Maternal circadian rhythm and its implications for offspring health

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access


This review presents data on the circadian system hierarchy and its unique reorganization at the onset of pregnancy, which plays a fundamental role in maintaining maternal homeostasis and creating optimal conditions for the implementation of the genetic program of fetal development. A particular emphasis is made on the protective mechanisms of the circadian rhythm of maternal melatonin, which is the primary messenger of biorhythms. This paper thoroughly discusses the mechanisms and consequences of maternal chronodisruption in pregnant women exposed to adverse environmental conditions (shift work, stress, irregular nutrition, etc.), as well as in those with chronodestruction-related diseases (obesity, diabetes mellitus, etc.). Elucidating the circadian system status in the patients and, in particular, whether they have a daily rhythm of melatonin production will determine a new approach to risk assessment and timely prevention of cardiovascular, metabolic, neuroendocrine and mental disorders in the offspring in later life.

Full Text

Restricted Access

About the authors

Inna I. Evsyukova

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Author for correspondence.
ORCID iD: 0000-0003-4456-2198

MD, Dr. Sci. (Med.), Professor

Russian Federation, 3 Mendeleevskaya Line, Saint Petersburg, 199034


  1. Menaker M, Murphy ZC, Sellix MT. Central control of peripheral oscillators. Curr Opin Neurobiol. 2013;23(5):741−746. doi: 10.1016/j.conb.2013.03.003
  2. Kvetnoy I, Ivanov D, Mironova E, et al. Melatonin as the cornerstone of neuroimmunoendocrinology. Int J Mol Sci. 2022;23(3):1835. DOI: 10.3390/ ijms23031835
  3. Green CB. Circadian posttranscriptional regulatory mechanisms in mammals. Cold Spring Harb Perspect Biol. 2018;10(6):a030692. doi: 10.1101/cshperspect.a030692
  4. Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system. Annu Rev Physiol. 2010;72:517−549. doi: 10.1146/annurev-physiol-021909-135821
  5. von Gall C. The effects of light and the circadian system on rhythmic brain function. Int J Mol Sci. 2022;23(5):2778. doi: 10.3390/ijms23052778
  6. Albrecht U. Timing to perfection: The biology of central and peripheral circadian clocks. Neuron. 2012;74(2):246−260. doi: 10.1016/j.neuron.2012.04.006
  7. Takahashi JS. Molecular architecture of the circadian clock in mammals. In: Sassone-Corsi P, Christen Y, editors. A time for metabolism and hormones. Berlin: Springer, 2016:13–24. doi: 10.1007/978-3-319-27069-2_2
  8. Bass J. Circadian mechanisms in bioenergetics and cell metabolism. In: Sassone-Corsi P, Christen Y, editors. A time for metabolism and hormones. Berlin: Springer, 2016: 25−32. doi: 10.1007/978-3-319-27069-2_3
  9. Schrader JA, Nunez AA, Smale L. Changes in and dorsal to the rat suprachiasmatic nucleus during early pregnancy. Neuroscience. 2010;171(2):513−523. doi: 10.1016/j.neuroscience.2010.08.057
  10. Torres-Farfan C, Mendez N, Ehrenfeld P, Seron-Ferre M. In utero circadian changes; facing light pollution. Current Opinion in Physiology. 2020;13:128–134. doi: 10.1016/j.cophys.2019.11.005
  11. Martin-Fairey CA, Zhao P, Wan L, et al. Pregnancy induces an earlier chronotype in both mice and women. J Biol Rhythm. 2019;34(3):323–331. doi: 10.1177/0748730419844650
  12. Wharfe MD, Mark PJ, Waddell BJ. Circadian variation in placental and hepatic clock genes in rat pregnancy. Endocrinology. 2011;152(9):3552−3560. doi: 10.1210/en.2011-0081
  13. Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol. 2007;50(4):938−948. doi: 10.1097/GRF.0b013e31815a5494
  14. Wharfe MD, Mark PJ, Wyrwoll CS, et al. Pregnancy-induced adaptations of the central circadian clock and maternal glucocorticoids. J Endocrinology. 2016;228(3):135–147. doi: 10.1530/JOE-15-0405
  15. Pan X, Taylor MJ, Cohen E, et al. Circadian clock, time-restricted feeding and reproduction. Int J Mol Sci. 2020;21(3):831. doi: 10.3390/ijms21030831
  16. Kaur S, Teoh AN, Shukri NHM, et al. Circadian rhythm and its association with birth and infant outcomes: research protocol of a prospective cohort study. BMC Pregnancy and Childbirth. 2020;20(1):96. doi: 10.1186/s12884-020-2797-2
  17. Hsu C-N, Tain Y-L. Light and circadian signaling pathway in pregnancy: Programming of adult health and disease. Int J Mol Sci. 2020;21(6):2232. doi: 10.3390/ijms21062232
  18. Serón-Ferré M, Richter HG, Valenzuela GJ, Torres-Farfan C. Circadian rhythms in the fetus and newborn: Significance of interactions with maternal physiology and the environment. In: Walker D, ed. Prenatal and Postnatal Determinants of Development. Neuromethods. New York: Humana Press; 20161;9:147−165. doi: 10.1007/978-1-4939-3014-2_7
  19. Waddell BJ, Wharfe MD, Crew RC, Mark PJ. A rhythmic placenta? Circadian variation Clock genes and placental function. Placenta. 2012;33(7):533−539. doi: 10.1016/j.placenta.2012.03.008
  20. Valenzuela FJ, Vera J, Venegas C, et al. Circadian system and melatonin hormone: Risk factors for complications during pregnancy. Obstet Gynecol Int. 2015;2015:825802. doi: 10.1155/2015/825802
  21. Nakamura Y, Tamura H, Kashida S, et al. Changes of serum melatonin level and its relationship to feto-placental unit during pregnancy. J Pineal Res. 2001;30(1):29−33. doi: 10.1034/j.1600-079x.2001.300104.x
  22. Erren TS, Reiter RJ. Melatonin: a universal time messenger. Neuro Endocrinol Lett. 2015;36(3):187−192.
  23. Mark PJ, Crew RC, Wharfe MD, Waddell BJ. Rhythmic three-part harmony: the complex interaction of maternal, placental and fetal circadian systems. J Biol Rhythms. 2017;32(6):534−549. doi: 10.1177/0748730417728671
  24. Astiz M, Oster H. Feto-maternal crosstalk in the development of the circadian clock System. Front Neurosci. 2021;14:631687. doi: 10.3389/fnins.2020.631687
  25. Cipolla-Neto J, do Amaral FG. Melatonin as a hormone: New physiological and clinical insights. Endocrine Reviews. 2018;39:990−1028. doi: 10.1210/er.2018-00084
  26. Edwards SM, Solveig A, Dunlop AL, Corwin EJ. The maternal gut microbiome during pregnancy. MCN Am J Matern Child Nurs. 2017;42(6):310−317. doi: 10.1097/NMC.0000000000000372
  27. Polidarova L, Olejnikova L, Pauslyova L, et al. Development and entrainment of the colonic circadian clock during ontogenesis. Am J Physiol Gastrointest Liver Physiol. 2014;306(4):346−356. doi: 10.1152/ajpgi.00340.2013
  28. Thomas L, Drew JE, Abramovich DR, Williams LM. The role of melatonin in the human fetus (review). Int J Mol Med. 1998;1(3):539−543.
  29. Mirmiran M, Maas YG, Ariagno RL. Development of fetal and neonatal sleep and circadian rhythms. Sleep Med Rev. 2003;7(4):321−334.
  30. Arendt J, Skene DJ. Melatonin as chronobiotic. Sleep Med Rev. 2005;9(1):25−39. doi: 10.1016/j.smrv.2004.05.002
  31. Seron-Ferre M, Mendez M, Abarzua-Catalan L, et al. Circadian rhythms in the fetus. Mol Cell Endocrinology. 2012;349(1):68−75. doi: 10.1016/j.mce.2011.07.039
  32. Oster H, Challet E, Ott V, et al. The functional and clinical significance of the 24-hour rhythm of circulating glucocorticoids. Endocr Rev. 2017;38:3–45. doi: 10.1210/er.2015-1080
  33. Lužná V, Houdek P, Liška K, Sumová A. Challenging the integrity of rhythmic maternal signals revealed gene-specific responses in the fetal suprachiasmatic nuclei. Front Neurosci. 2021;14:613531. doi: 10.3389/fnins.2020.613531
  34. Nehme PA, Amaral FG, Middleton B, et al. Melatonin profiles during the third trimester of pregnancy and health status in the offspring among day and night workers: A case series. Neurobiol Sleep Circadian Rhythm. 2019;6:70–76. doi: 10.1016/j.nbscr.2019.04.001
  35. Forrestel AC, Miedlich SU, Yurcheshen M, et al. Chronomedicine and type 2 diabetes: shining some light on melatonin. Diabetologia. 2017;60(5):808−822. doi: 10.1007/s00125-016-4175-1
  36. Nduhirabandi F, du Toit EF, Lochner A. Melatonin and the metabolic syndrome: a tool for effective therapy in obesity-associated abnormalities? Acta Physiol. 2012;205:209−223. doi: 10.1111/j.1748-1716/2012.0410.x
