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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Three main routes of HTLV-I transmission are known. The first is mother-to-child transmission, mainly due to ingestion of breast milk: breast-feeding has been reported to be the predominant route.8 Because of the high rate of mother-to-child transmission of HTLV-I among children breast-fed for 3–6 months, since 1989 we have advised HTLV-I carrier mothers to bottle feed their infants.9 Sexual transmission, mainly from men to women, is the second most frequent route.10 The third most prevalent route is blood transfusion, which includes HTLV-I-positive cellular components.11,12 However, the importance of this route has decreased since the start of screening of blood products for antibodies to HTLV-I in Japan in November 1987.13
ATLL develops after a long incubation period, with an estimated lifetime risk of approximately 5% in individuals infected before the age of 20 years.14 Because the prognosis for patients with ATLL is extremely poor,15 the prevention of mother-to-child transmission of HTLV-I is of the utmost importance.
Infection with HTLV-I has a peculiar geographic distribution, with half of all ATL patients in Japan found in Kyushu and Okinawa in the southwestern part this country.16 We have been doing epidemiologic surveys of HTLV-I in Okinawa since the discovery of HTLV-I.17
In the present study, to determine the chronologic change of HTLV-I prevalence and the reasons for this change in Okinawa, we surveyed the following five items: 1) prevalence of antibody to HTLV-I among healthy residents over the 30-year study period, 2) prevalence of antibody to HTLV-I among nursery school children over a 15-year period, 3) prevalence of antibody to HTLV-I and p40tax among pregnant women over a 15-year period, 4) the relationship between the feeding method and the seroconversion rate for antibody to HTLV-1 among children born to carrier mothers over a 13-year period, and 5) the feeding method among healthy residents.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). This area studied is located in the southwestern part of Okinawa, close to Taiwan, and is highly endemic for both HTLV-I and hepatitis B virus (HBV).17,18
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Healthy residents. Serum samples were collected from healthy individuals who were examined as part of a free health examination, which included determination of the presence of HBV markers. The examinations were announced by written notices distributed to all households. Serum sample collection was done three times: from 639 individuals from 1968 to 1970, from 1,382 from 1981 to 1984, and from 2,166 from 1996 to 1998. The data for 1968–1970 were obtained by testing stored serum samples because they were obtained before the discovery of HTLV-I. The data for 1996–1998 included the samples of nursery school children on Ishigaki Island. The samples were the same as used in our previous surveys of hepatitis A virus, HBV, hepatitis C virus, and Chlamydia pneumoniae infections in the same study area.18–22 The study subjects, except pregnant women, had not been informed of their antibody status for HTLV-I because no treatment is available for HTLV-I carriers.
The mothers of these children were questioned about the feeding method and the duration of breast-feeding in 1987 and 1995, if applicable. Data were obtained regardless of antibody to HTLV-I.
Nursery school children. Nursery school children in this area have been surveyed for HBV infection since 1979 as part of a primary care program for preschool children.23 A total of 2,506 serum samples obtained from nursery school children 1–4 years old between 1984 and 1999 were used in the present study. School administrators and teachers informed parents of these tests. Samples were not obtained from children who were absent from school or whose parents did not consent. Children less than 12 months of age were not included in this study because it has been reported that the titer of maternally derived antibody decreases exponentially in the first 3–6 months after birth and becomes seronegative at approximately 6–9 months after birth.24
Pregnant women and children born to HTLV-I carrier mothers. A total of 3,837 pregnant women in Ishigaki Island who visited obstetric hospitals from 1989 to 2000 were examined antibody to HTLV-I after informed consent was obtained. Samples obtained from seropositive women were also tested for antibody to p40tax. As an important point of primary care, since 1989 we have advised HTLV-I carrier mothers to bottle feed their babies. The children of these HTLV-I-seropositive mothers were tested for antibodies to HTLV-I. Detailed questions concerning the number of offspring, whether they had breast or bottle fed, and the duration of breast-feeding were asked. In the studied area, public health nurses interview the mothers regularly after birth, regardless of their status for antibody to HTLV-I, about the feeding method and duration of breast milk and record information in a ‘mother-and-baby notebook’, which is given to all pregnant women by the government. The data collected in this study could not have been from selective recall. We tested 76 HTLV-I carrier mothers (age range = 20–40 years, mean age = 30.9 years) and 175 children (age range = 1–19 years, mean age = 5.5 years, 83 males and 92 females) between 1989 and 1991 and 36 HTLV-I carrier mothers (age range = 22–43 years, mean age = 31.2 years) and 76 children (age range = 1–17 years, mean age = 4.5 years, 34 males and 42 females) between 1995 and 1999.9 No significant difference was found in the age of children born to carrier mothers when tested for antibody to HTLV-I between the two study periods. None of the children tested were married or had a history of blood transfusion or surgery. Children less than 12 months of age were not included for the reasons previously stated. There is a possibility that some aspect of the parent-child relationship other than feeding method influenced the status of antibody to HTLV-I of the child because there was more than one child born to some woman. However, it would be impossible to choose one child born to each carrier woman because of resultant selection bias.
