In Japan, multiple birth rates increased and reached a peak in 2005 because of the use of assisted reproductive technology (ART) in the management of infertility, whereas birth rates in general are decreasing. The rates of ART-related multiple births have gradually declined over the past few years (2006–2009), but remain higher than those of spontaneous multiple births, likely due to the effect of the single-embryo transfer policy for ART (Ooki, Reference Ooki2011).
These multiple gestations increase obstetrical complications for the mother, and prematurity and morbidity for the newborns (Santana et al., Reference Santana, Surita and Cecatti2018). Furthermore, death is much more common in multiple births than in singletons, especially in the perinatal period (Imaizumi, Reference Imaizumi2003; Imaizumi & Hayakawa, Reference Imaizumi and Hayakawa2013). If the newborns are in good condition, a specific feature associated with families with multiples is that rearing two or three children of the same age at the same time has been found to overburden parents — especially the mother — physically, mentally and socially (Denton, Reference Denton2005). However, there are few studies on maternal and child health for families with multiples.
Meanwhile, studies on monozygotic and dizygotic twins have been widely used to elucidate overall variations based on genetic and environmental differences between individuals. Environmental factors shared by co-twins include gestational age, total placental weight and maternal factors, such as maternal body size and smoking history. Individual placental characteristics, such as placental function, including nutrient capacity, anatomy and perinatal injury, can lead to differences in birth size between co-twins and are thus part of the environment unique to each twin. We are also interested in using this approach to analyze genetic and environmental contributions to individual differences in body size and development.
The goals of this registry are, therefore, not only to conduct research on human genetics and maternal and child health, but also to contribute to providing appropriate information for families with multiples.
Recruitment of Twins and Higher Order Multiple Births
Twins, triplets, quadruplets, quintuplets and their families in the West Japan Twins and Higher Order Multiple Births Registry (Yokoyama, Reference Yokoyama2002b, Reference Yokoyama2012; Yokoyama et al., Reference Yokoyama, Pitkäniemi, Kaprio and Silventoinen2012, Reference Yokoyama, Sugimoto and Ooki2005, Reference Yokoyama, Sugimoto, Silventoinen and Kaprio2008) have been recruited from several sources since the 1990s, including mothers responding to magazine articles featuring nursing guidance for families with multiple births, the Japanese Mothers’ Organization for Twins and Higher Order Multiple Births, and referrals from several public health centers in west Japan including Osaka City.
Osaka City is a metropolis with a population of approximately 2,700,000. The number of births per year is about 23,000. We have been collaborating with public health centers in Osaka City to provide appropriate childcare information for families with multiples based on evidence accumulated since 2008. Expectant mothers and fathers with multiples who live in the city have been offered childcare information for families with multiples based on several articles.
Table 1 presents a summary of the number of families with twins and higher order multiple births in this registry who participated in at least one survey: 3900 pairs of twins, 1385 sets of triplets, 18 sets of quadruplets, and 3 sets of quintuplets, and their families.
Table 1. Major characteristics
Note: *71 quadruplets excluding 1 infant death.
Zygosity Determination
Information on zygosity was based on validated questions on physical appearance to which mothers of twins responded (Ooki & Asaka, Reference Ooki and Asaka2004). The zygosity of each same-sex twin-pair was initially diagnosed using a three-item questionnaire based on physical resemblance when the twins were around 1 year of age. The items were ‘Were they like two peas in a pod?’, ‘Were they mistaken one for the other?’ and ‘If so, who mistook them?’ According to the degree of similarity, the first question was scored from 1 (like two peas in a pod) to 3 (quite different), the second question from 1 (very often) to 3 (never) and the third from 1 (parent) to 4 (nobody). In accordance with the cut-off point established for this scale, those with a total score of 6 to 10 were considered monozygotic twins and those with a score of 13 to 19 as dizygotic twins. Those with a total score of 11 or 12 were judged as indeterminate. The zygosity differed among the various collaborating public health centers according to factors such as the time of investigation (Table 1).
Health Checkups and Measurements
In Japan, the postnatal health monitoring system changes as the child ages. Birth weight, length, head circumference and chest circumference were measured at hospitals and recorded with information on gestational age. Until 6 years of age, routine health checkups are administered by the Ministry of Health, Labor and Welfare under the Maternal and Child Health Law. All information on physical and motor development of each child is recorded in the Maternal and Child Health Handbooks provided to expectant mothers by the authorities upon notification of the pregnancy. This handbook was established by the Maternal and Child Health Law. The purpose of this handbook is the maintenance of maternal and child health, and it includes information on health checkups during pregnancy, the condition of the newborn, the progress of infant growth, periodic medical checkups for the infant and vaccinations as recorded by obstetricians or pediatricians. After 6 years of age, Japanese children receive health checkups administered by the Ministry of Education, Culture, Sports, Science and Technology under the School Health Law. The physical measures from these school-based health checkups are routinely recorded in the school records and made available to each family.
Mothers participating in this study were offered childcare information for families with multiples based on several articles (Yokoyama, Reference Yokoyama2002a, Reference Yokoyama2002b; Yokoyama & Ooki, Reference Yokoyama and Ooki2004; Yokoyama et al., 2006, Reference Yokoyama, Sugimoto, Silventoinen and Kaprio2008, Reference Yokoyama, Sugimoto, Silventoinen, Pitkäniemi and Kaprio2009) published as a result of data from this registry and included birth weight of twins or multiples, maternal sleeping time after delivery, maternal health condition, coping methods, method of simultaneous feeding, and so on. Mothers were advised to refer to their records when completing the questionnaire. Tables 2 and 3 show the variables and physical measures. Follow-up questionnaires have been mailed out every 3–4 years for the purpose of longitudinal surveys.
