Fetal programming

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How we are ushered into life determines how we leave.
— Nathanielsz PW. (1999) Life in the Womb: The Origins of Health and Disease, Ithaca, NY, Promethean Press.[1] [also, quoted in[2]]

'Fetal programming', an important component of fetal development, refers to the real-time adaptive anatomical and physiological responses a fetus makes to the intrauterine environmental conditions it experiences while it is living, growing, and organizing itself in its mother's womb. The responses differ in character depending upon whether the environmental condition is beneficial or unfavorable to the viability of the fetus, and depending upon the precise nature of the environmental condition experienced by the fetus. The character of the responses are adaptive for fetal viability, consisting in setting (programming) structural, physiological, and metabolic features of the fetus, hence in the structural, physiological, and metabolic features of the its body after birth.

Thus a fetus's intrauterine environment contributes to the programming of its growth and developing self-organization. When a fetus experiences a suboptimal condition, such as failure of maternal supply of adequate nutrition, the fetus will grow and develop abnormally, resulting in a newborn infant with abnormal structural, metabolic, and physiological characteristics that can increase its susceptibility to disease in later life.[3] [Note 1]

Despite its immature state, a fetus constitutes a living system, a living complex adaptive system. Because it continually grows and self-organizes, it can respond with high sensitivity to environmental conditions; its structural, physiological and metabolic states have a great degree of plasticity. It adapts in real-time to adverse environmental conditions that threaten its viability. Those adaptations might include slowing its growth rate, reducing the number of cells in its organs, altering metabolic pathways, and altering its physiological responses to normal stimuli. If those adaptations serve to maintain the life of the fetus, they will persist throughout the fetus's development and result in an abnormally functioning newborn, persisting throughout childhood, adolescence, and adulthood. If the threatening intrauterine conditions no longer continue after birth, the child or adult may no longer have the ability to adapt to the newer conditions, and as a result, become susceptible to the maladaptations that constitute disease. A fetus adapted to survive to suboptimal nutrition may, in later life, be unable to adapt to conditions of enriched nutrition, responding abnormally.[3] [Note 1]

In effect, the fetus's adaptations 'program' the person it becomes to the responses it makes to its post-natal environment, as an infant and throughout the remainder of its lifetime.

The major, but not exclusive, environmental influences on the type and degree of fetal programming derive from the fetus's maternal connection via the placenta,[4] [5] hence in part from the health status of the mother, both physical and mental.

Overview

In a 2004 review, pioneer of fetal programming phenomena, David Barker, summarized the following as 'key teaching points':[6]

  • Studies have shown an association between low birthweight and risk for cardiovascular diseases and other chronic conditions [e.g., hypertension, stroke, metabolic syndrome, type 2 diabetes] later in life.[Note 2]
  • Developmental plasticity describes the fetuses ability to respond to their mother’s diet in utero.
  • Low birthweight and inadequate nutrition early in life may lead to lifelong alterations in the body’s setting of metabolism and hormones as well as the number of cells in key organs.
  • Low birthweight followed by rapid weight gain during infancy has been shown to further increase risk for disease.


In 2011, University of Columbia reseearchers, Zeltser and Leibel, emphasizing the role of the placenta, note:[7]

Following on the seminal observations of Barker and associates ([cites:[8]]), maternal hormonal and nutrient environment has been systematically implicated in effects on the developing fetus that ultimately influence susceptibility to a wide range of metabolic, neurodevelopmental, and psychiatric diseases in adulthood ([cites:[9] [10]]). There is a growing appreciation that perturbations in the maternal environment are conveyed to the fetus by changes in placental function ([cites:[11]]).[7]

In a more recent review, psychoneuroendocrinologist Sonja Entringer describes fetal programming this way:

Substantial evidence in humans and animals suggests that conditions during intrauterine life play a major role in shaping not only all aspects of fetal development and birth outcomes but also subsequent newborn, child, and adult health outcomes and susceptibility for many of the complex, common disorders that confer the major burden of disease in society (i.e., the concept of fetal, or developmental, origins of health and disease risk) [cites: [12] [13]].[14]

Focusing on pathophysiology, fetal programming also goes by the name, 'fetal origins of adult disease'. From a broader perspective than the pathophysiological, however, the fetus also responds to beneficial intrauterine environments, adapting its metabolism, physiology, and structure to health and lower susceptibility to disease in later life. For one example, in the studies of Barker mentioned above, the babies born with higher birth-weight due to more optimal maternal nutrition had significantly lower risk of developing coronary heart disease than did the lower birth-weight babies.[6]

Recognition of fetal programming led to recognition that the earliest stages of development, including infancy, could respond to environmental conditions in ways that influenced health status in later life, which, in turn, led to a new discipline, The Developmental Origins of Health and Disease.[15] [Note 3] [6]

Postnatal disease types sensitive to fetal programming

Cardiovascular disease

Metabolic disease

Neurodevelopmental disease

Psychiatric disease

Adverse types of fetal environmental conditions promoting fetal programming

Maternal nutritional abnormalities

You are what you eat, and so are your children.[16]

Maternal psychosocial stress

Paternal genetic abnormalities

Maternal hormonal abnormalities

Examples of fetal programming in humans

In 1986, David Barker and Clive Osmond reported on their studies of the relationships among infant mortality, childhood nutrition, and adult ischemic heart disease in England and Wales. By geographical regions, past infant mortality rates, highest where poverty was greatest, associated positively with present occurrences of ischemic heart disease, whereas increasing heart disease presently associated with increasing prosperity. From their analysis the investigators suggested that “poor nutrition in early life increases susceptibility to the effects of an affluent diet”.[17]

Fetal programming applies also to age-related cognitive decline. A long term follow-up study in men by Katri Raikkonen and colleagues showed that lower cognitive ability at mean age 67.9 years associated with lower birth-weight, birth-length, and birth-head-circumference.[18] Similarly, cognitive decline after age 20 years associated with those lower measures of intrauterine physical growth. The investigator found that in "predicting resilience to age related cognitive decline, the period before birth seems to be more critical" compared to the period of infancy.

Examples of fetal programming in non-human animals

In sheep, suboptimal maternal nutrition coincident with early fetal kidney development results in enhanced renal lipid deposition following juvenile obesity and could accelerate the onset of the adverse metabolic, rather than cardiovascular, symptoms accompanying the metabolic syndrome.[19]

Fetal programming response to maternal stress

[20]


Reverse fetal programming: fetal programming of mother

Holding ref: http://www.sciencedaily.com/releases/2012/06/120606155802.htm

References cited in text

  1. Nathanielsz PW. (1999) Life in the Womb: The Origin of Health and Disease. Promethean Press.
  2. Coles CD. What is “Fetal Programming”? | Clicking title opens PDF file.
  3. 3.0 3.1 Godfrey KM, Barker DJP. (2001) Fetal programming and adult health. Public Health Nutrition 4(2B):611-624. | Read Abstract in Notes section.
  4. Godfrey KM. (2002) The Role of the Placenta in Fetal Programming—A Review. Placenta 23, Supplement A, Trophoblast Research, 16, S20–S27. | available online here.
  5. Barker DJ, Thornburg KL. (2013)Placental programming of chronic diseases, cancer and lifespan: A review. Placenta 34:841-5.
  6. 6.0 6.1 6.2 Barker DJ. (2004) The developmental origins of adult disease. J Am Coll.Nutr 23(6 Suppl):5885-5955. | Click title for free access to full text.
  7. 7.0 7.1 Zeltser LM, Leibel RL. (2011) Roles of the placenta in fetal brain development. PNAS 108:15667-15668.
  8. Hales CN, Barker DJ (2001) The thrifty phenotype hypothesis. Br Med Bull 60:5–20.
  9. Fernandez-Twinn DS, Ozanne SE (2010) Early life nutrition and metabolic programming. Ann N Y Acad Sci 1212:78–96.
  10. Bale TL, et al. (2010) Early life programming and neurodevelopmental disorders. Biol Psychiatry 68:314–319.
  11. Jansson T, Powell TL (2007) Role of the placenta in fetal programming: Underlying mechanisms and potential interventional approaches. Clin Sci (Lond) 113:1–13.
  12. Entringer S, Buss C, Wadhwa PD. (2010) Prenatal stress and developmental programming of human health and disease risk: concepts and integration of empirical findings. Curr Opin Endocrinol Diabetes Obes 17:507–516.
  13. Barouki R, Gluckman PD, Grandjean P, et al. (2012) Developmental origins of noncommunicable disease: implications for research and public health. Environ Health 11:42.
  14. Entringer S. (2013) Impact of stress and stress physiology during pregnancy on child metabolic function and obesity risk. Curr Opin Clin Nutr Metab Care 16(3):320-327.
  15. Gillman MW. (2005) Developmental Origins of Health and Disease. ‘’N Engl J Med.’’ October 27; 353(17): 1848–1850. | Read excerpt in Notes section.
  16. Vanhees K, Vonhogen IG, van Schooten FJ, Godschalk RW. (2013) [You are what you eat, and so are your children: the impact of micronutrients on the epigenetic programming of offspring. Cell Mol Life Sci. 2013 Jul 27. [Epub ahead of print].
  17. Barker DJ, Osmond C. (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 10;1(8489):1077-81.
  18. Katri Raikkonen, Eero Kajantie, Anu-Katriina Pesonen, Kati Heinonen, Hanna Alastalo, Jukka T. Leskinen, Kai Nyman, Markus Henriksson, Jari Lahti, Marius Lahti, Riikka Pyhälä, Soile Tuovinen, Clive Osmond, David J. P. Barker,Johan G. Eriksson. (2013) Early Life Origins Cognitive Decline: Findings in Elderly Men in the Helsinki Birth Cohort Study. PLoS ONE 8(1): e54707.
  19. Fainberg HP, Sharkey D, Sebert S et al. (2012) Suboptimal maternal nutrition during early fetal kidney development specifically promotes renal lipid accumulation following juvenile obesity in the offspring. Reprod Fertil Dev [Epub ahead of print, Jul 30]
  20. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. (2008) Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359:61-73.


Notes

  1. 1.0 1.1 Abstract of article by Godfrey KM, Barker DJP. (2001): Low birthweight is now known to be associated with increased rates of coronary heart disease and the related disorders stroke, hypertension and non-insulin dependent diabetes. These associations have been extensively replicated in studies in different countries and are not the result of confounding variables. They extend across the normal range of birthweight and depend on lower birthweights in relation to the duration of gestation rather than the effects of premature birth. The associations are thought to be consequences of `programming', whereby a stimulus or insult at a critical, sensitive period of early life has permanent effects on structure, physiology and metabolism. Programming of the fetus may result from adaptations invoked when the materno-placental nutrient supply fails to match the fetal nutrient demand. Although the influences that impair fetal development and programme adult cardiovascular disease remain to be defined, there are strong pointers to the importance of maternal body composition and dietary balance during pregnancy.
  2. Note...
  3. Excerpt of article by Gillman MW. (2005): At first glance, it may seem implausible that your mother’s exposure to stress or toxins while she was pregnant with you, how she fed you when you were an infant, or how fast you grew during childhood can determine your risk for chronic disease as an adult. Mounting evidence, however, indicates that events occurring in the earliest stages of human development — even before birth — may influence the occurrence of diabetes, cardiovascular disease, asthma, cancers, osteoporosis, and neuropsychiatric disorders.