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Warning to Bearing Small and Raising Big
-Introduction to the Fetal Origins of Adult Disease Hypothesis-

Hideoki Fukuoka
Professor, Research Council, Waseda University

The trend of decreasing birth weight in Japan has not been brought under control. This must be regarded as a phenomenon that might damage the health of the next generation. Recent findings on this problem are described in this report.

1) Fetal Origins of Adult (Lifestyle-Related) Disease hypothesis

The possible causes of adult disease have been regarded as genetic factors and the load of a negative lifestyle. A new theory is recently drawing attention as the third mechanism of onset, however, because the conventional approach cannot provide a satisfactory explanation.

Fig. 1

The Fetal Origins of Adult (Lifestyle-Related) Disease hypothesis proposes that adult disease develops in the following two stages: if a fetus grows in a malnourished uterus, the predisposition for adult (lifestyle-related) disease is formed, and if a child is born with this predisposition, adult (lifestyle-related) disease develops by exposure to over-nutrition, excessive stress, or negative lifestyle due to lack of exercise after birth. Over the next 20 years, the number of diabetic patients is expected to increase sharply by about 1.7 to 1.8 times worldwide. This increase will occur mainly in developing countries. It is even predicted that the sharp increase will possibly interfere with national economic growth to a considerable extent. In other words, if pregnant women are malnourished and maternal weight gain is suppressed for the purpose of bearing children small and raising them big, the possibility that many diseases develop will increase. Such situation may eventually determine the fate of the nation. Epigenetic changes (gene expression regulatory system resulting from the environment without any change in the sequence of genetic DNA) in fetal life have been linked to the mechanism behind this. Although Japan is regarded as an affluent country, birth weight is decreasing unexpectedly, and the poor nutrition of pregnant women is largely responsible for this trend. Based on this current situation, there is concern that Japan has a high possibility of increasing incidence of adult disease. In this regard, many Japanese people should share this idea and try to ensure the health of the next generation.

Specific explanation is provided below. The shift in average birth weight is illustrated in Fig. 1. Average birth weight in both sexes was about 3,100 g in the period of 1950 to 1954, started to increase around 1960 in line with economic growth, reached 3,200 g in the mid-1970s, and has then kept declining. Average male birth weight was about 3,250 g in the 1970s, but has already decreased to 3,000 g or less this year. Average weight has decreased by 250 g for the past 40 years and by 150 g from the period of 1945 to 1954. Birth weight does not accurately demonstrate nutrient environment in the uterus, but is only an indirect indicator. Nevertheless, the 250 g decrease in average birthweight suggests that many pregnant women are seriously malnourished, considering that extremely severe, radical malnutrition is necessary to decrease the weight of newborns in animal experiments. Birth weight is even lower than that in 1945 to 1954, indicating that the current nutritional status is poorer than the time when we were poor.

Newborns weighing less than 2,500 g are defined as low birth weight children. The average incidence of low birth weight children in both sexes was 7% to less than 8% in 1950 to 1954, but decreased to 5% to less than 6% in line with economic growth. It then started to increase, however, and is still increasing (9.7% in 2007). Although the incidence is not more than 10% nationwide, it has exceeded 13% in not a few regions when data are analyzed in detail. The incidence is increasing in all prefectures.

The average incidence of low birth weight children among OECD member countries was 6.5% in 2003. The incidence was the highest (9.1%) in Japan and has further increased since then. This result suggests the possibility that the number of children with high risk of disease will increase in Japan. Among advanced countries, Japan has the highest concern for further increase in lifestyle disease, developmental disorders, future health disorders, etc. of children.

2) Decreasing birth weight and disease risk

D. Barker et al. from the U.K. studied the correlation between birth weight and mortality from ischemic heart disease (Fig. 2). They assessed mortality from myocardial infarction by birth weight based on data from regions where birth records from 1901 to 1945 were kept. It shows mortality increased, as birth weight decreased. Mortality also increased when body weight was too high. There was a strong correlation (J-shaped) between birth weight and disease risk in both males and females. This result suggests that birth weight determines the prognosis.

There was a widely known incident called Dutch Hunger Winter, which demonstrated that malnutrition in the uterus increases the risk of adult disease. During World War II, Nazi Germany imposed a food blockade in the western part of the Netherlands. The subsequent severely cold weather disabled food shipments, and a significant number of people died from hunger. Many children from mothers who were pregnant during this period developed diseases such as metabolic syndrome, diabetes, and myocardial infarction. This is a sad incident which proved that fetal malnutrition increases disease risk.

Many epidemiological studies have been conducted since then. A list of diseases for which the risk increases in relation to decreasing or increasing birth weight is presented in Table 1. Disease risk increases with decreasing birth weight for the following seven diseases: ischemic heart disease, type 2 diabetes, (essential) hypertension, metabolic syndrome, cerebral infarction, dyslipidemia, and neurodevelopmental abnormality. There have been no data that can deny this finding. Epidemiological studies for other diseases are also ongoing.

Fig. 2

Table 1

3) Effect of decreasing birth weight on biological tissues (example)

It is said that low birth weight children often develop hypertension and kidney disease. To verify this, studies have been conducted to determine the number of renal glomeruli (small, linty tissue that excretes waste matter from the blood and produces urine) in kidney slices from autopsies of deceased children. The result indicates that if birth weight is low, the number of renal glomeruli is small, and if the number of renal glomeruli is small, the load on renal glomeruli becomes larger, resulting in hypertrophy and a larger volume. One of the reports is presented in Fig. 3. If the number of renal glomeruli is already small when a small child is born, he or she has to live with a large handicap for the entire life. There is even a hypothesis that essential hypertension is triggered when the number of renal glomeruli is small. Although this is just an example, similar histological or functional changes are likely to occur in many organs.

In conclusion, fetal malnutrition increases the risk of disease. If we don't try to curb the current trend, concern over Japan's future remains. From the above points of view, we have started a large-scale mother-child birth cohort study in Waseda University, which has been unfeasible in Japan, mainly consisting of comprehensive nutrition, metabolism, and epigenetic analyses of the placenta, umbilical cord, and umbilical cord blood in pregnant women, as well as developmental observation and disease analysis in newborns. It will be a difficult study, so we would appreciate your support.

Fig. 3

Hideoki Fukuoka
Professor, Research Council, Waseda University

Graduated from the School of Medicine, Faculty of Medicine, The University of Tokyo in 1973. Held the posts of research assistant at The University of Tokyo (Department of Obstetrics and Gynecology, Faculty of Medicine), research assistant and lecturer at Kagawa Medical University (Department of Perinato-Gynecology), research associate on Department of Pharmacology at Washington University School of Medicine in St. Louis (US), special fellow of the Rockefeller Foundation in reproductive physiology, assistant professor at The University of Tokyo Graduate School (Department of Development Medical Sciences, Graduate School of Medicine) before taking up the current positions of visiting professor on the Institute for Epigenetic Regulation of Fetal Development in April 2007 and professor on the Comprehensive Research Organization Research Institute in June 2011 at Waseda University.

Member of The Endocrine Society (US), delegate of The Japan Endocrine Society, auditor of the Japan Society of Maternal Health, councilor of The Japanese Society for Bone and Mineral Research, Japan Osteoporosis Foundation, The Japanese Society of Diabetes and Pregnancy, The Japanese Association for Gender-Specific Medicine, The Japanese Society of Clinical Nutrition, Japan Society of Obstetrics and Gynecology Tokyo Regional Office, etc.
Certified clinical nutrition specialist (The Japanese Society of Clinical Nutrition)
Specialist in obstetrics and gynecology
Member of the 6th and 7th "Nutritional Allowances" [Eiyou syoyoryo] and "Guideline for Dietary Life of Pregnant Women [Ninpu no tame no syokuseikatu sisin]" committees, etc.

His representative works include the following (including joint authorship):
Nutrition and food problems during disasters [Saigaiji no eiyo/syokuryo mondai], Kenpakusha (Tokyo), pp.59-87
Vitamin and mineral science [Vitamin/mineral no kagaku], Asakura Publishing (Tokyo)

Medical nutrition [Ika eiyougaku], Kenpakusha (Tokyo), pp.798-823
How to save mental and physical crisis of children [Kodomo no sinsin no kiki wo dou sukuuka], NAP (Tokyo)
Nutrition in neonatal and infant periods [Sinseijiki, nyujiki no eiyou]

Clinical sport medicine 2009 Vol. 26 Sport nutrition and diet guide [Rinsyo sport igaku 2009 Vol. 26 Sport Eiyo/syokuji guide], Bunkodo (Tokyo)
Clinical nutrition medicine [Rinsyo eiyo igaku], Nanzando (Tokyo), pp.180-5
Management of SGA short-stature [SGA-sei teisintyosyo no management], Medical Review (Tokyo)
Tailor-made personal nutrition [Tailor-made kojin taiou eiyougaku], Kenpakusha (Tokyo)
NHK special----origin of disease 2 [NHK special yamai no kigen 2], edited and written by a group of reporters, NHK Publishing (Tokyo) Improve our health lifespan [Motto nobasou kenko jyumyo], Japan Meat Information Service Center (Tokyo)