  37. Tranquilli AL, Turi A, Giannubilo SR, Garbati E. Circadian melatonin concentration rhythm is lost in pregnant women with altered blood pressure rhythm. Gynecol Endocrinol. 2004;18(3):124−129. doi: 10.1080/09513590410001667841
  38. Guan Q, Wang Z, Cao J, et al. Mechanisms of melatonin in obesity: A review. Int J Mol Sci. 2022;23(1):218. doi: 10.3390/ijms23010218
  39. Begtrup LM, Specht IO, Hammer PEC, et al. Night work and miscarriage: A Danish nationwide register-based cohort study. Occup Environ Med. 2019;76(5):302−308. doi: 10.1136/oemed-2018-105592
  40. Suzumori N, Ebara T, Matsuki T, et al. Effects of long working hours and shift work during pregnancy on obstetric and perinatal outcomes: A large prospective cohort study-Japan environment and children’s study. Birth. 2020;47(1):67–79. doi: 10.1111/birt.12463
  41. Davari MH, Naghshineh E, Mostaghaci M, et al. Shift work effects and pregnancy outcome: A historical cohort study. J Family Reprod Health. 2018;12(2):84−88.
  42. Plano SA, Casiraghi LP, Moro PG, et al. Circadian and metabolic effects of light: implications in weight homeostasis and health. Front Neurol. 2017;8:558. doi: 10.3389/fneur.2017. 00558
  43. Fishbein AB, Knutson KL, Zee PC. Circadian disruption and human health. J Clin Invest. 2021;131(19):e148286. doi: 10.1172/JCI148286
  44. Halabi D, Richter HG, Mendez N, et al. Maternal chronodisruption throughout Pregnancy impairs glucose homeostasis and adipose tissue physiology in the male rat offspring. Front Endocrinol. 2021;12:678468. doi: 10.3389/fendo.2021.678468
  45. Strohmaier S, Devore EE, Vetter C, et al. Night shift work before and during pregnancy in relation to depression and anxiety in adolescent and young adult offspring. Eur J Epidemiol. 2019;34(7):625−635. doi: 10.1007/s10654-019-00525-2
  46. Peng X, Fan R, Xie L, et al. A growing link between circadian rhythms, type 2 diabetes mellitus and alzheimer’s disease. Int J Mol Sci. 2022;23(1):504. doi: 10.3390/ijms23010504
  47. Suarez-Trujillo A, Hoang N, Robinson L, et al. Effect of circadian system disruption on the concentration and daily oscillations of cortisol, progesterone, melatonin, serotonin, growth hormone, and core body temperature in periparturient dairy cattle. J Dairy Sci. 2022;105(3):2651−2668. doi: 10.3168/jds.2021-20691
  48. Hemmeryckx B, Frederix L, Lijnen HR. Deficiency of Вmal1 disrupts the diurnal rhythm of haemostasis. Exp Gerontol. 2019;118:1–8. doi: 10.1016/j.exger.2018.12.017
  49. Voiculescu SE, Zygouropoulos N, Zahiu CD, Zagrean AM. Role of melatonin in embryo fetal development. J Med Life. 2014;7(4):488−492.
  50. Nagai R, Watanabe K, Wakatsuki A, et al. Melatonin preserves fetal growth in rats by protecting against ischemia-reperfusion-induced oxidative-nitrosative mitochondrial damage in placenta. J Pineal Res. 2008;45(3):271−276. doi: 10.1111/j.1600-079X.2008.00586x
  51. Berbets A, Koval H, Barbe A, et al. Melatonin decreases and cytokines increase in women with placental insufficiency. J Matern Fetal Neonatal Med. 2021;34(3):373−378. doi: 10.1080/1476058.2019.1608432
  52. Varcoe TJ, Gatford KL, Kennaway DJ. Maternal circadian rhythms and the programming of adult health and disease. Am J Physiol Regul Integr Comp Physiol. 2017;314(2):231−241. doi: 10.1152/ajpregu.00248.2017
  53. Torres-Farfan C, Cipolla Neto J, Herzog ED. Editorial: Decoding the fetal circadian system and its role in adult sickness and health: Melatonin, a dark history. Front Endocrinol (Lausanne). 2020;11:380. doi: 10.3389/fendo.2020
  54. Reiter RJ, Tan DX, Korkmaz A, Rosales-Corral SA. Melatonin and stabile circadian rhythms optimize maternal, placental and fetal physiology. Hum Reprod Update. 2014;20(2):293−307. doi: 10.1093/humupd/dmt054
  55. Mendez N, Halabi D, Spichiger C, et al. Gestational chronodisruption impairs circadian physiology in rat male offspring, increasing the risk of chronic disease. Endocrinology. 2016;157(12):4654–4668. doi: 10.1210/en.2016-1282
  56. Carmona P, Pérez B, Trujillo C, et al. Long-term effects of altered photoperiod during pregnancy on liver gene expression of the progeny. Front Physiol. 2019;10:1377. doi: 10.3389/fphys.2019.0137
