Three pioneering epidemiological studies, i.e., the Dutch famine during World War II [21–24], a British study in the county of Hertfordshire (Barker hypothesis) [25–27], and the Helsinki Birth Cohort [28–32], indicated that a relationship exists between environmental aggression in the early developmental period and the incidence of NCDs in later life. Subsequent epidemiological studies on different ethnic groups in different locations worldwide, together with excellent animal studies, revealed the novel concept of the early establishment of metabolic adjustments by interorgan communication networks that affect the morbidity of NCDs throughout life [33–35], leading to a new scientific theory, DOHaD [6, 8, 36].

Two major parameters have been used in epidemiological studies to support the contribution of undernourishment in utero to the developmental risk of NCDs, i.e., maternal low-energy intake during pregnancy and a low birthweight less than 2500 g. Maternal low-energy intake means a low-energy supply for the maintenance of mothers and fetuses, while a low birthweight less than 2500 g is one of the parameters of anthropometry of newborns, with neither being identical to undernourishment in utero.

Epidemiological evidence to connect undernourishment in utero to the development of adult NCDs initially emerged in victims of the Dutch famine in 1944–1945 during World War II. The adult and/or elderly offspring of women exposed to the famine in gestation were predisposed to NCDs, such as schizophrenia, antisocial personalities, cognitive decline, coronary heart disease, hypertension, an atherogenic lipid profile, disturbed blood coagulation, obesity, impaired glucose tolerance, metabolic syndrome, increased stress responsiveness, obstructive airway disease, and decreased renal function [21–24]. Fetal exposure to the Chinese Famine in 1959–1961 also showed a similar trajectory toward a predisposition to NCDs [37–39]. The relationship between fetal exposure to the Chinese Famine and an increased risk of adult metabolic syndrome was stronger among subjects with a Western-style calorie-rich diet [40].

British studies by Barker et al. [25–27] and the Helsinki Birth Cohort study [28–32] together revealed that individuals born with a low birthweight less than 2500 g were predisposed to NCDs in adulthood, including coronary heart disease, impaired glucose tolerance, hypertension, metabolic syndrome, dyslipidemia, and cognitive decline. However, it is important to note that the concept of a low birthweight less than 2500 g is different from that of fetal growth restriction (FGR), intrauterine growth restriction (IUGR), or small for gestational age (SGA). In perinatal medicine, FGR or IUGR commonly means that the estimated fetal weight is less than the tenth percentile for gestational age as assessed through an ultrasound observation in utero [41], whereas SGA generally means that a birthweight is less than the tenth percentile for gestational age [42]. Their reference charts differ among populations, localizations, and even generations. Mean birthweight is more than 3400 g in the United States [43] but is approximately 3000 g in Japan [44]. Therefore, caution is needed in the interpretation of etiological data based on a low birthweight less than 2500 g because the basic characteristics of individuals with a low birthweight may differ among the populations studied. Furthermore, most premature newborns are classified as having a low birthweight even if their birthweight is within the normal range for their gestational ages. Thus, small babies are not always simply a result of undernourishment in utero. Nevertheless, significant relationships have been reported between a low birthweight and elevated adiposity in children [45, 46] and adults [29, 47, 48].

Although large numbers of theoretical models have been proposed to explain the mechanistic basis underlying possible associations between undernourishment in utero and obesity-related metabolic disorders in later life [49], the thrifty phenotype hypothesis by Hales and Barker [50] is the most promising model [13, 14, 51]. They proposed the concept of an adaptive response to undernourishment in utero that is a trade-off between saving energy consumption in utero and downsizing the fetal body. Embryonic and/or fetal predictive adaptive responses may adjust the development of their own metabolic regulation systems in response to the environmental characteristics surrounding their mothers for the purpose of matching themselves to the predicted postnatal circumstances and improving survivability in life after birth [52] (Fig. 16.2). The optimization of fetal body growth in utero is hypothesized to lead to a distinct and permanent metabolic phenotype, the thrifty phenotype, of enhanced energy economy, similar to a hybrid electric vehicle, for the purpose of matching the predicted postnatal circumstances of long-lasting insufficient food supply and improving survivability through a life of incessant starvation [50, 51] (Fig. 16.2).

