Fetal programming

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Fetal programming , also known as fetal programming , is a research area that deals with the influence of prenatal factors on the health of the offspring in later phases of life. A hereditary predisposition to certain health disorders due to epigenetics is even discussed. These include in particular:

  • Changes in development that lead to an increased risk of disease
  • Genetic changes that have an impact on disease risks
  • Epigenetic changes that affect future generations

Changes in the prenatal environment can be due to nutritional conditions, hormonal fluctuations or the influence of poisons (e.g. drugs or alcohol).

Research history

Dutch Famine Birth Cohort Study (about descendants of the Hongerwinter from 1944-45)

The first observations on the phenomenon of fetal programming were made in Dutch children and later adults whose mothers were pregnant during the winter of 1944–45. The German blockade had led to a pronounced shortage of food in the Netherlands and triggered the Dutch hunger winter (Hongerwinter) of 1944–45 . The extreme shortage of food has resulted in severe malnutrition in the general population. Pregnant women in different phases of pregnancy were also affected. The Dutch Famine Birth Cohort study later looked at the impact of food shortages on children born during or shortly after the famine.

It is clear that these children often had a lower birth weight and later in life suffered significantly more often from diabetes , overweight and cardiovascular diseases (e.g. coronary heart disease ). In the course of subsequent studies, it became clear that these children had inherited the tendency to develop these diseases as adults: even the grandchildren of women who were pregnant during starvation were smaller than other babies at birth - although their mothers were not during pregnancy suffered from lack of food.

Barker's hypothesis

In the 1980s, the British epidemiologist David Barker began further research on the results of the Dutch Famine Birth Cohort study. Based on his observations, he formulated the hypothesis of the "Thrifty Phenotypes", also known as the "Barker Hypothesis". Today it is the basis of research on fetal programming. The Barker hypothesis states that a fetus suffering from a lack of food adapts itself to the corresponding development. The existing nutrients are primarily made available to the heart, brain and other essential organs. The metabolic changes at this point are useful for survival - but can lead to problems if the lack of food is eliminated or if there is even an abundance of food. Adults with this metabolic setting therefore suffer from an increased risk of developing metabolic syndrome .

Influencing factors in pregnancy

Various influencing factors in pregnancy have already been investigated in retrospective and prospective studies on fetal programming. The effects of undernourishment and overeating of the fetus during pregnancy are best documented. Hormonal fluctuations during pregnancy can also affect the mental and physical health of the offspring. In the meantime, however, a large number of factors such as alcohol, medication, vitamin supplements and artificial sweeteners have been examined for their prenatal influence, often with unclear results.

Malnutrition / malnutrition

Malnutrition and malnutrition in the mother lead to intrauterine growth retardation and a low birth weight in the fetus. This in turn increases the risk of developing diabetes, high blood pressure, obesity, and other cardiovascular and metabolic diseases later in life. Famines are extremely rare in industrialized nations these days - but maternal malnutrition can certainly occur in connection with eating disorders such as anorexia .

Placental dysfunction (such as occur in preeclampsia) can lead to a lack of nutrients in the fetus and thus also have a negative impact on its later metabolic health.

Overeating / obesity during pregnancy

An oversupply of food during pregnancy can also lead to risks similar to malnutrition and malnutrition. In addition to the diet during pregnancy, the mother's BMI before conception is decisive for the risk of the offspring . The mechanism behind the increased risk is possibly an increased release of the fetal hormone leptin . According to the theory, leptin has a negative influence on the regulatory functions of the fetus and thus increases the later risk of developing high blood pressure.

Thyroid dysfunction

Thyroid hormones play an important role in the development of the fetal brain. Altered thyroid hormones in mothers who suffer from thyroid dysfunction (e.g. Hashimoto's thyroiditis ) can also have an impact on the baby's brain development. From around the 2nd trimester the fetus is able to produce thyroid hormones itself - in the 1st trimester, however, it is dependent on a supply from the mother. An insufficient supply of thyroid hormones in this phase can have an impact on the later psychiatric health of the offspring. The risk of seizures, ADHD and autism is also increased.

alcohol

Alcohol can cross the mother's placental barrier and therefore reach the unborn child via the umbilical cord. Excessive alcohol consumption by the mother (4–5 units per day) during pregnancy can lead to the development of a fetal alcohol syndrome. The exact mechanism by which alcohol disrupts fetal development is not fully understood. However, even lower amounts of alcohol are probably harmful during pregnancy, which is why pregnant women are generally completely advised against alcohol consumption.

Studies on fetal programming came to the conclusion that even one serving of alcohol per day during early pregnancy (1st trimester) significantly increases the risk that the offspring will consume more alcohol themselves in young adulthood. Alcohol has a far-reaching influence on the neuroendocrine development and behavior of the child.

Smoke

Less known than the harmful effects of alcohol on pregnancy is the link between smoking and its negative effects on the fetus. Smoking during pregnancy can lead to intrauterine growth retardation , prematurity and lower birth weight. But even after childbirth, fetal programming causes further damage from the influence of tobacco during pregnancy. Both the increased risk of sudden infant death syndrome and the development of asthma, metabolic syndrome and behavioral disorders in later adult life are well-founded, scientific evidence.

Medication

Antihypertensive drugs

Certain drugs such as antihypertensive drugs are suspected of being able to trigger "pharmacological" programming of the fetus. This relationship is particularly relevant because high blood pressure occurs in up to 10% of pregnancies and is therefore one of the most common pregnancy complications. Since high blood pressure can develop into potentially life-threatening preeclampsia during pregnancy , women with gestational hypertension are often treated with antihypertensive drugs.

Corticosteroids

In particular, studies on fetal programming focus on corticosteroids such as betamethasone . The data situation is not yet clear regarding the effects on the later health of the offspring; prenatal exposure to cortisone can lead to hyperactivity in children. However, single doses, such as those given in the context of promoting lung development in the case of impending premature births, have no influence on later cognitive performance and psychiatric health.

Diethylstilbestrol

The synthetic estrogen diethylstilbestrol was taken by many pregnant women, especially in 1950 and 1960. There appears to be a connection with the risk of breast cancer in female offspring.

Conditions / clinical pictures with a possible connection to fetal programming

Scientists have already been able to establish connections between the most varied of influences during pregnancy and a large number of common diseases of civilization.

Metabolic syndrome

As metabolic syndrome , the combination of diabetes, obesity and high blood pressure is called. David Barker was the first physician to study the influence of fetal factors on low birth weight and the connection with later cardiovascular diseases. Numerous epidemiological studies have since shown that there is a connection between prenatal influencing factors and the later development of diabetes, obesity, high blood pressure and thus metabolic syndrome.

In offspring of mothers who suffered from gestational diabetes during pregnancy , the risk of developing diabetes is increased by a factor of 3.6. The mechanism behind this is now also known: the excessive supply of glucose in the mother's blood activates beta cells in the pancreas of the fetus. After birth, there is no overstimulation from maternal glucose and there is reduced insulin secretion and thus reduced glucose tolerance.

Schizophrenia and other psychiatric illnesses

The mental status of the mother during pregnancy has a decisive influence on the later mental health of the child, this effect is probably mediated by hormones. Maternal depression as well as stressful states and PTSD are suspected of having a long-term negative effect on the health of the offspring and possibly causing epigenetic changes. In particular, the risk for the offspring of developing schizophrenia later is related to various prenatal influences.

Polycystic ovaries (polycystic ovary syndrome)

The Polycystic ovary syndrome is a disorder that affects 5-15% of women of childbearing age and is associated with menstrual irregularities. The cause of polycystic ovarian syndrome is not clear, but some studies have since investigated that prenatal influences (particularly an excess of androgens) can have an influence on the later development of the disease in female offspring. In a retrospective study, it was found that women who suffered from polycystic ovaries had a higher birth weight on average and were more likely to be born to overweight mothers.

Cancer (breast cancer, testicular cancer, brain tumors)

Initial evidence suggests that fetal programming has an impact on the risk of developing breast cancer or testicular cancer later. There also seems to be a connection with a higher birth weight for childhood brain tumors. For other types of cancer, the results are currently ambiguous.

