Foetal programming

Foetal programming is a theory that suggests that the environment of the foetus during development affects their disease risk later in life.

The three main routes of this programming are through maternal environment causing:

  • changes in the development that leads to greater disease risk.
  • genetic changes which alter disease risk.
  • epigenetic changes which alter disease risk of not only their child but their children’s children - i.e. after famine the grandchildren of women pregnant are born smaller than expected even with the return of normal nutrition.

These maternal environmental changes can be through nutritional changes,[1] hormonal changes[2] or exposure to toxins.

History

Dutch famine 1944-45

In 1944-45, a German blockade led to a lack of food supplies in the Netherlands, which later became known as the Dutch famine. This famine meant that the population became severely malnourished, including women in various stages of pregnancy.

The Dutch Famine Birth Cohort Study looked at the effects of this lack of nutrition on the children born during or after this famine. Over the course of their lifetime, it showed that they were at greater risk of diabetes, cardiovascular disease, obesity, and other non-communicable diseases.

Barker Hypothesis

In the 1980’s David Barker began research on this topic. The Barker Hypothesis, or Thrifty phenotype, is the basis for much of the research on foetal programming. This hypothesis stated that if the foetus is exposed to low nutrition it will adapt to that environment. Nutrients are diverted to the heart, brain, and other essential organs. The body also undergoes metabolic alterations that allow for survival with low nutrition but cause problems in normal or high nutrition.[3] This leads to increased risk of developing metabolic syndrome.

Nutritional

The developing foetus gains an impression of the world into which they will be born via its mother’s nutritional status, and its development can be thus modulated to provide it with the best chance of survival. However, excessive or insufficient nutrition in the mother can provoke maladaptive developmental responses in the foetus which present as diseases postnatally. It is possible that has such a profound effect on the foetus’ adult life as to even outweigh lifestyle factors.[1]

Excessive nutrition

BMI prior to pregnancy and weight gain during pregnancy are both linked to high blood pressure in the offspring in adulthood. Mouse models suggest that this is due to high foetal levels of the hormone leptin, which is prevalent in the blood of individuals who are overweight or obese. It is thought that this hormone has a negative impact on regulatory systems in the foetus such that it is impossible to maintain blood pressure within normal limits. [4]

Insufficient nutrition

Pre-eclampsia, involving oxygen deprivation and death of the trophoblastic cells making up most of the placenta, is a disease often associated with the maladaptive long-term consequences of inappropriate foetal programming. Here, a poorly developed and poorly functioning placenta fails to meet the foetus’ nutritional needs during gestation, either by altering its selectivity for nutrients which can cross into foetal blood or restricting total volume thereof. The consequences of this for the foetus in adult life include cardiovascular and metabolic conditions. [5]

Hormonal influence

A delicate balance of hormones during pregnancy is thought highly relevant to foetal programming and may significantly influence offspring outcomes.[6] Placental endocrine transfer to the developing foetus could be altered by the mental state of the mother, due to affected glucocorticoid transfer across the placenta.[6]

Thyroid

Thyroid hormones have an essential role during the early development of the foetus brain; therefore, mothers suffering from thyroid disease and the consequent altered thyroid hormone levels may encourage structural and functional changes to the foetal brain. The foetus is able to produce its own thyroid hormones from the beginning of the second trimester, however, maternal thyroid hormones are important for brain development before and after the baby is able to synthesize the hormones in utero.[7] The baby may experience an increased risk of neurological or psychiatric disease later in their life.[7]

Mental state

The mental state of the mother during pregnancy is able to affect the foetus in utero, predominantly via hormones and genetics.[8] The mother's mood including maternal prenatal anxiety, depression and stress during pregnancy correlates with altered outcomes for the child.[8] Although, not every foetus exposed to these factors is affected in the same way to the same degree, therefore genetic and environmental factors are suspected to significantly influence.[8]

Depression

Maternal depression is one of the greatest risks for increased vulnerability to adverse outcomes for a developing baby in the uterus, in particular susceptibility to a variety of psychological conditions.[9] The mechanisms able to explain the connection between maternal depression and the offspring's future health are mostly unclear and a current area of active research.[9] Genetic inheritance making the child more susceptible may play a role, including the effect on the intrauterine environment for the baby whilst the mother suffers from depression.[9]

Stress

Stress suffered by the mother during pregnancy can have effects to the developing baby including early labour, low birth weight and induce a risk for later psychiatric complications later in life.[6] There are also effects to the mother, such as postpartum depression and consequently, finding new parenting more difficult compared to those who did not experience so much stress during their pregnancy.[6]

Toxins

Toxins such as alcohol, tobacco and certain drugs exposed to the baby during their development are thought to contribute to foetal programming, especially via alterations to the HPA axis.[10] Especially if exposed to during a critical window of foetal development, this is thought to exert most consequence for the foetus.[10]

Alcohol

Prenatal and/or early postnatal exposure to alcohol (ethanol) has been found to exert negative effects on child neuroendocrine and behavioural factors.[11] Alcohol passes through the placenta, through ingestion by the mother during her pregnancy, and is accessed by the baby in utero.[11] the changes posed to the foetus by ethanol exposure may significantly effect growth and development; these disorders constitute foetal alcohol spectrum disorders (FASD).[11] The exact interactions between ethanol and the developing foetus are complex and largely uncertain, however there are thought to be both direct and indirect effects on a developing baby as it develops.[11] Predominant effects are thought to be the foetus' endocrine, metabolic and physiological functions.[11]

Smoking

The negative consequences of smoking are well-known, although the consequences may be even more apparent during pregnancy.[8] Exposure to tobacco smoke during pregnancy, commonly known as in utero maternal tobacco smoke exposure (MTSE), can contribute to the different response of babies of smoking mothers.[8] About 20% of mothers smoke whilst pregnant and this is associated with increased risk of complications, for example, preterm birth, decreased foetal growth leading to decreased birth weight, and impaired lung development of the baby whilst they develop in the womb.[8]

Drugs

There is evidence for pharmacological programming during the first trimester: foetal programming.[12] One such drug type suspected to influence the developing baby are anti-hypertensive drugs used during pregnancy.[12] Pre-eclampsia (a conditional of hypertension during pregnancy), is a serious problems for proportion of pregnant mothers and can predispose the mother to a variety you complications including increased risk of mortality and problems during parturition.[12]

References

  1. 1 2 Fleming TP, Velazquez MA, Eckert JJ, Lucas ES, Watkins AJ (February 2012). "Nutrition of females during the peri-conceptional period and effects on foetal programming and health of offspring". Animal Reproduction Science. 130 (3–4): 193–7. doi:10.1016/j.anireprosci.2012.01.015. PMID 22341375.
  2. ↑ Talge NM, Neal C, Glover V (March 2007). "Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 48 (3–4): 245–61. doi:10.1111/j.1469-7610.2006.01714.x. PMID 17355398.
  3. ↑ Remacle C, Bieswal F, Reusens B (November 2004). "Programming of obesity and cardiovascular disease". International Journal of Obesity and Related Metabolic Disorders. 28 Suppl 3 (S3): S46–53. doi:10.1038/sj.ijo.0802800. PMID 15543219.
  4. ↑ Taylor PD, Samuelsson AM, Poston L (March 2014). "Maternal obesity and the developmental programming of hypertension: a role for leptin". Acta Physiologica. 210 (3): 508–23. doi:10.1111/apha.12223. PMID 24433239.
  5. ↑ Myatt L (April 2006). "Placental adaptive responses and fetal programming". The Journal of Physiology. 572 (Pt 1): 25–30. doi:10.1113/jphysiol.2006.104968. PMC 1779654. PMID 16469781.
  6. 1 2 3 4 Hoffman MC (July 2016). "Stress, the Placenta, and Fetal Programming of Behavior: Genes' First Encounter With the Environment". The American Journal of Psychiatry. 173 (7): 655–7. doi:10.1176/appi.ajp.2016.16050502. PMID 27363547.
  7. 1 2 Andersen SL, Olsen J, Laurberg P (December 2015). "Foetal programming by maternal thyroid disease". Clinical Endocrinology. 83 (6): 751–8. doi:10.1111/cen.12744. PMID 25682985.
  8. 1 2 3 4 5 6 Suter MA, Anders AM, Aagaard KM (January 2013). "Maternal smoking as a model for environmental epigenetic changes affecting birthweight and fetal programming". Molecular Human Reproduction. 19 (1): 1–6. doi:10.1093/molehr/gas050. PMC 3521486. PMID 23139402.
  9. 1 2 3 Davis EP, Hankin BL, Swales DA, Hoffman MC (August 2018). "An experimental test of the fetal programming hypothesis: Can we reduce child ontogenetic vulnerability to psychopathology by decreasing maternal depression?". Development and Psychopathology. 30 (3): 787–806. doi:10.1017/S0954579418000470. PMID 30068416.
  10. 1 2 Bekdash R, Zhang C, Sarkar D (September 2014). "Fetal alcohol programming of hypothalamic proopiomelanocortin system by epigenetic mechanisms and later life vulnerability to stress". Alcoholism, Clinical and Experimental Research. 38 (9): 2323–30. doi:10.1111/acer.12497. PMC 4177357. PMID 25069392.
  11. 1 2 3 4 5 Weinberg J, Sliwowska JH, Lan N, Hellemans KG (April 2008). "Prenatal alcohol exposure: foetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome". Journal of Neuroendocrinology. 20 (4): 470–88. doi:10.1111/j.1365-2826.2008.01669.x. PMID 18266938.
  12. 1 2 3 Bayliss H, Churchill D, Beevers M, Beevers DG (January 2002). "Anti-hypertensive drugs in pregnancy and fetal growth: evidence for "pharmacological programming" in the first trimester?". Hypertension in Pregnancy. 21 (2): 161–74. doi:10.1081/prg-120013785. PMID 12175444.
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