Fetal programming: Difference between revisions

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{{Short description|Theory that suggests environmental factors during fetal development affect disease risks}}

{{copy edit|date=November 2018}}

'''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.

'''Fetal programming''' is a theory which suggests that the environment surrounding the fetus during its developmental phase plays a seminal role in determining its disease risk during the later stages.

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 whichthat alter disease risk;

* [[Epigenetics|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,<ref name = "Fleming_2012">{{cite journal | vauthors = Fleming TP, Velazquez MA, Eckert JJ, Lucas ES, Watkins AJ | title = Nutrition of females during the peri-conceptional period and effects on foetal programming and health of offspring | journal = Animal Reproduction Science | volume = 130 | issue = 3–4 | pages = 193–7 | date = February 2012 | pmid = 22341375 | doi = 10.1016/j.anireprosci.2012.01.015 }}</ref> hormonal fluctuations<ref>{{cite journal | vauthors = Talge NM, Neal C, Glover V | title = Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | volume = 48 | issue = 3–4 | pages = 245–61 | date = March 2007 | pmid = 17355398 | doi = 10.1111/j.1469-7610.2006.01714.x | pmc = 11016282 }}</ref> or exposure to toxins.

== History ==

=== Dutch famine 1944–45 ===

In 1944-451944–45, settingthe upGerman blockade of Germanthe blockadeNetherlands led to a lack of food supplies in the [[Netherlands]], which later was described ascausing the [[Dutch famine of 1944–45|Dutch famine]]. OccurrenceThe offamine thiscaused faminesevere ledmalnutrition toamong the population -, including women in various stages of pregnancy - suffering from severe malnutrition. 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 ofthroughout their lifetimelife, Thesethese children were at greater risk of suffering from[[Diabetes mellitus|diabetes]], [[cardiovascular disease]], [[obesity]], and other [[non-communicable diseasesdisease]]s.{{citation needed|date=April 2023}}

=== DutchBarker famine 1944-45hypothesis ===

In the 1980’s1980s, [[David Barker (epidemiologist)|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 ofdeveloping heart, brain, and other essential fetal organs of the fetus. The body also undergoes metabolic alterations that ensure survival in spite ofdespite low nutrition but may cause problems in situations with normal or high nutrition.<ref>{{cite journal | vauthors = Remacle C, Bieswal F, Reusens B | title = Programming of obesity and cardiovascular disease | journal = International Journal of Obesity and Related Metabolic Disorders | volume = 28 Suppl 3 | issue = S3 | pages = S46–53S46-53 | date = November 2004 | pmid = 15543219 | doi = 10.1038/sj.ijo.0802800 | doi-access = free }}</ref> This leads to increased risk of developing [[metabolic syndrome]].

In 1944-45, setting up of German blockade led to lack of food supplies in the [[Netherlands]], which later was described as the [[Dutch famine of 1944–45|Dutch famine]]. Occurrence of this famine led to the population - including women in various stages of pregnancy - suffering from severe malnutrition. 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 lifetime, These children were at greater risk of suffering from diabetes, cardiovascular disease, obesity, and other non-communicable diseases.

=== BarkerNutritional Hypothesisstatus ===

The developing fetus forms an impression of the world into which it will be born via its mother’smother's nutritional status, and. itsIts 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 canin turn manifest in the form of post-natal diseases. It is possible thatThis thismay hashave such a profound effect on the fetus’fetus’s adult life that it can even outweigh lifestyle factors.<ref name = "Fleming_2012" />

In the 1980’s [[David Barker (epidemiologist)|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 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.<ref>{{cite journal | vauthors = Remacle C, Bieswal F, Reusens B | title = Programming of obesity and cardiovascular disease | journal = International Journal of Obesity and Related Metabolic Disorders | volume = 28 Suppl 3 | issue = S3 | pages = S46–53 | date = November 2004 | pmid = 15543219 | doi = 10.1038/sj.ijo.0802800 }}</ref> This leads to increased risk of developing [[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, and 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 can manifest in 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.<ref name = "Fleming_2012" />

