What Adult Problems Can Start with Fetal Undernutrition?

Patient Presentation
After watching a movie set during World War II, a pediatrician’s teenage son said, “That movie wasn’t very realistic. They didn’t have the right arms for a lot of the troops. Plus somebody forgot when they filmed it that the Battle of the Bulge occurred in the winter. There was no snow on the ground in the movie. Plus, if you look, all the people, including the civilians, look pretty healthy. Their faces are fat and they all have shoes and decent looking clothes. The people should be looking sicker at the end of the war.” “I noticed the people too. They all looked pretty well fed and clothed as you said. In 1944-45 there was a total famine Netherlands, and I bet in Belgium too so people wouldn’t be looking that good,” she remarked. During the ensuing conversation, the teen noted that war and famine continue today. The pediatrician said, “Yes and the health problems because of poor nutrition and other problems continue even after the children grow up.” “Like what kinds of problems?” he asked. “I know that there is an increased risk of heart disease and diabetes. There’s probably more but I haven’t read about it in quite a while,” she said. “Do people know what makes the problems even when people are old?” he asked. “Probably, but again I haven’t read about this in a long time. Maybe I’ll see if I can find you an answer,” she replied.

Developmental origins of health and disease (DOHaD) is a scientific hypothesis that proposes that fetal nutrition has permanent effects on growth, metabolism, and structure. These changes, or biological programming, are felt to occur at critical periods in fetal development “…when developmental changes in the organism towards increasing complexity, greater plasticity, and more efficient functioning occurs rapidly and may be most easily modified either in favorable or unfavorable directions.” Fetal undernutrition has been studied more than overnutrition, and various nutritional components (protein, micronutrients) have been studied but to a lesser degree. Exposure to fetal undernutrition during these critical periods may create a “thrifty phenotype” where adaptions to the fetal nutrient-limited environment allows the fetus to survive, but induces permanent changes that later on are unhealthy. Epidemiological studies linking birthweight to adult chronic diseases have shown a variety of outcomes (see Learning Point below). Many times the relationship shows a “U” shaped pattern of extremes of birth weight (lowest and highest) having the greatest risks of adult chronic diseases.

Although not entirely elucidated, it is felt that fetal programming through epigenetics is at least part of the mechanism. “Epigenetics encompasses change to marks on the genome that are copied from one cell generation to the next, which may alter gene expression, but which do not involved changes in the primary DNA sequence.”

  • DNA methylation is one of the most epigenetic mechanisms studied. One of the most common examples is after translation, a cytosine residue sitting next to a guanine residue is methylated to form a cytosine-phosphate-guanine dinucleotide (CpG).
    These CpGs are important gene regulators. For example, folic acid carries a methyl group and is being studied for possible DNA methylation.

  • Histones are proteins which package and order the chromatin. They can be chemically modified in many different ways including methylation, acetylation, phosphorylation, etc. Acetylation is one of the most studied mechanisms.
    Butyrate (from dietary fiber), diallyl disulfide (from garlic) or retinoic acid (from spinach, carrots, eggs) can control gene expression through histones.

  • microRNAs are small RNA molecules encoded in the genome that control gene expression. They appear to be able to directly affect gene expression but also through other mechanisms such as DNA methylation or histone modifications.
    Retinoic acids, curcumin (from tumeric) and genistein (from soy) are different nutritional factors that can control gene expression through microRNAs.

Epigenetics affect can the total number of cells produced and tissue remodeling. For example, in pregnant animals who experience protein deprivation, the total number of nephrons are permanently decreased and the offspring later has an increased risk of hypertension. There is also evidence of fetal tissue remodeling in response to fetal undernutrition particularly in the pancreas, liver and hypothalamus. Even umbilical cord tissue has been related to later outcomes such as childhood adiposity. Areas that seem to be prioritized for adequate fetal nutrition are the brain, heart and adrenal gland at the expense of other organs such as the liver, kidney, pancreas, lung and skeletal muscle. It is theorized that the functions of these latter organs are ones that the pregnant mother performs for the fetus, therefore they are more affected.

Epigenetic patterns are inherited and it is felt that this is at least one reason for transmission of some of the risk factors to subsequent generations (ie the child or grandchild of the fetus).

While epigenetics are felt to place the fetus at risk, environmental factors potentially can add to it or help to mitigate it. The social theories are framed around the idea that multiple environmental stressors (often chronic such as chronic poverty) accumulate during the person’s lifetime and increase disease vulnerability. This duality may be part of the reason for racial and socioeconomic differences in health and disease outcomes. For example, low birth weight is lowest in teen US African American women, but low birth weight increases with advancing maternal age. This is possibly because the older mother has been exposed to more lifetime stressors. On the positive side, there is also data which supports other “critical” times when the offspring may experience environments which help to mitigate these developmental effects. For example, at risk children who experience early positive social experiences have shown some mitigating effects to abnormal stress responses.

Learning Point
Fetal undernutrition has been associated adult problems and diseases such as:

  • Poorer “human capital”
    • Shorter stature
    • Increased obesity/lower lean body mass – small infants become big children/adults
    • Lower cognition
    • Lower academic achievement, work capacity, income
    • Increased stress responses
    • Decreased immune function
  • Increased disease risk
    • Coronary artery disease and mortality
    • Hypertension
    • Diabetes or insulin resistance or glucose intolerance
    • Chronic kidney disease – decreased glomerular filtration
    • Chronic lung disease – decreased lung function
  • Fetal overnutrition
    • Fetal macrosomia
    • Metabolic disease

Questions for Further Discussion
1. What are problems associated with acute malnutrition?
2. How common is food insecurity in your area?
3. What resources are available to provide appropriate nutrition to reproductive age women, children and teens in your area?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Fetal Health and Development

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

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Growth and chronic disease: findings in the Helsinki Birth Cohort.
Ann Hum Biol. 2009 Sep-Oct;36(5):445-58.

Canani RB, Costanzo MD, Leone L, et al.
Epigenetic mechanisms elicited by nutrition in early life.
Nutr Res Rev. 2011 Dec;24(2):198-205.

Fall CH. Fetal malnutrition and long-term outcomes.
Nestle Nutr Inst Workshop Ser. 2013;74:11-25.

Rubin LP. Maternal and pediatric health and disease: integrating biopsychosocial models and epigenetics.
Pediatr Res. 2016 Jan;79(1-2):127-35.

Reichetzeder C, Dwi Putra SE, Li J, Hocher B. Developmental Origins of Disease – Crisis Precipitates Change. Cell Physiol Biochem. 2016;39(3):919-38.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital