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SEROLOGIC SCREENING FOR , , HERPESSIMPLEX VIRUS, , AND Z-DXOl?~snIlA GONDII IN TWO URBAN POPULATIONS OF PREGNANT WOMEN IN CHILE1

Pablo Vzlzl;2 Jorge Toves-Pereyra, 3 Sergio Stagno, 4 Francisco Gonzhfez,’ Enrique Donoso, G Chades A. Allford, 7 Zimara Hirsch, 8 and Luk Rodtiguezg

I NTRODUCTION these agents represent naturally acquired . There are only a few reports Although the prevalence of concerning the epidemiology of congeni- congenital and perinatal infections is tal and perinatal infections in Chile (l- high, however, it is.unclear whether their $&In general, these reports show that incidence during the childbearing years the prevalences of with most of (and hence their potential to cause fetal the causative agents are high and that disease) is different from that observed in most infections are acquired at an early communities such as those in developed age. Since against cytomeg- countries where lower prevalences are the alovirus (CMV), virus rule. Therefore, in order to help assess (HSV), and Toxopl’asma gondii have not the importance of CMV, HSV, rubella, yet been introduced, high prevalences of HBV, and ToxopLasmagondii as causesof z 2 < ’ This article is also being published in Spanish in the 4 Department of Pediatrics, University of Alabama. Bir- 2 BoLefin de /a Oficina Sanitankz Panameticana, 99(5), mingham. Alabama, . % 1985. The work reported here was supported by Grant s Division of and Gynecology, Dr. Sotero de1 x ‘4 LHZ503Q from the Pan American Health Organita- Rio Hospital, Puente Alto, Chile. u 6 Department of Obstetrics and Gynecology. School of tion and the Kellogg Foundation, by Grant HD-10699 2 from the U.S. National Institute of Child Health and Medicine, Catholic University, Santiago, Chile. Development, by the Pontifical Catholic LJni- ’ Department of Pediatrics, University of Alabama. 2 versity of Chile, and by the Southeastern Metropolitan 8 Department OfPediatrics, School of Medicine, Catholic Health Service of Santiago, Chile. University, Santiago, Chile. 2 a Department of Pediatrics, School of Medicine, Catholic ” Central Laboratory, School of Medicine, Catholic Uni- n, University, Santiago, Chile. versity. Santiago, Chile. ’ Department ofpediatrics, School of Medicine, Catholic University, Santiago, Chile. 53 perinatal infections, we determined the counted for approximately 5% of all rate of susceptibility to these infections seen at area public health during among women of both clinics in one year. low and middle socioeconomic status in The 372 middle-income Santiago, Chile. The report presented women in the study population were en- here indicates the prevalences of these in- rolled at the obstetrics clinic of the Hos- fections early in gestation and compares pital of the Catholic University of Chile the results with other results obtained ( Universidad Catdica de Ck’e). All of from the same population and from these women were white, their mean age other populations in other countries. was 27.2 years, and their mean gesta- tional age at enrollment was 14 weeks. This population accounted for nearly 20% of all pregnant women seen at the M A’I’ERIALS obstetric clinic in one year. AND METHODS Serum samples obtained at enrollment from all of the subjects were The study population con- stored at - 20°C until tested by one of sisted of 833 pregnant women residing in us (P.V.) at the laboratory at the Santiago, Chile, who were enrolled in University of Alabama in Birmingham. the study between January and March of IgG-class against CMV, HSV I 1983, at their first or second prenatal and HSV II, , vi- clinic visit. The age distribution of the rus, and Toxoplasma go&ii were assessed study population, by income group, is using commercially available - shown in Table 1. linked immunosorbent assay(ELISA) kits. The 461 low-income women That is, serum samples were assayed on in this population, all white, were drawn microtiter plates in accordance with the from three different public health clinics method recommended by the manufac- operated for beneficiaries of the National turer of the “Cytomegalisa,” “Herpe- Health Service in the southeast area of l&a,” “Rubelisa,” and “Toxoelisa” kits Santiago; their mean age was 24.5 years (M.A. Bioproducts, Wakersville, Mary- and their mean gestational age at enroll- land, USA). The anti-HBc antibodies ment was 18 weeks. This population ac- were also determined by a commercially available ELISA (Corzyme, Abbott Labo- ratories). The samples that were positive for anti-HBc were subsequently tested b TABLE1. Distributionof the study population,by income for surface antigen (HBsAg) and HBe an- and age groups. 3 tigen (HBeAg) by another ELISA (aus- zime II, Abbott HBe, Abbott Laborato- 4 Middle-income Low-income z. ries). All these assaysare routinely done group group % Age group in our laboratory. .g (in years) No. % No. % 9, %4 16-20<15 -28 - 7.5 12221 26.54.6 s 21-2526-30 132118 35.531.7 11996 25.820.8 a, 31-35 61 16.4 68 14.7 136 33 8.9 35 7.6 54 Total 372 100 461 100 In each run we included ap- cal comparisons were analyzed by the propriate positive and negative controls. Chi square test. Because the Herpelisa kit used to test an- tibodies to HSV I and II had not been li- censed by the U.S. Food and Drug Ad- ministration, we felt it was necessary to RESULTS verify that test’s specificity. Dr. A. Nah- Among pregnant women mias of Emory University in Atlanta, from the lower of the two socioeconomic Georgia, generously provided us with 30 groups, the rate of seropositivity was serum specimens known to contain ei- 96.5% for CMV, 97.2% for HSV, 94.8% ther type I or type II antibodies (deter- for rubella, 68.2 % for Toxoplasma gon- mined. by testing them against specific dii, and 1.4% for HBV, These rates dif- HSV I and II ). We found fered significantly from somewhat lower that specimens containing HSV I anti- rates found for the group of women with bodies had a high rate of cross-reactivity intermediate socioeconomic status in the with the HSV type II antigen used in the casesof Ch4V,HSV, and ToxopZasmagon- Herpelisa test. (HSV type II antibodies dii (Table 2). did not cross-react with HSV type I anti- gen.) Because of this cross-reactivity, we have reported our results without distin- guishing between types I and II. Statisti-

