Fetal programming

Fetal programming, also known as prenatal programming, is the theory that environmental cues experienced during fetal development play a seminal role in determining health trajectories across the lifespan.

Three main forms of programming that occur due to changes in the maternal environment are:

• Changes in development that lead to greater disease risk;
• Genetic changes which alter disease risk;
• Epigenetic changes which alter disease risk of not only the child but also that of the next generation - i.e. after a famine, grandchildren of women who were pregnant during the famine, are born smaller than the normal size, despite nutritional deficiencies having been fulfilled.

These changes in the maternal environmental can be due to nutritional alteration,^[1] hormonal fluctuations^[2] or exposure to toxins.

History

Dutch famine 1944–45

In 1944–45, the German blockade of the Netherlands led to a lack of food supplies, causing the Dutch famine of 1944–45. The famine caused severe malnutrition among the population, including women in various stages of pregnancy. The Dutch Famine Birth Cohort Study examined the impact of lack of nutrition on children born during or after this famine. It showed that over the course of their life, these children were at greater risk of diabetes, cardiovascular disease, obesity, and other non-communicable diseases.^{[citation needed]}

Barker hypothesis

In the 1980s, David Barker began a research study on this topic. The Barker Hypothesis, or Thrifty phenotype, forms the basis for much of the research conducted on fetal programming. This hypothesis states that if the fetus is exposed to low nutrition, it will adapt to that particular environment. Nutrients are diverted towards the development of the heart, brain, and other essential organs of the fetus. The body also undergoes metabolic alterations that ensure survival in spite of low nutrition but may cause problems in situations with normal or high nutrition.^[3] This leads to increased risk of metabolic syndrome.

Nutritional status

The developing fetus forms an impression of the world into which it will be born via its mother's nutritional status. Its development is thus modulated to create the best chance of survival. However, excessive or insufficient nutrition in the mother can provoke maladaptive developmental responses in the fetus, which in turn manifest in the form of post-natal diseases. It is possible that this has such a profound effect on the fetus’ adult life that it can even outweigh lifestyle factors.^[1]

Excessive nutrition

Body mass index prior to pregnancy and weight gain during pregnancy are both linked to high blood pressure in the offspring during adulthood. Mouse models suggest that this is due to high levels of the fetal hormone leptin, which is present in the blood of individuals that are overweight or obese. There is a theory that this hormone has a negative impact on the regulatory systems of the fetus, and renders it impossible to maintain normal blood pressure levels.^[4]

Insufficient nutrition

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

Hormonal influence

A delicate balance of hormones during pregnancy is regarded as being highly relevant to fetal programming and may significantly influence the outcome on the offspring.^[6] Placental endocrine transfer from the mother to the developing fetus could be altered by the mental state of the mother, due to affected glucocorticoid transfer that takes place across the placenta.^[6]

Thyroid

Thyroid hormones play an instrumental role during the early development of the fetus's brain. Therefore, mothers suffering from thyroid-related issues and altered thyroid hormone levels may inadvertently trigger structural and functional changes in the fetal brain. The fetus is able to produce its own thyroid hormones from the onset of the second trimester; however, maternal thyroid hormones are important for brain development before and after the baby is able to synthesize the hormones while still in the uterus.^[7] Due to this, the baby may experience an increased risk of neurological or psychiatric diseases later in life.^[7]

Cortisol

Cortisol (and glucocorticoids more generally) is the most well studied hormonal mechanism that may have prenatal programming effects.^[8] Although cortisol has normative developmental effects during prenatal development, excess cortisol exposure has deleterious effects on fetal growth,^[9] the postnatal function of physiological systems such as the hypothalamic-pituitary-adrenal axis ^[10] and brain structure or connectivity (eg., amygdala).^[11][12]

During gestation, cortisol concentrations in maternal circulation are up to ten times higher than cortisol concentrations in fetal circulation.^[13] The maternal-to-fetal cortisol gradient is maintained by the placenta, which forms a structural and enzymatic barrier to cortisol.^[14][15] During the first two trimesters of gestation intrauterine cortisol is primarily produced by the maternal adrenal glands.^[16] However, during the third trimester the fetal adrenal glands begin to endogenously produce cortisol and become responsible for most intrauterine cortisol by the time the fetus reaches term.^[16]

Psychological stress and psychopathology

Mental state of the mother during pregnancy affects the fetus in the uterus, predominantly via hormones and genetics.^[17] The mother's mood, including maternal prenatal anxiety, depression and stress during pregnancy correlates with altered outcomes for the child.^[17] That being said, not every fetus exposed to these factors is affected in the same way and to the same degree, and genetic and environmental factors are believed to have a significant degree of influence.^[17]

Depression

Maternal depression poses one of the greatest risks for increased vulnerability to adverse outcomes for a baby that is developing in the uterus, especially in terms of susceptibility to a variety of psychological conditions.^[18] Mechanisms that may explain the connection between maternal depression and the offspring's future health are mostly unclear and form a current area of active research.^[18] Genetic inheritance that may be rendering the child more susceptible may play a role, including the effect on the intrauterine environment for the baby whilst the mother suffers from depression.^[18]