According to the “match” aspect of the thrifty phenotype hypothesis, a previous study reported that small babies in Gambia, including those born during a nutritionally debilitating hunger season, maintained healthy metabolic as well as cardiovascular conditions into adulthood with the complete absence of metabolic syndrome if they retained their frugal lifestyle in rural areas [53] (Fig. 16.2).

As for the mismatch feature of the thrifty phenotype, it was hypothesized that the thrifty phenotype may become disadvantageous for the survival of the fittest when nutrition is more abundant in the postnatal environment than had been expected from the prenatal environment of undernourishment because the enhanced energy economy of the thrifty phenotype may cause a mismatch to the excess energy supply associated with the modern lifestyle of overeating, thereby predisposing adults to NCDs, particularly those related to obesity and/or diabetes [12–14, 50, 54–56] (Fig. 16.2).

Developing countries have been undergoing rapid and prominent economic improvements over the past few decades, and generations that experienced a low-energy supply during fetal life due to maternal poverty and/or political turmoil have now shifted to a life with an obesogenic diet [17] (Fig. 16.1). Therefore, individuals expected to have acquired the thrifty phenotype in utero encounter a mismatch to the excess energy supply provided by a calorie-rich obesogenic diet and develop a risk of NCDs, particularly those related to obesity and/or type 2 diabetes [54] (Figs. 16.1 and 16.2). The prevalence of diabetes has been rapidly increasing in developing countries, such as China, India, and Malaysia [57–59].

In Japan, the prevalence of obesity or being overweight has consistently increased among adult males as well as mature and elderly women, whereas undernourishment is common among young women of childbearing age because of their strong desire to be thin [60]. A decrease in the body mass index of young Japanese women has been followed by an increase in low birthweight neonates as well as a decrease in mean birthweight [56, 61, 62]. The mean total caloric intake of the Japanese population has continuously decreased since 1970 [56, 61], suggesting that the incidence of obesity has increased despite a reduced energy supply. This paradoxical shift toward a possible obesity-prone phenotype in a relatively short period, less than half a century, in middle-aged and elderly Japanese populations argues against the major contribution of a Western lifestyle with a calorie-rich diet and insufficient exercise due to the widespread use of cars in favor of a presumed increase in the number of individuals with the thrifty phenotype due to undernourishment in utero. Kubota et al. reported that mean energy intake in pregnant Japanese women was less than 1600 kcal/day through pregnancy, 30% (second trimester) and 37% (third trimester) below the recommendations of the Ministry of Health, Labour, and Welfare in Japan [63], which suggests large numbers of relatively undernourished fetuses due to insufficient maternal energy intake. Thus, it is plausible that a nutritional imbalance in pregnant Japanese women may have established the thrifty phenotype in a large proportion of the next generation, thereby contributing, at least partly, to the development of obesity and/or type 2 diabetes with less energy intake [56, 62].

A systematic review revealed that small babies were more predisposed to adult obesity if they showed rapid catch-up growth soon after birth [64] (Fig. 16.2). The interaction between a prenatal low-energy supply and subsequent rapid catch-up growth soon after birth, presumably being equal to a rapid encounter with a postnatal high-energy supply, i.e., immediate and drastic mismatch, appeared to increase the risk of obesity and its associated metabolic disorders [10, 12, 65–68]. However, controversy surrounds the critical window or period of catch-up growth. Settler et al. suggested the importance of the first few weeks of postnatal life [69, 70]. Botton et al. showed that neonates with a faster weight gain velocity during the first 3 months showed a greater weight gain velocity after 3 years of age, leading to a larger fat mass in adolescence [71]. Ong et al. demonstrated the importance of growth until 2 years of age [64]. In contrast, several studies have reported that low birthweight children who grew excessively in later childhood were also at a higher risk of adult obesity [29, 72].