TABLE2. Resultsobtained from ELISAtesting of sera tom two differ- ent populations of pregnant women in Chile for exposure to five agents causing congenital and perinafal disease (cnw=cytomega- lovirus; HSV= herpL!Ssimplex virus; and HBV= ).

No. of pregnant women in group Socioeconomic background of No. No. % Agent populationgroup tested positive positive

CMV Low 456b 440 963 t Middle 370b 321 86.8a Rubella Low 461 437 94.8 virus t Middle 372 351 94.4

HSV . Low 458b 445 97.2a i Middle 37P 326 87.ga Toxoplasma Low 449b 306 68.2a gondii I Middle 370b 179 48.4a HEV Low 513c 7 1.4 L Middle 358 5 1.4

a The difference between the results for the two scciceconomic groups is statistically significant (p< 0.001). b Seven of the study subjectswere not tested far CMV,four were nol tested for HN, and 14 were not tested for Toxp/asma goncb. c In addition to sera from study subjects. sera from 52 other low-income women were tested for HENThe serum samplestested were obtainedfrom pregnantwomen coming to the three participating clmics during the study period. Within the middle-class pop- TABLE 3. Indicated prevalencesof three HBV markers, ulation group, none of five samples test- (anti-HE& HBsAg, and HBeAg)among the 871 pregnant ing positively for anti-HBc were positive women participating in the study. for HBsAg or HBeAg. However, of seven No. of Positivesera samples testing positively for anti-HBc in subjects the lower-class population group, one Marker tested No. % was positive for HBsAg and two were Anti-HBc 871 12a 1.4 positive for both HBsAg and HBeAg. HBsAg 871 0.34 The rate of HBsAg carriers among the to- HBeAg 871 0.22 tal population studied thus appeared to a FM of these subjects came from the mlddle-class group and seven be 0.34 % (Table 3). came from the lower-class group. The age distributions of sero- b The sera posfilve for HBsAg and HEeAg came from among the 12 test- ing positively for antr-HBc Onlythese 12 sera were tested for HEsAg and negative women within both popula- HE&g. tions for CMV, HSV, rubella, and Toxo- @sma gondii are shown in Figure 1. As

LEGEND A. Cytomegalovirus 8. * P< 0.025 30 30 ** P< 0.010 9 *** P

Cl5 16-20 21-25 26.30 31-35 236

70 D. Toxoplasma gondii

C. Rubella virus 60

,,/ ,m

-/I , I I I I I <,5 16-20 21-25 26-30 31-35 a36 $15 16-20 21.25 26-30 31-35 236 Age (years) Age (years)

FIGURE1. Percentagesof the two Santiagostudy populatfonsresponding negativelyto ELISA serologictesting for IgG antibodiesto cytomegalovirus,herpes simplex virus, rubella virus, and Toxoplasmago&i, by age group. may been seen, the number of women positive rates (97.5% and 87.5 %, re- susceptible to CMV, HSV, and Toxop~usma spectively). These rates are similar to gondii declined notably with advancing those reported from communities in Ja- age. pan (7)) Guatemala (8), Barbados (9), Saint Lucia (1 Q), and Tanzania (11) , and higher than those reported from the United States (I, 15, and 18) and Great D ISCUSSION Britain (12). AND CONCLUSIONS Populations highly immune to CMV are at risk of recurrent CMV infec- The results of this study sup- tion, which can result in congenital in- port the conclusion that rubella, cyto- volvement in approximately 1% of all megalovirus, herpes simplex, and toxo- cases (1.3, 14). In fact, a previous study plasma infections are acquired at an early conducted in Santiago by Stagno et al. age in Chile, and consequently that only reported that 1.7 % of the infants born to a small proportion of females remain sus- low-income women were congenitally in- ceptible by the time they reach child- fected with CMV, even though 98% of bearing age. Despite this high degree of the women were seropositive (1). , however, the risk of congeni- tal and perinatal infections with these in- Rubella fectious agents may still be high. That is partly because recurrent infections (due Our results show that only to viral reactivation or reinfection), 4% to 6% of the population escapesru- which are common occurrences with CMV bella infection during childhood and ad- u and HSV, can result in of the olescence. This pattern of rubella seropo- s agent from mother to baby. At the same sitivity has been previously described for 2 time, the relatively few pregnant women Chile, Argentina, Brazil, and Uruguay $j (2), while considerably lower rates of who are still susceptible to these infec- % seropositivity around age 20 have been tious agents are frequently exposed and 2 hence at high risk of acquiring the infec- found in various other countries (includ- t tions. ing Jamaica, , Panama, and Trini- 2 dad and Tobago-2 IT). These different 3 Cytomegalovirus patterns have been correlated with population density (15). 8 As demonstrated previously, Also, in the late 196Os, some CMV infection in Santiago is acquired at countries like the United States and s an early age (I), probably due to the Great Britain showed an intermediate common practices of breast-feeding and pattern, with rapid acquisition of infec- s keeping children in day care centers, tion during childhood but only 80-85 % 2 both of which have been shown to in- seropositivity at the end of the second 3 creasethe incidence of CMV infections in decade of life (16-l 7). This latter pattern g infants and young children (5, 6). Our seems to be one in which the susceptible . present study shows that despite signifi- female population experiences a rela- 4; cant differences in seropositivity between tively higher risk of acquiring rubella vi- < the groups of low and middle socioeco- rus infection during pregnancy. r$j nomic status, both groups had high sero- Regarding , in the b United States routine of children from 15 months to 12 years of age, combined with selective immuniza- children, as suggested by a lower rate of tion of pubertal girls and women of seropositivity now than 10 to 20 years ago childbearing age, has achieved its goal of (2, 15-17, 22-30). The studies providing decreasing both the incidence of rubella this information, which were able to dif- infection in childhood and the incidence ferentiate between HSV I and HSV II anti- of congenital rubella syndrome (la-21), bodies, showed that the increasing prev- although no change has been observed in alence of HSV antibodies with age is the percentages of women who are sero- largely related during the first 15 years of negative. In Great Britain, where rubella life to HSV I infections, and is principally immunization has been aimed only at related thereafter to HSV II infections pubertal girls and women of childbear- (23, 24, 26, 30). ing age, it has not had the same success in controlling congenital rubella (18). Toxoplasma In our two Chilean popula- The prevalences of toxo- tions, because of widespread infection in plasma antibodies found in our study the community, the few women that re- populations are consistent with previous main susceptible may be at relatively reports on other Chilean populations (3, high risk of acquiring rubella. 4). Our data show a statistically signifi- cant difference between the prevalences Herpes Simplex among women in our low and middle so- There are no seroepidemiolo- cioeconomic groups, probably as a result gic or virologic studies, nor any well-doc- of different sanitary conditions, different umented casereports, concerning genital exposure to cats, and different eating HSV infections among pregnant women habits. A previous study suggested that in Santiago. Infection with HSV, as shown the most important factor leading to in- by our serologic study and as indicated fection with toxoplasma in a low-income by clinical experience, is very common Santiago population was the practice of during childhood. The ~-90% rates of eating raw or undercooked meat (4). seropositivity we found are most likely a reflection of past HSV I infections, The Hepatitis B prevalence of HSV II antibodies could not The 0.34% prevalence of HB- be ascertained with accuracy in our study, sAg shown in our study is similar to the because the ELISA test we used has poor 0.3-O .4 % prevalence of HBsAg found in specificity for HSV type II antibodies. Chilean blood donors. However, the Different rates of seropositiv- 1.4% prevalence of anti-HBc differed WI ity, ranging from 50% to loo%, have somewhat from the 5.4% prevalence of % been described in reports from Canada anti-HBc among blood donors (31-33). 2 (2~9, Great Britain (27), and the United This difference could be partly explained States (22-25i), suggesting that acquisi- s by the fact that cohorts of pregnant $2 tion of HSV infection is related to socio- ‘G women are less likely to include many u economic conditions and age-state- 8a prostitutes, drug addicts, and homosex- ments that are consistent with our uals-all groups known to be at rela- current data. In some parts of the world 2 tively high risk of HBV infection. there has been an apparent decline in the What is quite remarkable (Ta- incidence of herpetic infection among ble 4) is that the prevalence of two hepa- titis B markers (HBsAg and anti-HBcAg) 58 seems to be much lower in Chile than in TABLE4. Seroposilfvityfur the markers HBsAg and anti-HBc among populationsin a vatfety of countriesand geographicareas.

% positivefor: Country or area and Anti- source of data Populationstudied HBsAg HBcAg Chile (31, 32) Blooddonors 0.4 5.3 Generalpopulation 0.3 - Pregnantwomen 0.34 1.4 Argentina (31) Blooddonors 0.8 9.4 Brazil (31) Blooddonors 2.1 27.6 DominicanRepublic (31) Blooddonors 4.1 81.1 Latin America (average)(31) Blooddonors 1.6 21.3 United States Houston(35) Blooddonors 0.9 - Phoenix(35) Blood donors 0. I - SouthAt/antic states (35) Blood donors 27 - Mountainstates (35) Blood donors 1.44 - New England (35) Blood donors 1.69 - New YorkState (35) Blood donors 0.4 4.9 (34) Generalpopulation 11.72 28 Tokyo(35) Blooddonors 2.1 - Five South Pacificislands (37) Generalpopulation I-10 - Moscow(35) Blooddonors 4.2 - SouthernAfrica (36) Black urban population 4-9 - other countries of comparable socioeco- mation about the patients. We are in- nomic development, including some in debted to all of them. We would also like the (31-37). With acute and to acknowledge the secretarial assistance chronic hepatitis B viral infections being of Mrs. Silvia Gutierrez. infrequent during pregnancy, it appears that this infection must be very unusual among neonates in Chile. SUMMARY In seeking information about the epidemiology of congenital and peri- A CKNOWLEDGMENTS natal infections in Chile, a serologic sur- We are grateful to Drs. Robert vey was made of 833 pregnant women Pass, Patricia Vella, and Alfred0 Perez residents of Santiago, 46 1 belonging to a for reading the manuscript and suggest- “low-income” group and the remaining ing improvements, and to Mrs. Cecilia 372 to a “middle-income” group. Sera Moya, who collected and compiled infor- from these subjects were tested by ELISA for antibodies to cytomegalovirus, herpes simplex virus, rubella virus, hepatitis B virus, and Toxoplasma gondii. The results indicated that over 3 I?Iiedmann, G., E. Thiermann, and A. 90% of the women were seropositive for veghme. Toxoplasmosis en Chile: Estado ac- :ual de 10sestudios clinicos y epidemiol6gicos. antibodies to cytomegalovirus, rubella Sol Chil Parasitol18:86, 1963. virus, and herpes simplex virus. A lower proportion (59%) were positive for anti- 4 Stagno, S., and E. Thiermann. Acquisition of toxoplasma infection by children in a develop- bodies against toxoplasma, and only ing country. Bd. WHO 49~627, 1967. 1.4% tested positively for antibody against hepatitis B core antigen (anti- 5 Dworsky, M. E., M. Yow, S. Stagno, R. F. Pass, and C. Alford. Cytomegalovirus in breast milk HBc). and transmission to the infant. Pediatr Re.r These findings support the 16:239A, 1982. conclusion that infection with cytomega- 6 August, A., M. Dworsky, and D. Reynolds. lovirus, herpes simplex virus, and rubella Cytomegalovirus infection in a day care center. virus, as well as with toxoplasma to a N EngLJ Med 3071477, 1982. lesser degree, tends to occur at a very 7 Numazaki, Y., N. Yano, T. Morizuka, S. Ta- early age in Chile, and so only a small kai, and N. Ishida. Primary infection with hu- proportion of females remain susceptible man cytomegalovirus: Vnus isolation from by the time they reach childbearing age. healthy infants and pregnant women. Am J Epidemio/91:410, 1970. Despite this, however, the rate of con- genital and perinatal infections may still 8 Cruz, J. R., L. S. Mata, and J. J. Urrutia. Cyto- be high, partly because of the danger of megaloviruria durante el primer afio de vida: estudio prospective en una poblaci6n indigena recurrent infections (common occur- de Guatemala. Bd Of San& Panam 83:218, rences with cytomegalovirus and herpes 1977. simplex virus), and partly because those 9 Evans, A., E Cox, G. Nankervis, E. Opton, R. women who remain susceptible are at Shope, A. V. Wells, and B. West. A health and high risk of acquiring these infections. seroepidemiological survey of a community in It also appears that the preva- Barbados. 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