Detection of antibody to HTLV-I. Screening for antibody to HTLV-I was done using the passive particle agglutination method (PA) (model FP 151; Fujirebio, Inc., Tokyo, Japan) for all samples. Samples positive by PA were confirmed by enzyme-linked immunosorbent assay (ELISA) (Eitest-ATL; Eisai, Tokyo, Japan) and by Western blot analysis (Eitest ATL-WB; Eisai) using antigens prepared from MT-2 cells. Since 1992, a new version of the ELISA has been used (New Eitest-ATL; Eisai, Tokyo, Japan). In the Western blot analysis, four proteins (p19, p24, p28, and gp68) were tested. Serum samples reactive to p19 plus at least two of the three remaining proteins were considered positive. Samples positive by all three methods were classed as positive for antibody to HTLV-I. Samples positive only by the PA test were considered negative, as were those positive by the PA test and ELISA but negative by Western blot analysis.
Detection of antibody to p40tax. Antibody to p40tax was measured by an ELISA using a recombinant p40tax protein expressed in Escherichia coli with a full length HTLV-I tax gene as the antigen. The cut-off value was set at the average of the p40tax ELISA absorbance value obtained from HTLV-I-seronegative specimens plus three standard deviations.25
Statistical analysis.
The chi-square test, Fisher’s exact test, and Mantel-Haenszel test were used for categorical variables for between group comparisons. A P value < 0.05 was considered significant. The Cochran-Armitage test for linear trends was used to analyze chronologic changes in the prevalence of antibody to HTLV-I and the relationship between duration of breast-feeding and the prevalence of antibody to HTLV-I. The age-adjusted prevalence of antibody to HTLV-I was calculated by direct standardization with the 1985 population of Ishigaki Island as the standard population (0–9 years old, total = 8,236, 4,238 males and 3,998 female; 10–19 years old, total = 6,777, 3,477 males and 3,300 females; 20–29 years old, total = 5,448, 2,712 males and 2,736 females; 30–39 years old, total = 6,693, 3,584 males and 3,109 females; 40–49 years old, total = 4,282, 2,254 males and 2,028 females; 50–59 years old, total = 4,256, 2,091 males and 2,165 females; 
60 years old, total = 5,169, 2,218 males and 2,951 females).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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–3 (Table 1 = total, Table 2 = males, and Table 3 = females). The AAP of antibody to HTLV-I decreased, although it was not statistically significant (from 9.1% in 1968–1970 to 7.8% in 1981–1984 and to 6.3% in 1996–1998). In each test period the prevalence of antibody to HTLV-I increased with age. The prevalence of antibody to HTLV-I was significantly higher in women than in men in 1981–1984 and in 1996–1998 (P = 0.001 and P < 0.0001, by Fisher’s exact test). The prevalence of antibody to HTLV-I in children less than 20 years old decreased significantly: 9 (4.6%) of 196 in 1968–1970, 7 (1.7%) of 413 in 1981–1984, and 1 (0.1%) of 939 in 1996–1998 (1968–1970 versus 1996–1998; P < 0.0001 and 1981–1984 versus 1996–1998; P = 0.001, by Fisher’s exact test). There was no significant difference between male and female healthy residents less than 20 years old.
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. No significant difference was found between males and females in any year. The prevalence of antibodies to HTLV-I among nursery school children decreased significantly from 1.8% in 1984 to 0.2% in 1998 (P = 0.0103, by Fisher’s exact test). The prevalence of these antibodies among nursery school children decreased significantly over the study period (P = 0.0277, by Cochran-Armitage test for linear trends).
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. The overall prevalence of antibodies to HTLV-I among pregnant women was 4.6% (177 of 3,837). This prevalence significantly decreased over the study period: 5.6% (76 of 1,362) in 1989–1992, 4.4% (61 of 1,387) in 1993–1996, and 3.7% (40 of 1,088) in 1997–2000 (1989–1992 versus 1997–2000; P = 0.0275, by chi-square test). Of the 177 pregnant women positive for antibody to HTLV-I, 8 (46.3%) were positive for antibody to p40tax. The percentage of patients positive for p40tax fluctuated: 50% (38 of 76) in 1989–1992, 37.7% (23 of 61) in 1993–1996, and (52.5%) 21 of 40 in 1997–2000. No significant difference was found in the percentage of patients positive for p40tax during the three periods.
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. The rate of non-breast-feeding or breast-feeding 
3 months among breast-feeders increased from 66.9% (117 of 175) in 1986–1991 to 73.7% (56 of 76) in 1995–1999, although it failed to reach statistical significance. The prevalence antibodies to HTLV-I among children born to carrier mothers decreased significantly from 16.0% (28 of 175) in 1986–1991 to 3.9% (3 of 76) in 1995–1999 (P = 0.0063, by Fisher’s exact test). In 1986–1991, as the duration of breast-feeding increased, the prevalence of antibody to HTLV-I among children born to carrier mothers increased significantly (P = 0.0066, by Cochran-Armitage test for linear trends). The rate of mother-to-child infection among non-breast-feeders also decreased from 12.8% (10 of 78) in 1986–1991 to 3.2% (1 of 31) in 1995–1999. The overall rate of mother-to-child infection among breast-feeders decreased significantly from 18.6% in 1986–1991 to 4.4% in 1995–1999 (P = 0.0355, by Fisher’s exact test). The positivity rates for antibody to HTLV-I in all categories of breast-feeding ( 3 months, 6 months, 12 months, and > 12 months) decreased from the period 1986–1991 to 1995–1999 (5.1% versus 4.0%, 22.7% versus 0%, 26.1% versus 0%, and 38.5% versus 11.1%, respectively).
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. Data were obtained by interviewing healthy mothers in 1987 and 1995. Prior to 1967, all mothers breast-fed their children. After 1968, the use of bottled and mixed milk (breast milk and bottled milk) increased, with bottled milk becoming predominant after 1990 (400 of 450 [89%]). The percentage of healthy mothers breast-feeding for more than one year decreased significantly from 68.3% in 1937–1947 to 0.4% in 1990–1995 (P < 0.0001, by Fisher’s exact test).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In each study period, the prevalence of antibody to HTLV-I after the age of 20 years was always higher in women than in men. We previously reported that the man-to-woman transmission rate of married couples was 60%/10 years, in contrast to a woman-to-man transmission rate of 0.4%/10 years.10 The difference in the prevalence of antibody to HTLV-I between men and women probably reflected man-to-woman transmission in the sexually active ages. No sex difference was seen in the prevalence of antibody to HTLV-I among nursery school children, who are not at a sexually active age.
The significant chronologic decrease in the prevalence of antibody to HTLV-I among healthy residents less than 20 years old, including nursery school children, indicates that mother-to-child infection or infection in childhood has decreased. However, the prevalence of antibody to HTLV-I in 1999 increased slightly. We can not clarify why the prevalence of this antibody had increased. Since the prevalence of antibody to HTLV-I after 1994 was so low (< 1.0%), it was difficult to evaluate the annual change in the prevalence of this antibody. A follow-up study will be needed to clarify this matter. Mother-to-child transmission rates among breast-feeders have been reported to range from 5.7% to 39%.8,30,31 We also reported that the mother-to-child transmission rate by breast-feeding was 18.6% in our study area in 1986–1991 and that the HTLV-I transmission rate increased with the duration of breast-feeding from HTLV-I carrier mothers.9 The mother-to-child transmission rate among breast-feeders significantly decreased from 1986–1991 to 1995–1999 in Okinawa. Although maternal antibody to p40tax is a marker of relative infectivity in mother-to-child transmission,25 its prevalence among HTLV-I carrier mothers did not change between 1986 and 2000. Therefore, it is reasonable to assume that the decrease in HTLV-I infection was, at least partly, caused by a shortening of the breast-feeding period.
The mother-to-child transmission rate among non-breast-feeders in this area in 1986–1991 (12.8%), which was higher than that of other HTLV-I-endemic areas in Japan (0.4–4.1%), also decreased in 1995–1999 (3.2%).8,31 This decrease can not be explained by the change of feeding method. The mode of perinatal HTLV-I transmission was unclear except for breast-feeding. In follow-up studies of non-breast-feeders, mother-to-child transmission was not correlated with the status of antibody to HTLV-I in cord blood.32 Bittencourt and others reported that a cesarean section protected against mother-to-child transmission of HTLV-I among non-breast-fed children.33 Therefore, transplacental mother-to-child infection seems to be rare. Since 1991, when we begun educating doctors about this route and advised them to protect against nosocomial infection, obstetricians and gynecologists in this study area have taken precautions to ensure that newborns do not swallow blood at the time of delivery. Their efforts may also have contributed to the relative decrease in the transmission rate of HTLV-I from 12.8% to 3.2% in the present study.
Infection with HTLV-I in Okinawa seems to have decreased mainly due to a reduction in the number of mothers breast-feeding and a shortening of the breast-feeding period. In addition, mother-to-child transmission among non-breast-feeders also decreased, indicating that there may be other factors that led to the decrease in mother-to-child transmission.
Received January 16, 2003. Accepted for publication October 12, 2003.
Authors’ addresses: Kenichiro Kashiwagi, Hisashi Nakashima, and Norihiko Kubo, Department of Environmental Medicine and Infectious Disease, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, 812-8582, Japan. Norihiro Furusyo and Jun Hayashi, Department of General Medicine, Kyushu University Hospital, Higashi-ku, Fukuoka, 812-8582, Japan. Naoko Kinukawa, Department of Medical Informatics, Kyushu University Hospital, Higashi-ku, Fukuoka, 812-8582, Japan. Seizaburo Kashiwagi, National Kyushu Medical Center Hospital, Chuoh-Ku, Fukuoka, 810-8563, Japan.
Reprint requests: Norihiro Furusyo, Department of General Medicine, Kyushu University Hospital, Higashi-ku, Fukuoka, 812-8582, Japan, Telephone: 81-92-642-5909, Fax: 81-92-642-5916, E-mail: furusyo{at}genmedpr.med.kyushu-u.ac.jp.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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