  57. Salazar ER, Richter HG, Spichiger C, et al. Gestational chronodisruption leads to persistent changes in the rat fetal and adult adrenal clock and function. J Physiol. 2018;596:5839–5857. doi: 10.1113/JP276083
  58. Lamadé EK, Hendlmeier F, Wudy SA, et al. Rhythm of fetoplacental 11β-hydroxysteroid dehydrogenase type 2-fetal protection from morning maternal glucocorticoids. J Clin Endocrinol Metab. 2021;106(6):1630−1636. doi: 10.1210/clinem/dgab113
  59. Ryan J, Mansell T, Fransquet P, Saffery R. Does maternal mental well-being in pregnancy impact the early human epigenome? Epigenomics. 2017;9(3):313–332. doi: 10.2217/epi-2016-0118
  60. Sacchi C, Marino C, Nosarti C, et al. Association of intrauterine growth restriction and small for gestational age status with childhood cognitive outcomes: A systematic. Review and meta-analysis. JAMA Pediatr. 2020;174(8):772−781. doi: 10.1001/jamapediatrics.2020.1097
  61. Vollmer B, Edmonds CJ. School age neurological and cognitive outcomes of fetal growth retardation or small for gestational age birth weight. Front Endocrin. 2019;10:186. doi: 10.3389/fendo. 2019.00186
  62. Bhunu B, Intapad IRS. Insights into the mechanisms of fetal growth restriction-induced programming of hypertension. Integr Blood Pressure Control. 2021;14:141−152. doi: 10.2147/IBPC.S312868
  63. Amaral FGD, Andrade-Silva J, Kuwabara WMT, Cipolla-Neto J. New insights into the function of melatonin and its role in metabolic disturbances. Expert Rev Endocrinol Metab. 2019;14(4):293−300. doi: 10.1080/17446651.2019.1631158
  64. Ivanov DO, Evsyukova II, Mironova ES, et al. Maternal melatonin deficiency leads to endocrine pathologies in children in early ontogenesis. Int J Mol Sci. 2021;22:2058. doi: 10.3390/ijms22042058
  65. Korkmaz A, Rosales-Corral S, Reiter RJ. Gene regulation by melatonin linked to epigenetic phenomena. Gene. 2012;503(1):1−11. doi: 10.1016/j.gene.2012.04.040
  66. Perez-Gonzalez A, Castaneda-Arriaga R, Alvarez-Idaboy JR, et al. Melatonin and its metabolites as chemical agents capable of directly repairing oxidized DNA. J Pineal Res. 2019;66(2):e12539. doi: 10.1111/jpi.12539
  67. Ireland KE, Maloyan A, Myatt L. Melatonin improves mitochondrial respiration in syncytiotrophoblasts from placentas of obese women. Reprod Sci. 2018;25(1):120−130. DOI: 101177/1933719117704908
  68. Xu D-X, Wang H, Ning H, et al. Maternally administered melatonin differentially regulates lipopolysaccharide-induced proinflammatory and anti-infammatory cytokines in maternal serum, amniotic fluid, fetal live, and fetal brain. J Pineal Res. 2007;43(1):74−79. DOI: 10.1111.j.1600-079X.2007.004445.x
  69. Chitimus DM, Popescu MR, Voiculescu SE, et al. Melatonin’s impact on antioxidative and anti-inflamatory reprogramming in homeostasis and disease. Biomolecules. 2020;10(9):1211. doi: 10.3390/biom1009211
  70. Tan DX, Manchester LC, Qin L, Reiter RJ. Melatonin: A mitochondrial targeting molecule involving mitochondrial protection and dynamics. Int J Mol Sci. 2016;17(12):2124. doi: 10.3390/ijms17122124
  71. Kopustinskiene DM, Bernatoniene J. Molecular mechanisms of melatonin-mediated cell protection and signaling in health and disease. Pharmaceutics. 2021;13(2):129. doi: 10.3390/pharmaceutics13020129
  72. Mendez N, Abarzua-Catalan L, Vilches N, et al. Timed maternal melatonin treatment reverses circadian disruption of the fetal adrenal clock imposed by exposure to constant light. PloS One. 2012;7(8):e42713. doi: 10.1371/journal.pone0042713
  73. Hansell JA, Richter HJ, Camm EJ, et al. Matrenal melatonin: Effective intervention against developmental programming of cardiovascular dysfunction in adult offspring of complicated pregnancy. J Pineal Res. 2021;72(1):e12766. doi: 10.1111/jpi.12766

Supplementary files

There are no supplementary files to display.

Copyright (c) 2022 Eсо-Vector

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 66759 от 08.08.2016 г. 
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия Эл № 77 - 6389
от 15.07.2002 г.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies