Fetal programming

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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.

Contents

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

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]

Related Research Articles

<span class="mw-page-title-main">Endocrine system</span> Hormone-producing glands of a body

The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems. In humans, the major endocrine glands are the thyroid gland, parathyroid gland, pituitary gland, pineal gland, the testes (male), ovaries (female), and the adrenal glands. The hypothalamus, pancreas, and thymus also function as endocrine glands, among other functions. Other organs, such as the kidneys, also have roles within the endocrine system by secreting certain hormones. The study of the endocrine system and its disorders is known as endocrinology.

<span class="mw-page-title-main">Placenta</span> Organ that connects the fetus to the uterine wall

The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate maternal and fetal circulations, and is an important endocrine organ, producing hormones that regulate both maternal and fetal physiology during pregnancy. The placenta connects to the fetus via the umbilical cord, and on the opposite aspect to the maternal uterus in a species-dependent manner. In humans, a thin layer of maternal decidual (endometrial) tissue comes away with the placenta when it is expelled from the uterus following birth. Placentas are a defining characteristic of placental mammals, but are also found in marsupials and some non-mammals with varying levels of development.

<span class="mw-page-title-main">Hypothalamic–pituitary–adrenal axis</span> Set of physiological feedback interactions

The hypothalamic–pituitary–adrenal axis is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland, and the adrenal glands. These organs and their interactions constitute the HPA axis.

<span class="mw-page-title-main">Pregnancy</span> Time of offspring development in mothers body

Pregnancy is the time during which one or more offspring develops (gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.

Environmental toxicants and fetal development is the impact of different toxic substances from the environment on the development of the fetus. This article deals with potential adverse effects of environmental toxicants on the prenatal development of both the embryo or fetus, as well as pregnancy complications. The human embryo or fetus is relatively susceptible to impact from adverse conditions within the mother's environment. Substandard fetal conditions often cause various degrees of developmental delays, both physical and mental, for the growing baby. Although some variables do occur as a result of genetic conditions pertaining to the father, a great many are directly brought about from environmental toxins that the mother is exposed to.

Prenatal development includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal development until birth.

<span class="mw-page-title-main">Complications of pregnancy</span> Medical condition

Complications of pregnancy are health problems that are related to, or arise during pregnancy. Complications that occur primarily during childbirth are termed obstetric labor complications, and problems that occur primarily after childbirth are termed puerperal disorders. While some complications improve or are fully resolved after pregnancy, some may lead to lasting effects, morbidity, or in the most severe cases, maternal or fetal mortality.

<span class="mw-page-title-main">Nutrition and pregnancy</span> Nutrient intake and dietary planning undertaken before, during and after pregnancy

Nutrition and pregnancy refers to the nutrient intake, and dietary planning that is undertaken before, during and after pregnancy. Nutrition of the fetus begins at conception. For this reason, the nutrition of the mother is important from before conception as well as throughout pregnancy and breastfeeding. An ever-increasing number of studies have shown that the nutrition of the mother will have an effect on the child, up to and including the risk for cancer, cardiovascular disease, hypertension and diabetes throughout life.

Metabolic imprinting refers to the long-term physiological and metabolic effects that an offspring's prenatal and postnatal environments have on them. Perinatal nutrition has been identified as a significant factor in determining an offspring's likelihood of it being predisposed to developing cardiovascular disease, obesity, and type 2 diabetes amongst other conditions.

Prenatal stress is exposure of an expectant mother to psychosocial or physical stress, which can be caused by daily life events or by environmental hardships. This psychosocial or physical stress that the expectant mother is experiencing has an effect on the fetus. According to the Developmental Origins of Health and Disease (DOHaD), a wide range of environmental factors a woman may experience during the perinatal period can contribute to biological impacts and changes in the fetus that then causes health risks later in the child's life.

<span class="mw-page-title-main">Circumvallate placenta</span> Medical condition

Circumvallate placenta is a rare condition affecting about 1-2% of pregnancies, in which the amnion and chorion fetal membranes essentially "double back" on the fetal side around the edges of the placenta. After delivery, a circumvallate placenta has a thick ring of membranes on its fetal surface. Circumvallate placenta is a placental morphological abnormality associated with increased fetal morbidity and mortality due to the restricted availability of nutrients and oxygen to the developing fetus.

<span class="mw-page-title-main">Maternal physiological changes in pregnancy</span>

Maternal physiological changes in pregnancy are the adaptations that take place during pregnancy that enable the accommodation of the developing embryo and fetus. These are normal physiological adaptations that cause changes in behavior, the functioning of the heart, blood vessels, and blood, metabolism including increases in blood sugar levels, kidney function, posture, and breathing. During pregnancy numerous hormones and proteins are secreted that also have a broad range of effects.

<span class="mw-page-title-main">Prenatal nutrition</span>

Prenatal nutrition addresses nutrient recommendations before and during pregnancy. Nutrition and weight management before and during pregnancy has a profound effect on the development of infants. This is a rather critical time for healthy development since infants rely heavily on maternal stores and nutrient for optimal growth and health outcome later in life.

Prenatal memory, also called fetal memory, is important for the development of memory in humans. Many factors can impair fetal memory and its functions, primarily maternal actions. There are multiple techniques available not only to demonstrate the existence of fetal memory but to measure it. Fetal memory is vulnerable to certain diseases so much so that exposure can permanently damage the development of the fetus and even terminate the pregnancy by aborting the fetus. Maternal nutrition and the avoidance of drugs, alcohol and other substances during all nine months of pregnancy is important to the development of the fetus and its memory systems. The use of certain substances can entail long-term permanent effects on the fetus that can carry on throughout their lifespan.

<span class="mw-page-title-main">High-risk pregnancy</span> Medical condition

A high-risk pregnancy is one where the mother or the fetus has an increased risk of adverse outcomes compared to uncomplicated pregnancies. No concrete guidelines currently exist for distinguishing “high-risk” pregnancies from “low-risk” pregnancies; however, there are certain studied conditions that have been shown to put the mother or fetus at a higher risk of poor outcomes. These conditions can be classified into three main categories: health problems in the mother that occur before she becomes pregnant, health problems in the mother that occur during pregnancy, and certain health conditions with the fetus.

The fetal endocrine system is one of the first systems to develop during prenatal development of a human individual. The endocrine system arises from all three embryonic germ layers. The endocrine glands that produce the steroid hormones, such as the gonads and adrenal cortex, arise from the mesoderm. In contrast, endocrine glands that arise from the endoderm and ectoderm produce the amine, peptide, and protein hormones.

The fetal origins hypothesis proposes that the period of gestation has significant impacts on the developmental health and wellbeing outcomes for an individual ranging from infancy to adulthood. The effects of fetal origin are marked by three characteristics: latency, wherein effects may not be apparent until much later in life; persistency, whereby conditions resulting from a fetal effect continue to exist for a given individual; and genetic programming, which describes the 'switching on' of a specific gene due to prenatal environment. Research in the areas of economics, epidemiology, and epigenetics offer support for the hypothesis.

<span class="mw-page-title-main">Medical imaging in pregnancy</span> Types of pregnancy imaging techniques

Medical imaging in pregnancy may be indicated because of pregnancy complications, intercurrent diseases or routine prenatal care.

Maternal fetal stress transfer is a physiological phenomenon in which psychosocial stress experienced by a mother during her pregnancy can be transferred to the fetus. Psychosocial stress describes the brain's physiological response to perceived social threat. Because of a link in blood supply between a mother and fetus, it has been found that stress can leave lasting effects on a developing fetus, even before a child is born. According to recent studies, these effects are mainly the result of two particular stress biomarkers circulating in the maternal blood supply: cortisol and catecholamines.

COVID-19 impact on pregnant women is the prenatal maternal stress that COVID-19 places the fetus and on the expectant mother. This impact can include psychosocial or physical stress caused by daily life events or by environmental hardships. Mental health issues, such as maternal depression, affect 10-20% of women and are linked to a variety of negative child outcomes. Prenatal stress has been demonstrated to affect the critical development stages in postnatal life that persist throughout adulthood. Health risks include impaired cognitive development, low birth weight, and risk of mental disorders in the offspring. Epigenetics may also be associated with the biological processes involved in prenatal stress, possibly leading to fetal programming.

References

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  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.
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  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. 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.
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  17. 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.
  18. 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. PMC   7040571 . PMID   30068416.
  19. 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.
  20. 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. PMC   8942074 . PMID   18266938. S2CID   4574957.
  21. 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. S2CID   30016072.
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