As there is a risk of MTCT of HTLV-1, the HSGP HTLV-1 MTCT was organized in 2011. To determine how many pregnant women are infected with HTLV-1 in Hokkaido, which is the northernmost and the second largest island in Japan with a population of 5 467 000 and 39 392 newborns in 2011, the HSGP HTLV-1 MTCT asked all facilities that may care for pregnant women in Hokkaido in July 2013 to provide information on the number of pregnant women who underwent screening for anti-HTLV-1 antibody using particle agglutination or chemiluminescent enzyme immunoassay, and the numbers of those with positive, equivocal, and negative test results in the screening and confirmation tests using western blotting or PCR methods in 2012, respectively. A total of 111 facilities participated in this study and provided information on 33 617 pregnant women who underwent screening in 2012, corresponding to approximately 85% of all pregnant women who gave birth in Hokkaido in 2012. Of 81 candidates for a confirmation test because of positive (n = 77) or equivocal (n = 4) results on screening, 63 (78%) underwent the confirmation test and, finally, 34 (0.1%) and 33 563 (99.8%) women were judged to be HTLV-1 carriers and non-carriers, respectively. It was concluded that the prevalence rate of HTLV-1 carriers was low, one per 1000 pregnant women in Hokkaido. Approximately 40 infants are born yearly to mothers infected with HTLV-1 in Hokkaido.
adult T-cell leukemia/lymphoma
human T-lymphotropic virus type 1-associated myelopathy
- HSGP HTLV1 MTCT
Hokkaido Study Group for the Prevention of human T-lymphotropic virus type 1 mother-to-child transmission
human T-lymphotropic virus type 1
The Japanese Ministry of Health; Labour and Welfare
tropical spastic paraparesis
Human T-lymphotropic virus type 1 (HTLV-1, also known as human T-cell leukemia virus type 1) causes ATLL [1, 2], which often occurs in HTLV-1-endemic areas, such as southwestern Japan, the Caribbean islands, Central and South America, Intertropical Africa, and the Middle East . It also causes HAM/TSP. Among HTLV-1 carriers, estimated lifetime risks for ATLL are 6–7% and 2–3% for Japanese males and females, respectively , and 0.25% for HAM/TSP in Japanese . In a US prospective study, 3.7% of HTLV-1 carriers were diagnosed with HAM/TSP .
HTLV-1 is primarily transmitted vertically from mother to child [6, 7]. MTCT of HTLV-1 occurs mainly via breast milk, and refraining from breast-feeding was shown to be effective in reducing MTCT [7-9]: an expected outcome of withholding breast-feeding is a reduction of MTCT rate from 15–20% to 2–3% [7, 8]. As ATLL is likely to develop after a long incubation period of more than 20 years in HTLV-1 carriers via MTCT , prevention of milk-borne transmission is the most efficient and feasible way to reduce the disease burden . Therefore, detection of pregnant women carrying HTLV-1 may have a crucial role in the reduction of the number of HTLV-1 carriers and ATLL. In 2010, the JMHLW decided to financially support blood testing for the detection of HTLV-1 in pregnant women. Japanese clinical guidelines for obstetric practice edited in 2011 by the Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists recommended carrying out a screening test for anti-HTLV-1 antibody using particle agglutination or chemiluminescent enzyme immunoassay, with western blotting and/or PCR for confirmation in all pregnant women and providing information on safe feeding methods, such as formula milk feeding, frozen-thawed breast milk, and short-term breast-feeding within 3 months after birth in those carrying HTLV-1 .
The HSGP HTLV-1 MTCT, organized by the local government of Hokkaido in 2011, investigated the prevalence of HTLV-1 carriers among pregnant women living in Hokkaido, which is the northernmost and the second largest island in Japan with a population of 5 467 000  and 39 392 newborns in 2011 .
MATERIALS AND METHODS
The present study was conducted with the approval of the institutional review board of Hokkaido University Hospital and conforms to the provisions of the Declaration of Helsinki (as revised in Tokyo 2004). The Hokkaido Study Group for the Prevention of HTLV-1 MTCT asked all 197 facilities located in Hokkaido capable of providing maternity care for pregnant women on 1 July 2013 to participate in this study and requested information on women who were screened for the presence of anti-HTLV-1 antibody until 23 August 2013. We collected the following information: number of women with screening test for anti-HTLV-1 antibody; number of women with positive, negative, and equivocal test results in the screening. When there were women with positive or equivocal test results in the screening, we also requested information on the number of women who underwent a confirmation test by western blotting or PCR and test results in these women. The data gathered by the HSGP HTLV-1 MTCT were analyzed in this study.
A total of 139 facilities responded, but 28 facilities indicated that they did not provide care for pregnant women or had not carried out screening tests in pregnant women. Finally, 111 facilities participated in this study and provided information on a total of 33 617 pregnant women who were screened for anti-HTLV-1 antibody, corresponding to approximately 85% of all pregnant women (approximately 39 000) who gave birth in Hokkaido in 2012. The number of women undergoing screening per facility was 303 ± 274, ranging from one to 1479. Of the 33 617 women, 77 (0.23%) showed positive results, four (0.01%) had equivocal test results, and the remaining 33 536 had negative test results on the screening test (Fig. 1). Sixty-three (78%) of the 81 candidates for a confirmation test because of positive or equivocal test results on the screening test underwent a confirmation test with the western blotting method: test results were positive in 34, negative in 26, and equivocal in three even after the confirmation test. One of the three with equivocal test results on the western blotting test underwent PCR test and was shown to be negative for HTLV-1. Thus, 34 (0.10%) and 33 563 (99.8%) of the 33 617 women were finally judged to be HTLV-1 carriers and non-HTLV-1 carriers, respectively. HTLV-1 status remained undetermined in 20 women (0.06%), consisting of 18 who did not undergo a confirmation test and two with equivocal results on the confirmation test.