Psychological stress

Maternally experienced psychological stress that occurs either prior to or during gestation can have intergenerational effects on offspring. Stress experienced during gestation has been linked with preterm delivery, low birth weight, and increased risk of psychopathology.^[6] The new mother may suffer from after-effects too, such as postpartum depression, and subsequently may find parenting more difficult as compared to those who did not experience as much stress during their pregnancies.^[6]

Toxins

Toxins such as alcohol, tobacco and certain drugs to which the baby is exposed to during its development are thought to contribute to fetal programming, especially via alterations to the HPA axis.^[19] If the exposure occurs during a critical phase of fetal development, it could have drastic and dire consequences for the fetus.^[19]

Alcohol

Prenatal and/or early postnatal exposure to alcohol (ethanol) has been found to have a negative effect on child's neuroendocrine and behavioral factors.^[20] Alcohol passes through the placenta on being ingested by the mother during her pregnancy, and makes its way to the baby in utero.^[20] Changes posed to the fetus through ethanol exposure may significantly effect growth and development; these are collectively known as fetal alcohol spectrum disorders (FASD).^[20] The exact interaction between ethanol and the developing fetus is complex and largely uncertain, however, several direct and indirect effects have been observed as the fetus matures.^[20] Predominant among these are irregularities in the fetus's endocrine, metabolic and physiological functions.^[20]

Smoking

The negative consequences of smoking are well-known, and these may be even more apparent during pregnancy.^[17] Exposure to tobacco smoke during pregnancy, commonly known as in utero maternal tobacco smoke exposure (MTSE), can contribute towards various problems in babies of smoking mothers.^[17] About 20% of mothers smoke whilst pregnant and this is associated with increased risk of complications, such as preterm birth, decreased fetal growth leading to lower birth weight, and impaired fetal lung development.^[17]

Drugs

There is evidence pointing towards pharmacological programming of the fetus during the first trimester.^[21] One type of drugs which is suspected of influencing the developing baby when used during pregnancy is anti-hypertensive drugs.^[21] Pre-eclampsia (a condition of hypertension during pregnancy), is a serious problem for the majority of pregnant mothers and can predispose the mother to a variety of complications, including increased risk of mortality and problems during parturition.^[21]

References

1. 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. S2CID 22295003.
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. 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. 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. S2CID 32873121.
8. Moisiadis VG, Matthews SG (July 2014). "Glucocorticoids and fetal programming part 2: Mechanisms". Nature Reviews. Endocrinology. 10 (7): 403–11. doi:10.1038/nrendo.2014.74. PMID 24863383. S2CID 11475810.
9. O'Donnell KJ, Meaney MJ (April 2017). "Fetal Origins of Mental Health: The Developmental Origins of Health and Disease Hypothesis". The American Journal of Psychiatry. 174 (4): 319–328. doi:10.1176/appi.ajp.2016.16020138. PMID 27838934.
10. Kapoor A, Petropoulos S, Matthews SG (March 2008). "Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids". Brain Research Reviews. 57 (2): 586–95. doi:10.1016/j.brainresrev.2007.06.013. PMID 17716742. S2CID 30865698.
11. Buss C, Davis EP, Shahbaba B, Pruessner JC, Head K, Sandman CA (May 2012). "Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems". Proceedings of the National Academy of Sciences of the United States of America. 109 (20): E1312-9. doi:10.1073/pnas.1201295109. PMC 3356611. PMID 22529357.
12. Graham AM, Rasmussen JM, Entringer S, Ben Ward E, Rudolph MD, Gilmore JH, et al. (January 2019). "Maternal Cortisol Concentrations During Pregnancy and Sex-Specific Associations With Neonatal Amygdala Connectivity and Emerging Internalizing Behaviors". Biological Psychiatry. 85 (2): 172–181. doi:10.1016/j.biopsych.2018.06.023. PMC 6632079. PMID 30122286.
13. Travers S, Martinerie L, Boileau P, Xue QY, Lombès M, Pussard E (April 2018). "Comparative profiling of adrenal steroids in maternal and umbilical cord blood". The Journal of Steroid Biochemistry and Molecular Biology. 178: 127–134. doi:10.1016/j.jsbmb.2017.11.012. PMID 29191401. S2CID 3705475.
14. Chapman K, Holmes M, Seckl J (July 2013). "11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action". Physiological Reviews. 93 (3): 1139–206. doi:10.1152/physrev.00020.2012. PMC 3962546. PMID 23899562.
15. Stirrat LI, Sengers BG, Norman JE, Homer NZ, Andrew R, Lewis RM, Reynolds RM (February 2018). "Transfer and Metabolism of Cortisol by the Isolated Perfused Human Placenta". The Journal of Clinical Endocrinology and Metabolism. 103 (2): 640–648. doi:10.1210/jc.2017-02140. PMC 5800837. PMID 29161409.
16. Ishimoto H, Jaffe RB (June 2011). "Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit". Endocrine Reviews. 32 (3): 317–55. doi:10.1210/er.2010-0001. PMC 3365797. PMID 21051591.
17. 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.
18. 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. PMC 7040571. PMID 30068416.
19. 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.
20. 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. PMC 8942074. PMID 18266938. S2CID 4574957.
21. 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. S2CID 30016072.

External links

• MRC Lifecourse Epidemiology Unit page at the University of Southampton
• Fetal Programming page on the Centre for Fetal Programming's website.