=== Excessive nutrition ===

BMI[[Body priormass toindex]] before 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 thatwho are overweight or obese. There is a theory that this hormone hashurts a negative impact onthe regulatory systems of the fetus, and renders it impossible to maintain normal blood pressure levels. <ref>{{cite journal | vauthors = Taylor PD, Samuelsson AM, Poston L | title = Maternal obesity and the developmental programming of hypertension: a role for leptin | journal = Acta Physiologica | volume = 210 | issue = 3 | pages = 508–23 | date = March 2014 | pmid = 24433239 | doi = 10.1111/apha.12223 | s2cid = 22295003 | doi-access = free }}</ref>

=== Insufficient nutrition ===

[[Pre-eclampsia]], involving oxygen deprivation and death of the [[Trophoblast|trophoblastic cells]] makingthat make up most of the placenta, is a disease which is often associated with the maladaptive long-term consequences of inappropriate foetalfetal programming. Here, aan poorlyinadequately developed and poorly functioning placenta fails to meet the foetus’fetus’s nutritional needs during gestation, either by altering its selectivityselection for nutrients whichthat can cross into foetalfetal blood or restricting total volume thereof. The consequencesConsequences of this for the foetusfetus in adult life include cardiovascular and metabolic conditions. <ref>{{cite journal | vauthors = Myatt L | title = Placental adaptive responses and fetal programming | journal = The Journal of Physiology | volume = 572 | issue = Pt 1 | pages = 25–30 | date = April 2006 | pmid = 16469781 | pmc = 1779654 | doi = 10.1113/jphysiol.2006.104968 }}</ref>

== Hormonal influence ==

A delicate balance of hormones during pregnancy is thoughtregarded as highly relevant to foetalfetal programming and may significantly influence offspringthe outcomesoutcome of the offspring.<ref name="Hoffman_2016">{{cite journal | vauthors = Hoffman MC | title = Stress, the Placenta, and Fetal Programming of Behavior: Genes' First Encounter With the Environment | journal = The American Journal of Psychiatry | volume = 173 | issue = 7 | pages = 655–7 | date = July 2016 | pmid = 27363547 | doi = 10.1176/appi.ajp.2016.16050502 | doi-access = free }}</ref> Placental endocrine transfer from the mother to the developing foetusfetus could be altered by the mental state of the mother, due to affected [[glucocorticoid]] transfer that takes place across the placenta.<ref name="Hoffman_2016" />

=== Thyroid ===

Thyroid hormones haveplay an essentialinstrumental role during the early development of the foetusfetus's brain;. thereforeTherefore, mothers suffering from thyroid-related diseaseissues and the consequent altered thyroid hormone levels may encourageinadvertently trigger structural and functional changes toin the foetalfetal brain. The foetusfetus is able tocan produce its own thyroid hormones from the beginningonset of the second trimester,; however, maternal thyroid hormones are important for brain development before and after the baby is able tocan synthesize the hormones while still in uterothe uterus.<ref name="Andersen_2016">{{cite journal | vauthors = Andersen SL, Olsen J, Laurberg P | title = Foetal programming by maternal thyroid disease | journal = Clinical Endocrinology | volume = 83 | issue = 6 | pages = 751–8 | date = December 2015 | pmid = 25682985 | doi = 10.1111/cen.12744 | s2cid = 32873121 | doi-access = free }}</ref> TheDue to this, the baby may experience an increased risk of neurological or psychiatric diseasediseases later in their life.<ref name="Andersen_2016" />

=== Mental stateCortisol ===

Cortisol (and glucocorticoids more generally) is the most well-studied hormonal mechanism that may have prenatal programming effects.<ref>{{cite journal | vauthors = Moisiadis VG, Matthews SG | title = Glucocorticoids and fetal programming part 2: Mechanisms | journal = Nature Reviews. Endocrinology | volume = 10 | issue = 7 | pages = 403–11 | date = July 2014 | pmid = 24863383 | doi = 10.1038/nrendo.2014.74 | s2cid = 11475810 }}</ref> Although cortisol has normative developmental effects during prenatal development, excess cortisol exposure has deleterious effects on fetal growth,<ref>{{cite journal | vauthors = O'Donnell KJ, Meaney MJ | title = Fetal Origins of Mental Health: The Developmental Origins of Health and Disease Hypothesis | journal = The American Journal of Psychiatry | volume = 174 | issue = 4 | pages = 319–328 | date = April 2017 | pmid = 27838934 | doi = 10.1176/appi.ajp.2016.16020138 | doi-access = free }}</ref> the postnatal function of physiological systems such as the hypothalamic-pituitary-adrenal axis <ref>{{cite journal | vauthors = Kapoor A, Petropoulos S, Matthews SG | title = Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids | journal = Brain Research Reviews | volume = 57 | issue = 2 | pages = 586–95 | date = March 2008 | pmid = 17716742 | doi = 10.1016/j.brainresrev.2007.06.013 | s2cid = 30865698 }}</ref> and brain structure or connectivity (e.g., amygdala).<ref>{{cite journal | vauthors = Buss C, Davis EP, Shahbaba B, Pruessner JC, Head K, Sandman CA | title = Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 20 | pages = E1312-9 | date = May 2012 | pmid = 22529357 | pmc = 3356611 | doi = 10.1073/pnas.1201295109 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Graham AM, Rasmussen JM, Entringer S, Ben Ward E, Rudolph MD, Gilmore JH, Styner M, Wadhwa PD, Fair DA, Buss C | display-authors = 6 | title = Maternal Cortisol Concentrations During Pregnancy and Sex-Specific Associations With Neonatal Amygdala Connectivity and Emerging Internalizing Behaviors | journal = Biological Psychiatry | volume = 85 | issue = 2 | pages = 172–181 | date = January 2019 | pmid = 30122286 | pmc = 6632079 | doi = 10.1016/j.biopsych.2018.06.023 }}</ref>

The mental state of the mother during pregnancy is able to affect the foetus in utero, predominantly via hormones and genetics.<ref name="Suter_2013">{{cite journal | vauthors = Suter MA, Anders AM, Aagaard KM | title = Maternal smoking as a model for environmental epigenetic changes affecting birthweight and fetal programming | journal = Molecular Human Reproduction | volume = 19 | issue = 1 | pages = 1–6 | date = January 2013 | pmid = 23139402 | pmc = 3521486 | doi = 10.1093/molehr/gas050 }}</ref> The mother's mood including maternal prenatal anxiety, depression and stress during pregnancy correlates with altered outcomes for the child.<ref name="Suter_2013" /> 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.<ref name="Suter_2013" />

During gestation, cortisol concentrations in maternal circulation are up to ten times higher than cortisol concentrations in fetal circulation.<ref>{{cite journal | vauthors = Travers S, Martinerie L, Boileau P, Xue QY, Lombès M, Pussard E | title = Comparative profiling of adrenal steroids in maternal and umbilical cord blood | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 178 | pages = 127–134 | date = April 2018 | pmid = 29191401 | doi = 10.1016/j.jsbmb.2017.11.012 | s2cid = 3705475 }}</ref> The maternal-to-fetal cortisol gradient is maintained by the placenta, which forms a structural and enzymatic barrier to cortisol.<ref>{{cite journal | vauthors = Chapman K, Holmes M, Seckl J | title = 11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action | journal = Physiological Reviews | volume = 93 | issue = 3 | pages = 1139–206 | date = July 2013 | pmid = 23899562 | pmc = 3962546 | doi = 10.1152/physrev.00020.2012 }}</ref><ref>{{cite journal | vauthors = Stirrat LI, Sengers BG, Norman JE, Homer NZ, Andrew R, Lewis RM, Reynolds RM | title = Transfer and Metabolism of Cortisol by the Isolated Perfused Human Placenta | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 2 | pages = 640–648 | date = February 2018 | pmid = 29161409 | pmc = 5800837 | doi = 10.1210/jc.2017-02140 }}</ref> During the first two trimesters of gestation intrauterine cortisol is primarily produced by the maternal adrenal glands.<ref name="Development and function of the hum">{{cite journal | vauthors = Ishimoto H, Jaffe RB | title = Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit | journal = Endocrine Reviews | volume = 32 | issue = 3 | pages = 317–55 | date = June 2011 | pmid = 21051591 | pmc = 3365797 | doi = 10.1210/er.2010-0001 }}</ref> 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.<ref name="Development and function of the hum"/>