In Vitro Fertilization and Fetal Programming

Studies on in vitro fertilization and fetal programming came to the conclusion that perconceptional differences already have an influence on the later health of offspring. For example, the bone age of girls (but not boys) who were conceived by in vitro fertilization is increased in adolescence and they have higher LH and DHEAS values. Blood pressure and fasting glucose values ​​were also different in adolescents who were conceived by artificial insemination.

Individual evidence

  1. ^ TP Fleming, MA Velazquez, JJ Eckert, ES Lucas, AJ Watkins: Nutrition of females during the peri-conceptional period and effects on foetal programming and health of offspring . In: Animal Reproduction Science . tape 130 , no. 3–4 , February 2012, pp. 193-7 , doi : 10.1016 / j.anireprosci.2012.01.015 , PMID 22341375 .
  2. ^ NM Talge, C. Neal, V. Glover: Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? In: Journal of Child Psychology and Psychiatry, and Allied Disciplines . tape 48 , no. 3–4 , March 2007, pp. 245-61 , doi : 10.1111 / j.1469-7610.2006.01714.x , PMID 17355398 .
  3. ↑ a b Lidush Goldschmidt, Gale A. Richardson, Natacha M. De Genna, Marie D. Cornelius, Nancy L. Day: Prenatal alcohol exposure and offspring alcohol use and misuse at 22 years of age: A prospective longitudinal study . In: Neurotoxicology and Teratology . tape 71 , January 2019, p. 1–5 , doi : 10.1016 / j.ntt.2018.11.001 , PMID 30399401 , PMC 6330135 (free full text) - ( online [accessed on July 9, 2020]).
  4. ^ C. Nicholas Hales, David JP Barker: The thrifty phenotype hypothesis . In: British Medical Bulletin . tape 60 , no. 1 , November 1, 2001, ISSN  1471-8391 , p. 5–20 , doi : 10.1093 / bmb / 60.1.5 ( online [accessed on July 9, 2020]).
  5. ↑ C. Remacle, F. Bieswal, B. Reusens: Programming of obesity and cardiovascular disease . In: International Journal of Obesity and Related Metabolic Disorders . 28 Suppl 3, S3, November 2004, p. S46-53 , doi : 10.1038 / sj.ijo.0802800 , PMID 15543219 .
  6. ^ A b Hoffman MC: Stress, the Placenta, and Fetal Programming of Behavior: Genes' First Encounter With the Environment . In: The American Journal of Psychiatry . tape 173 , no. 7 , July 2016, p. 655-7 , doi : 10.1176 / appi.ajp.2016.16050502 , PMID 27363547 .
  7. ↑ Links to Fetal Programming Studies - Science Simply Explained! In: Baby belly blog. April 25, 2020, accessed July 9, 2020 .
  8. ^ L. Myatt: Placental adaptive responses and fetal programming . In: The Journal of Physiology . tape 572 , Pt 1, April 2006, p. 25-30 , doi : 10.1113 / jphysiol.2006.104968 , PMID 16469781 , PMC 1779654 (free full text).
  9. ^ PD Taylor, AM Samuelsson, L. Poston: Maternal obesity and the developmental programming of hypertension: a role for leptin . In: Acta Physiologica . tape 210 , no. 3 , March 2014, p. 508-23 , doi : 10.1111 / apha.12223 , PMID 24433239 .
  10. ↑ SL Andersen, J. Olsen, P. Laurberg: Foetal programming by maternal thyroid disease . In: Clinical Endocrinology . tape 83 , no. 6 , December 2015, p. 751-8 , doi : 10.1111 / cen.12744 , PMID 25682985 .
  11. ^ Stine Linding Andersen, Jørn Olsen, Peter Laurberg: Foetal programming by maternal thyroid disease . In: Clinical Endocrinology . tape 83 , no. 6 , December 2015, p. 751–758 , doi : 10.1111 / cen.12744 ( online [accessed July 9, 2020]).
  12. ↑ No alcohol during pregnancy. In: DGEinfo. German Nutrition Society V., September 2014, pp. 139–142 , accessed on July 9, 2020 .
  13. ↑ J. Weinberg, JH Sliwowska, N. Lan, KGC Hellemans: Prenatal alcohol exposure: foetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome . In: Journal of Neuroendocrinology . tape 20 , no. 4 , April 2008, p. 470-88 , doi : 10.1111 / j.1365-2826.2008.01669.x , PMID 18266938 .
  14. ↑ R. Bekdash, C. Zhang, D. Sarkar: Fetal alcohol programming of hypothalamic proopiomelanocortin system by epigenetic mechanisms and later life vulnerability to stress . In: Alcoholism, Clinical and Experimental Research . tape 38 , no. 9 , September 2014, p. 2323-30 , doi : 10.1111 / acer.12497 , PMID 25069392 , PMC 4177357 (free full text).
  15. ↑ a b G. Banderali, A. Martelli, M. Landi, F. Moretti, F. Betti: Short and long term health effects of parental tobacco smoking during pregnancy and lactation: a descriptive review . In: Journal of Translational Medicine . tape 13 , no. 1 , December 2015, ISSN  1479-5876 , p. 327 , doi : 10.1186 / s12967-015-0690-y , PMID 26472248 , PMC 4608184 (free full text) - ( online [accessed July 9, 2020]).
  16. ↑ a b M. A. Suter, AM Anders, KM Aagaard: Maternal smoking as a model for environmental epigenetic changes affecting birthweight and fetal programming . In: Molecular Human Reproduction . tape 19 , no. 1 , January 2013, p. 1–6 , doi : 10.1093 / molehr / gas050 , PMID 23139402 , PMC 3521486 (free full text).
  17. ^ H. Bayliss, D. Churchill, M. Beevers, DG Beevers: Anti-hypertensive drugs in pregnancy and fetal growth: evidence for "pharmacological programming" in the first trimester? In: Hypertension in Pregnancy . tape 21 , no. 2 , January 2002, p. 161-74 , doi : 10.1081 / prg-120013785 , PMID 12175444 .
  18. ↑ Noel P French, Ronald Hagan, Sharon F Evans, Annie Mullan, John P Newnham: Repeated antenatal corticosteroids: Effects on cerebral palsy and childhood behavior . In: American Journal of Obstetrics and Gynecology . tape 190 , no. 3 , March 2004, p. 588-595 , doi : 10.1016 / j.ajog.2003.12.016 ( online [accessed July 9, 2020]).
  19. ↑ Stuart R. Dalziel, Vanessa K. Lim, Anthony Lambert, Dianne McCarthy, Varsha Parag: Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomized controlled trial . In: BMJ . tape 331 , no. 7518 , September 24, 2005, ISSN  0959-8138 , p. 665 , doi : 10.1136 / bmj.38576.494363.E0 , PMID 16143712 , PMC 1226245 (free full text) - ( online [accessed on July 9, 2020]).
  20. ↑ JR Palmer: Prenatal Diethylstilbestrol Exposure and Risk of Breast Cancer . In: Cancer Epidemiology Biomarkers & Prevention . tape 15 , no. 8 , August 1, 2006, ISSN  1055-9965 , p. 1509–1514 , doi : 10.1158 / 1055-9965.EPI-06-0109 ( online [accessed July 9, 2020]).
  21. ↑ Barbara T. Alexander: Fetal programming of hypertension . In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology . tape 290 , no. 1 , January 2006, ISSN  0363-6119 , p. R1 – R10 , doi : 10.1152 / ajpregu.00417.2005 ( online [accessed July 9, 2020]).
  22. ↑ Aleksandra Marciniak, Jolanta Patro-Małysza, Żaneta Kimber-Trojnar, Beata Marciniak, Jan Oleszczuk: Fetal programming of the metabolic syndrome . In: Taiwanese Journal of Obstetrics and Gynecology . tape 56 , no. 2 , April 2017, p. 133–138 , doi : 10.1016 / j.tjog.2017.01.001 ( online [accessed July 9, 2020]).
  23. ↑ DJ Barker, C. Osmond, J. Golding, D. Kuh, ME Wadsworth: Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease . In: BMJ . tape 298 , no. 6673 , March 4, 1989, ISSN  0959-8138 , p. 564–567 , doi : 10.1136 / bmj.298.6673.564 , PMID 2495113 , PMC 1835925 (free full text) - ( online [accessed July 9, 2020]).
  24. ^ Avoxa-Mediengruppe Deutscher Apotheker GmbH: Fetal programming: innate, but not inherited. Retrieved July 9, 2020 .
  25. ^ EP Davis, BL Hankin, DA Swales, MC Hoffman: An experimental test of the fetal programming hypothesis: Can we reduce child ontogenetic vulnerability to psychopathology by decreasing maternal depression? In: Development and Psychopathology . tape 30 , no. 3 , August 2018, p. 787-806 , doi : 10.1017 / S0954579418000470 , PMID 30068416 , PMC 7040571 (free full text).
  26. ↑ Majella Byrne, Esben Agerbo, Birgit Bennedsen, William W. Eaton, Preben Bo Mortensen: Obstetric conditions and risk of first admission with schizophrenia: A Danish national register based study . In: Schizophrenia Research . tape 97 , no. 1-3 , December 2007, pp. 51–59 , doi : 10.1016 / j.schres.2007.07.018 ( online [accessed July 9, 2020]).
  27. ↑ DH Abbott, DK Barnett, CM Bruns, DA Dumesic: Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? In: Human Reproduction Update . tape 11 , no. 4 , July 1, 2005, ISSN  1460-2369 , p. 357–374 , doi : 10.1093 / humupd / dmi013 ( online [accessed July 9, 2020]).
  28. ↑ Jl Cresswell, Djp Barker, C. Osmond, P. Egger, Diw Phillips: Fetal growth, length of gestation, and polycystic ovaries in adult life . In: The Lancet . tape 350 , no. 9085 , October 1997, p. 1131–1135 , doi : 10.1016 / S0140-6736 (97) 06062-5 ( online [accessed July 9, 2020]).
  29. ↑ Leena Hilakivi-Clarke, Sonia de Assis: Fetal origins of breast cancer . In: Trends in Endocrinology & Metabolism . tape 17 , no. 9 , November 2006, pp. 340–348 , doi : 10.1016 / j.tem.2006.09.002 ( online [accessed on July 9, 2020]).
  30. ↑ Tom Grotmol, Elisabete Weiderpass, Steinar Tretli: Conditions in utero and cancer risk . In: European Journal of Epidemiology . tape 21 , no. 8 , October 17, 2006, ISSN  0393-2990 , p. 561-570 , doi : 10.1007 / s10654-006-9036-7 ( online [accessed July 9, 2020]).
  31. ↑ T. Harder, A. Plagemann, A. Harder: Birth Weight and Subsequent Risk of Childhood Primary Brain Tumors: A Meta-Analysis . In: American Journal of Epidemiology . tape 168 , no. 4 , June 30, 2008, ISSN  0002-9262 , p. 366–373 , doi : 10.1093 / aje / kwn144 ( online [accessed July 9, 2020]).
  32. ↑ M. Ceelen, MM van Weissenbruch, JPW Avoid, FE van Leeuwen, HA Delemarre-van de Waal: Pubertal development in children and adolescents born after IVF and spontaneous conception . In: Human Reproduction . tape 23 , no. 12 , September 1, 2008, ISSN  0268-1161 , p. 2791–2798 , doi : 10.1093 / humrep / den309 ( online [accessed July 9, 2020]).
  33. ↑ Manon Ceelen, Mirjam M. van Weissenbruch, Jan PW Vermeiden, Flora E. van Leeuwen, Henriette A. Delemarre-van de Waal: Cardiometabolic Differences in Children Born After in Vitro Fertilization: Follow-Up Study . In: The Journal of Clinical Endocrinology & Metabolism . tape 93 , no. 5 , May 2008, ISSN  0021-972X , p. 1682–1688 , doi : 10.1210 / jc.2007-2432 ( online [accessed July 9, 2020]).

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