Obesity has prevailed in developed countries, particularly in North America, over the past several decades as a result of the oversupply of nutrients relative to the amount required to meet normal metabolic demands, and this has mainly been attributed to lifestyle such as the excess consumption of energy-rich meals and declines in physical activity. However, the DOHaD theory proposes an alternative explanation for the increasing prevalence of obesity, i.e., a transgenerational negative chain by overnourishment in utero and/or in the early postnatal period, namely, fetuses and/or infants who experienced an early environment of excessive nutrients are predisposed to obesity and associated metabolic disorders in later life [9]. Salsberry et al. showed that maternal prepregnancy obesity was a significant risk factor for overweight adolescent offspring [73]. Maternal prepregnancy obesity and excessive weight gain during pregnancy have been causatively associated with the incidence of large-for-gestational-age infants [74–77] who are at high risk of childhood and adolescent obesity [74, 77, 78]. On the other hand, fetal exposure to diabetes or gestational diabetes during pregnancy, which may be linked to fetal exposure to high glucose levels, has been reported to increase the risk of childhood and adult obesity, diabetes, metabolic syndrome, and cardiovascular diseases [79, 80]. Human and animal studies revealed that an intrauterine high-energy supply consistently elevated the risk of NCDs in later life [81–83].

Recent human and animal studies have suggested that paternal obesity also induces the programming of offspring phenotypes related to the risk of NCDs via genetic and/or epigenetic changes in spermatozoa [84, 85].

Since not only undernourishment in utero but also overnourishment in utero have been causatively associated with the risk of NCDs in later life, a “U-shaped curve” has been proposed for the relationship between nutritional conditions in utero and the risk of developing adult NCDs [10–16] (Fig. 16.1). In developed countries, particularly those in which obesity is prevalent, the transgenerational risk of early exposure to an excess energy supply in the pre-contraceptive period and/or intrauterine period has been proposed to play a crucial role in increasing the risk of NCDs in addition to the simple lifestyle of an obesogenic diet and reduced physical activity [17] (Fig. 16.1). The rate of increases in the number of NCD patients in developing countries is distinctly higher than that in developed countries [15, 16]; therefore, the sequence of prenatal undernourishment and subsequent postnatal overnourishment may be a stronger risk factor for the development of adult NCDs in neonates undernourished in utero than continuous exposure to overnourishment throughout the entire life including the fetal period. Humans have struggled to adapt to starvation for millions of years; however, those in developed countries now need to adjust to an opposite environment, i.e., excess energy supply, throughout life even before birth.

Pathophysiological theories have been proposed for undernourishment in utero, such as a predictive adaptive response, the thrifty phenotype, and a mismatch; however, a pathophysiological theory has not yet been well established explaining the contribution of overnourishment in utero to the prevalence of NCDs in adulthood. It has not yet been fully clarified whether permanent phenotypic changes in response to overnourishment in utero are advantageous for the survival of the fittest in later life with an excess energy intake.

The core concepts of preemptive medicine are the early identification of high-risk populations and early interventions during a latent period without symptoms or notable abnormalities in routine laboratory and physical examinations [5, 18, 19]. Evidence for the protective efficiency of such early interventions against the incidence of NCDs as well as medical economic cost performance is extremely limited. We propose the following candidates as realistic early interventions: (1) preparation of home and school educational programs on lifestyle based on scientific evidence, particularly lifelong benefits including the next generation [86]; (2) educational interventions before conception concerning nutritional aspects for fertile women, including the transgenerational negative chain according to the DOHaD theory [10–16, 87]; (3) nutritional interventions for lean and obese pregnant women, if effective [88, 89]; and (4) providing appropriate management of gestational diabetes [79, 80].

Since catch-up growth has been reported to increase the risk of NCDs [10, 12, 29, 64–67, 69–72], nutritional interventions for nursing women and/or bottle feeding neonates may be candidates for early interventions. Nevertheless, a previous study reported that children born small for their gestational age without catch-up growth were at high risk of a short stature in adulthood and need to be referred for growth hormone treatment [90]. Therefore, establishing standard methods to achieve optimal growth in neonates and/or infants is challenging because numerous factors, including genetic and epigenetic backgrounds, may be involved in their growth patterns.

One of the important concepts of preemptive medicine is identifying high-risk individuals in early life [5, 18, 19]. A simple assessment of birthweight is not sufficiently specific to clearly identify high-risk individuals. Extensive efforts have been made over the past few decades to establish effective biomarkers for the use in clinical practice with the ability to identify individuals at high risk of developing NCD [91–96]. The application of “omics” technologies has generated hundreds to thousands of biomarker candidates; however, very few of these have been translated into clinical care [95, 96]. The identification of useful biomarkers, their authorization, and governmental approval followed by translation into clinical settings will be long and difficult. Nevertheless, the rewards will be fruitful not only for individuals but also for socioeconomic contributions.