==== 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.<ref name="Davis_2018">{{cite journal | vauthors = Davis EP, Hankin BL, Swales DA, Hoffman MC | title = An experimental test of the fetal programming hypothesis: Can we reduce child ontogenetic vulnerability to psychopathology by decreasing maternal depression? | journal = Development and Psychopathology | volume = 30 | issue = 3 | pages = 787–806 | date = August 2018 | pmid = 30068416 | doi = 10.1017/S0954579418000470 }}</ref> 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.<ref name="Davis_2018" /> 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.<ref name="Davis_2018" />

== Psychological stress and psychopathology ==

==== Stress ====

The mentalMental state of the mother during pregnancy isaffects ablethe tofetus affectin the foetus in uterouterus, predominantly via hormones and genetics.<ref name="Suter_2013">{{cite journal | vauthors = Suter MA, Anders AM, Aagaard KM | title = Maternal smoking as a model for environmental epigenetic changes affecting birthweight and fetal programming | journal = Molecular Human Reproduction | volume = 19 | issue = 1 | pages = 1–6 | date = January 2013 | pmid = 23139402 | pmc = 3521486 | doi = 10.1093/molehr/gas050 }}</ref> The mother's mood, including maternal prenatal anxiety, depression and stress during pregnancy correlates with altered outcomes for the child.<ref name="Suter_2013" /> AlthoughThat being said, not every foetusfetus exposed to these factors is affected in the same way and to the same degree, thereforeand genetic and environmental factors are suspectedbelieved to significantlyhave a significant degree of influence.<ref name="Suter_2013" />

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.<ref name="Hoffman_2016" /> 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.<ref name="Hoffman_2016" />

==== Depression ====

Maternal depression isposes one of the greatest risks for increased vulnerability to adverse outcomes for a developing baby that is developing in the uterus, especially in particularterms of susceptibility to a variety of psychological conditions.<ref name="Davis_2018">{{cite journal | vauthors = Davis EP, Hankin BL, Swales DA, Hoffman MC | title = An experimental test of the fetal programming hypothesis: Can we reduce child ontogenetic vulnerability to psychopathology by decreasing maternal depression? | journal = Development and Psychopathology | volume = 30 | issue = 3 | pages = 787–806 | date = August 2018 | pmid = 30068416 | pmc = 7040571 | doi = 10.1017/S0954579418000470 }}</ref> TheMechanisms mechanismsthat able tomay explain the connection between maternal depression and the offspring's future health are mostly unclear and form a current area of active research.<ref name="Davis_2018" /> Genetic inheritance makingthat 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.<ref name="Davis_2018" />

=== Psychological stress ===

StressMaternally sufferedexperienced bypsychological thestress motherthat occurs either before or during pregnancygestation can have intergenerational effects toon offspring. Stress experienced during gestation thehas developingbeen babylinked includingwith earlypreterm labourdelivery, low birth weight, and induce aincreased risk for laterof psychiatric complications later in lifepsychopathology.<ref name="Hoffman_2016" /> ThereThe arenew alsomother effectsmay tosuffer thefrom motherafter-effects too, such as postpartum depression, and consequently,subsequently findingmay newfind parenting more difficult as compared to those who did not experience soas much stress during their pregnancypregnancies.<ref name="Hoffman_2016" />

== Toxins ==

Toxins such as alcohol, tobacco, and certain drugs exposed to which the baby is exposed during theirits development are thought to contribute to foetalfetal programming, especially via alterations to the HPA axis.<ref name="Bekdash_2014">{{cite journal | vauthors = Bekdash R, Zhang C, Sarkar D | title = Fetal alcohol programming of hypothalamic proopiomelanocortin system by epigenetic mechanisms and later life vulnerability to stress | journal = Alcoholism,: Clinical and Experimental Research | volume = 38 | issue = 9 | pages = 2323–30 | date = September 2014 | pmid = 25069392 | pmc = 4177357 | doi = 10.1111/acer.12497 }}</ref> EspeciallyIf ifthe exposedexposure tooccurs during a critical windowphase of foetalfetal development, thisit iscould thoughthave todrastic exertand mostdire consequenceconsequences for the foetusfetus.<ref name="Bekdash_2014" />