Regional differences in the prevalence of pregnant women with HTLV-1 were analyzed (Fig. 2). More than 500 women per city were screened in 13 cities (overall carrier rate, 0.11% [32/29 842]): no HTLV-1 carriers were detected in five cities indicated in blue, whereas carrier rate ranged from 0.07% in Obihiro to 0.31% in Hakodate in the remaining eight cities, with a total of 32 HTLV-1 carriers (Fig. 2). Less than 500 women per city were screened in other cities (indicated with no color) in which two women were determined to be HTLV-1 carriers (overall carrier rate of 0.05% [2/3775]). There were no marked regional differences in the prevalence of pregnant women with HTLV-1 in Hokkaido.
The present study covered approximately 85% of all pregnant women who gave birth in Hokkaido in 2012 and demonstrated that one in 1000 pregnant women carried HTLV-1 in Hokkaido. Thus, although the overall rate of HTLV-1 carriers was not so high among pregnant Hokkaido women, there were two cities (Hakodate and Otaru) with somewhat higher prevalence rates of more than 0.2%. Furthermore, it was disclosed that malpractice occurred in 22% (18/81) of women who were candidates for the confirmation test; therefore, the confirmation test was skipped in these 18 women. A campaign may be needed to eliminate such an incident in MTCT of HTLV-1.
A nationwide survey conducted in 2006–2007 in first-time blood donors revealed that the number of HTLV-1 carriers is increasing in non-endemic areas around Tokyo in Japan . This was considered to reflect the movement of more HTLV-1 carriers to non-endemic areas occurring with economic growth . According to that survey , the prevalence rates of HTLV-1 carriers were 0.04%, 0.18%, 0.10%, and 0.46% in female donors aged 16–19 years, 20–29 years, 30–39 years, and 40–49 years, respectively, in Hokkaido. These observations suggest that the prevalence of HTLV-1 carriers is 1–2 per 1000 pregnant women in Hokkaido, which is consistent with the results of the present study.
Although the present study was not able to analyze HTLV-1 prevalence rate by maternal age, HTLV-1 carriers decreased with decreasing age irrespective of gender among blood donors in all areas of Japan according to a study conducted in 2006–2007, although possible reasons for this trend were not discussed . For example, among females in their 20s, 30s, 40s, 50s, and 60s, the prevalence rates were 0.09%, 0.15%, 0.37%, 0.65%, and 0.80%, respectively, in Kanto district, including metropolitan Tokyo area, whereas they were 0.74%, 0.95%, 2.18%, 4.28%, and 7.34%, respectively, in Kyushu (southern and third largest island of Japan) , suggesting a high-risk cohort born by 1960 and a low-risk cohort born after 1960. The major routes of HTLV-1 transmission are MTCT (mainly by breast-feeding) , sexual transmission (predominantly male to female) [15, 16], and transfusion of cellular blood components , but this has been eliminated since the implementation of viral screening of donated blood in 1986 . Short-term breast-feeding within 6 months is effective for reduction of the risk of MTCT [7, 8]. We speculate that the ready availability of milk formula and concomitant increase in the number of female workers occurring in the mid-1950s in Japan with economic growth contributed greatly to the trend towards reduction in the number of HTLV-1 carriers caused by breast-feeding.
Relatively higher prevalence rates of HTLV-1 carriers were seen in two cities (i.e. Hakodate and Otaru) that were two major cities in Hokkaido during the early to mid-twentieth century. Japan had excluded foreigners until the mid-nineteenth century at which time the Japanese Government decided to open Hakodate port to foreign countries. Furthermore, many Japanese moved to Hokkaido in the late nineteenth century as part of an effort to cultivate the land and Otaru has been a port of Sapporo, the capital city of Hokkaido, since the early twentieth century. These two seaside locations had been exposed to busy human and materials traffic because they represented the main entrances to Hokkaido for Japanese as well as for foreigners. An early study suggested a higher prevalence of HTLV-1 carriers in southern areas of Japan with rather than without harbors  and the prevalence of ATLL was higher in seaside areas than in inland areas of Japan . The higher prevalence rates of HTLV-1 carriers in the two cities, Hakodate and Otaru, may be associated with their seaside locations in southern areas of Hokkaido Island.
In conclusion, data on the HTLV-1 status of approximately 85% of all pregnant women who gave birth in Hokkaido in 2012 were analyzed. HTLV-1 carriers were identified in 0.1% (34/33 617) of these women. Thus, although its prevalence is low, these results suggest that approximately 40 infants are born to mothers with HTLV-1 in Hokkaido yearly, and approximately 20% of these 40 would be HTLV-1 carriers unless appropriate interventions are implemented . Therefore, a campaign to encourage safe feeding methods in those at higher risk of HTLV-1 MTCT is recommended.
We thank all of the physicians who provided data on the results of screening and confirmation tests.
All authors declare that they have no financial relationships with biotechnology manufacturers, pharmaceutical companies, or other commercial entities with an interest in the subject matter or materials discussed in this manuscript.