroprevalence of HSV-2 among native women in the big cities suggests that exchange occurs and that HSV-2 is emerging among the native population. This study, however, did not resolve the intriguing question of why the incidence of neonatal herpes in the Netherlands and some other European countries is so much lower than in the USA and why HSV-1 is such a dominant cause of this severe disease.
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