Table 2. Variables list of twins and multiples
Note: Circles indicate there is data available.
Table 3. Variables list of body and physical aspect for twin and multiples
Note: Circles indicate there is data available.
Focus of the Study
One of the major focuses of this study has been to investigate physical growth and development features of twins and triplets in childhood (Yokoyama, Reference Yokoyama2012; Yokoyama et al., Reference Yokoyama, Sugimoto and Ooki2005, Reference Yokoyama2012, Reference Yokoyama, Pitkäniemi, Kaprio and Silventoinen2013; Yokoyama, Sugimoto, Pitkäniemi et al., Reference Yokoyama, Sugimoto, Pitkäniemi, Kaprio and Silventoinen2011; Yokoyama et al., Reference Yokoyama, Sugimoto, Silventoinen and Kaprio2008, Reference Yokoyama, Sugimoto, Silventoinen, Pitkäniemi and Kaprio2009; Yokoyama, Sugimoto, Sono et al., Reference Yokoyama, Sugimoto, Sono, Kaprio and Silventoinen2011). We analyzed the genetic architecture of the growth process (Silventoinen et al., Reference Silventoinen, Kaprio and Yokoyama2010; Silventoinen, Karvonen et al., Reference Silventoinen, Karvonen, Sugimoto, Kaprio, Dunkel and Yokoyama2011; Silventoinen, Kaprio et al., Reference Silventoinen, Kaprio and Yokoyama2011) and participated in the CODATwins project (Yokoyama et al., Reference Yokoyama, Jelenkovic, Sund, Sung, Hopper, Ooki and Silventoinen2016, Reference Yokoyama, Jelenkovic, Hur, Sund, Fagnani, Stazi and Silventoinen2018). In addition, the present dataset is the largest triplet sample in the world to provide longitudinal data. The weight and height deficit of triplets compared to the general population of Japan was found to remain between 10% and 17% for weight and between 2% and 5% for height until 12 years of age. In addition, our study of triplets found that left-handedness is associated with lower birth weight when fully controlling for gestational age (Heikkilä et al., Reference Heikkilä, Van Beijsterveldt, Haukka, Iivanainen, Saari-Kemppainen, Silventoinen and Vuoksimaa2018). Left-handers also had significantly delayed motor development and smaller infant head circumference compared to right-handers (Heikkilä et al., Reference Heikkilä, Van Beijsterveldt, Haukka, Iivanainen, Saari-Kemppainen, Silventoinen and Vuoksimaa2018).
Several other studies on maternal and child health for families with multiples have also been conducted (Yokoyama, Reference Yokoyama2002a, Reference Yokoyama2002b, Reference Yokoyama2003; Yokoyama & Ooki, Reference Yokoyama and Ooki2004; Yokoyama & Shimizu, Reference Yokoyama and Shimizu1999, Reference Yokoyama and Shimizu2001). We previously reported that triplet pregnancies showed significantly higher fundal heights compared with twin pregnancies; at 36 weeks of gestational age, those of triplet and twin pregnancies were 47 and 40 cm, respectively. We also noted that the prevalence of cerebral palsy in triplets and quadruplets was higher than that in twins. Lower gestational age was associated with a greater risk of cerebral palsy (Yokoyama et al., Reference Yokoyama, Shimizu and Hayakawa1995). Meanwhile, according to a population-based study, the risk of child maltreatment is higher in multiple births. However, findings from our study showed that multiple birth was not associated with increased risk of child maltreatment (Yokoyama et al., Reference Yokoyama, Oda, Nagai, Sugimoto and Mizukami2015). Compared with singletons, multiples had a significantly higher rate of risk factors for child maltreatment including low birth weight, disorders of the nervous system, and poor maternal health. Using another population-based study, the rate of exclusive breastfeeding among twins or triplets at 4 months of age was significantly lower than among singletons, 4.1% among twins and triplets compared with 44.7% among singletons. Moreover, twins and triplets were independently associated with a higher rate of bottle-feeding; the odds ratio indicated that mothers who had twins or triplets were 2.44 times more likely to choose bottle-feeding with formula milk only than those who had singletons (Yokoyama et al, Reference Yokoyama, Wada, Sugimoto, Katayama, Saito and Sono2006).
Future Directions
The nurturing of multiples entails a higher burden on the mother physically, mentally and economically than that of singletons (Yokoyama et al., Reference Yokoyama2002a, Reference Yokoyama2002b;Yokoyama & Shimizu, Reference Yokoyama and Shimizu2001; Yokoyama et al., Reference Yokoyama, Sugimoto and Ooki2005). This registry, therefore, aims not only to conduct research on human genetics and maternal and child health, but also to contribute to providing appropriate information for families with multiples. Follow-up questionnaires will be mailed out every 3–4 years for longitudinal studies. We will also continue to collaborate with public health centers in Osaka City and other municipalities to help provide information to families with multiples and to conduct population-based studies of twins and multiples in the future.
Collaborations are welcomed. Potential collaborations with investigators using similar measures and who are interested in pooling resources are especially encouraged.
Acknowledgments
The authors would like to gratefully acknowledge the help of Kenka Lee in the data analysis.
Financial Support
This research was supported by Ministry of Education, Science, Sports and Culture, Grant-in-Aid for Scientific Research (C), 1998–1999; Scientific Research (B), 2000–2002; Challenging Exploratory Research, 2000–2002; Scientific Research (B), 2004–2007; Challenging Exploratory Research, 2005–2007; Scientific Research (B), 2008–2012 and Scientific Research (B), 2015–2019.