=== Alcohol ===

Prenatal and/or early postnatal exposure to alcohol (ethanol) has been found to exerthurt negative effects ona child's neuroendocrine and behaviouralbehavioral factors.<ref name="Weinberg_2008">{{cite journal | vauthors = Weinberg J, Sliwowska JH, Lan N, Hellemans KG | title = Prenatal alcohol exposure: foetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome | journal = Journal of Neuroendocrinology | volume = 20 | issue = 4 | pages = 470–88 | date = April 2008 | pmid = 18266938 | doi = 10.1111/j.1365-2826.2008.01669.x | pmc = 8942074 | s2cid = 4574957 }}</ref> Alcohol passes through the placenta, throughon being ingestioningested by the mother during her pregnancy, and ismakes accessedits byway to the baby ''in utero''.<ref name="Weinberg_2008" /> the changesChanges posed to the foetusfetus bythrough ethanol exposure may significantly effect growth and development; these disordersare constitutecollectively foetalknown as fetal alcohol spectrum disorders (FASD).<ref name="Weinberg_2008" /> The exact interactionsinteraction between ethanol and the developing foetusfetus areis complex and largely uncertain, however, there are thought to be bothseveral direct and indirect effects onhave abeen developing babyobserved as itthe fetus developsmatures.<ref name="Weinberg_2008" /> Predominant effectsamong these are thoughtirregularities to bein the foetusfetus's endocrine, metabolic, and physiological functions.<ref name="Weinberg_2008" />

=== Smoking ===

The negative consequences of [[smoking]] are well-known, although theand consequencesthese may be even more apparent during pregnancy.<ref name="Suter_2013" /> Exposure to tobacco smoke during pregnancy, commonly known as ''in utero'' maternal tobacco smoke exposure (MTSE), can contribute totowards thevarious differentproblems response ofin babies of smoking mothers.<ref name="Suter_2013" /> About 20% of mothers smoke whilst pregnant and this is associated with increased risk of complications, forsuch example,as preterm birth, decreased foetalfetal growth leading to decreasedlower birth weight, and impaired fetal lung development of the baby whilst they develop in the womb.<ref name="Suter_2013" />

=== Drugs ===

There is evidence forpointing towards pharmacological programming of the fetus during the first trimester: foetal programming.<ref name="Bayliss_2002">{{cite journal | vauthors = Bayliss H, Churchill D, Beevers M, Beevers DG | title = Anti-hypertensive drugs in pregnancy and fetal growth: evidence for "pharmacological programming" in the first trimester? | journal = Hypertension in Pregnancy | volume = 21 | issue = 2 | pages = 161–74 | date = January 2002 | pmid = 12175444 | doi = 10.1081/prg-120013785 | s2cid = 30016072 }}</ref> One suchtype drugof typedrugs which is suspected toof influenceinfluencing the developing baby are anti-hypertensive drugswhen used during pregnancy is anti-hypertensive drugs.<ref name="Bayliss_2002" /> Pre-eclampsia (a conditionalcondition of hypertension during pregnancy), is a serious problemsproblem for the proportionmajority of pregnant mothers and can predispose the mother to a variety youof complications, including increased risk of mortality and problems during parturition.<ref name="Bayliss_2002" />

== References ==

{{Reflist}}

<references />

== External Links ==

== External Linkslinks ==

* [https://www.southampton.ac.uk/populationhealth/research/mrc_lifecourse_epidemiology.page MRC Lifecourse Epidemiology Unit page at the University of Southampton]

* [https://www.cfp-research.com/About%20CFP/About%20fetal%20programming.aspx Fetal Programming page on the Centre for Fetal Programming's website.]