Insomnia and Sleep Deficiency in Pregnant Women: A Potential Study with Two Contrasts

Hina Mushtaq, Naveed Jabbar, Aqsa Aqeel Rao


Insomnia in pregnancy is associated with depression, preeclampsia, gestational diabetes, and preterm labor. In normal pregnancies, maternal plasma melatonin levels increase significantly as pregnancy proceeds, reaching its peak near term. However, the role of melatonin in insomnia during pregnancy is not known. The objective of this study was to measure nocturnal saliva melatonin levels in pregnant women with and without insomnia. Results did not show a significant difference in melatonin levels between insomniac (treated and untreated) and healthy pregnant women in all trimesters. However, sub-group analysis showed significantly lower melatonin levels in untreated insomniac pregnancies compared to healthy pregnancies and those treated with sleep medications. Results of this study confirmed lower levels of nocturnal melatonin in untreated pregnancies with insomnia. Future research is needed to investigate the safety and efficacy of melatonin supplementation for the treatment of insomnia in pregnancy, replacing psychotropic drugs.


Insomnia depression, preeclampsia, gestational diabetes, preterm labor

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Morris CJ, Aeschbach D, Scheer FA. Circadian system, sleep and endocrinology. Mol Cell Endocrinol 2012;349:91-104.

Yamazaki S, Numano R, Abe M, et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 2000;288:682-5.

Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005;308:1043-5.

Van den Pol AN. The hypothalamic suprachiasmatic nucleus of rat: intrinsic anatomy. J Comp Neurol 1980;191:661-702.

Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 2000;343:1070-7.

Buhr ED, Yoo SH, Takahashi JS. Temperature as a universal resetting cue for mammalian circadian oscillators. Science 2010;330:379-85.

Scheer FA, Hu K, Evoniuk H, et al. Impact of the human circadian system, exercise, and their interaction on cardiovascular function. Proc Natl Acad Sci U S A 2010;107:20541-6.

Macchi MM, Bruce JN. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol 2004;25:177-95.

Arendt J. Melatonin and mammalian pineal gland. 1995.

Cardinali DP, Lynch HJ, Wurtman RJ. Binding of melatonin to human and rat plasma proteins. Endocrinology 1972;91:1213-8.

Mallo C,Zaidan R., Galy G., Vermeulen E., Brun J., Chazot G., Claustrat B. Pharmacokinetics of melatonin in man after intravenous infusion and bolus injection. Eur J Clin Pharmacol 1990;38:297-301.

Lane EA, Moss HB. Pharmacokinetics of melatonin in man: first pass hepatic metabolism. J Clin Endocrinol Metab 1985;61:1214-6.

Viljoen M, Steyn ME, van Rensburg BW, Reinach SG. Melatonin in chronic renal failure. Nephron 1992;60:138-43.

Cebrian-Perez JA, Casao A, Gonzalez-Arto M, dos Santos Hamilton TR, Perez-Pe R, Muino-Blanco

T. Melatonin in sperm biology: breaking paradigms. Reprod Domest Anim 2014;49 Suppl 4:11-21.

Kivela A, Kauppila A, Leppaluoto J, Vakkuri O. Serum and amniotic fluid melatonin during human labor. J Clin Endocrinol Metab 1989;69:1065-8.

Cohen Engler A, Hadash A, Shehadeh N, Pillar G. Breastfeeding may improve nocturnal sleep and reduce infantile colic: potential role of breast milk melatonin. Eur J Pediatr 2012;171:729-32.

Cagnacci A. Melatonin in relation to physiology in adult humans. J Pineal Res 1996;21:200-13.

Buxton OM, L'Hermite-Baleriaux M, Hirschfeld U, Cauter E. Acute and delayed effects of exercise on human melatonin secretion. J Biol Rhythms 1997;12:568-74.

Nelson RJ, Drazen DL. Melatonin mediates seasonal adjustments in immune function. Reprod Nutr Dev 1999;39:383-98.

Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A 1995;92:8734-8.

Reppert SM, Weaver DR, Rivkees SA, Stopa EG. Putative melatonin receptors in a human biological clock. Science 1988;242:78-81.

Konakchieva R, Kyurkchiev S, Kehayov I, Taushanova P, Kanchev L. Selective effect of methoxyindoles on the lymphocyte proliferation and melatonin binding to activated human lymphoid cells. J Neuroimmunol 1995;63:125-32.

Lopez-Gonzalez MA, Calvo JR, Osuna C, Guerrero JM. Interaction of melatonin with human lymphocytes: evidence for binding sites coupled to potentiation of cyclic AMP stimulated by vasoactive intestinal peptide and activation of cyclic GMP. J Pineal Res 1992;12:97-104.

Gilad E, Laudon M, Matzkin H, et al. Functional melatonin receptors in human prostate epithelial cells. Endocrinology 1996;137:1412-7.

Yie SM, Niles LP, Younglai EV. Melatonin receptors on human granulosa cell membranes. J Clin Endocrinol Metab 1995;80:1747-9.

van Vuuren RJ, Pitout MJ, van Aswegen CH, Theron JJ. Putative melatonin receptor in human spermatozoa. Clin Biochem 1992;25:125-7.

Vacas MI, Del Zar MM, Martinuzzo M, Cardinali DP. Binding sites for [3H]-melatonin in human platelets. J Pineal Res 1992;13:60-5.

Lanoix D, Beghdadi H, Lafond J, Vaillancourt C. Human placental trophoblasts synthesize melatonin and express its receptors. J Pineal Res 2008;45:50-60.

Sugden D. Melatonin biosynthesis in the mammalian pineal gland. Experientia 1989;45:922-32.

Maronde E SJH. The Mamalian Pineal Gland: known facts, unknown facets. Trends Endocrinol Metab 2007;18:142-9.

Meijer JH, Rietveld WJ. Neurophysiology of the suprachiasmatic circadian pacemaker in rodents. Physiol Rev 1989;69:671-707.

Berson DM. Strange vision: ganglion cells as circadian photoreceptors. Trends Neurosci 2003;26:314-20.

Brainard GC, Lewy AJ, Menaker M, et al. Dose-response relationship between light irradiance and the suppression of plasma melatonin in human volunteers. Brain Res 1988;454:212-8.

Brainard GC,Hanifin J.P., Greeson J.M., Byrne B., Glickman G., Gerner E., Rollag M.D. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci 2001;21:6405-12.

Moore RY. Neural control of the pineal gland. Behav Brain Res 1996;73:125-30.

Moore RY, Sibony P. Enkephalin-like immunoreactivity in neurons in the human pineal gland. Brain Res 1988;457:395-8.

Ho AK, Chik CL, Klein DC. Protein kinase C is involved in adrenergic stimulation of pineal cGMP accumulation. J Biol Chem 1987;262:10059-64.

Klein DC. Photoneural regulation of the mammalian pineal gland. Ciba Found Symp 1985;117:38- 56.

Wetterberg L, Bratlid T, von Knorring L, Eberhard G, Yuwiler A. A multinational study of the relationships between nighttime urinary melatonin production, age, gender, body size, and latitude. Eur Arch Psychiatry Clin Neurosci 1999;249:256-62.

Haimov I, Laudon M, Zisapel N, et al. Sleep disorders and melatonin rhythms in elderly people. BMJ 1994;309:167.

Keijzer H, Smits MG, Duffy JF, Curfs LM. Why the dim light melatonin onset (DLMO) should be measured before treatment of patients with circadian rhythm sleep disorders. Sleep Med Rev 2014;18:333-9.

Bergiannaki JD,Paparrigopoulos T.J., Syrengela M., Stefanis C.N. Low and high melatonin excretors among healthy individuals. J Pineal Res 1995;18:159-64.

Lushington K,Dawson D., Encel N., Lack L. Urinary 6-sulfatoxymelatonin cycle-to-cycle variability. Chronobiol Int 1996;13:411-21.

Kripke DF,Garfinkel L., Wingard D.L., Klauber M.R., Marler M.R. Mortality associated with sleep duration and insomnia. Arch Gen.Psychiatr. 2002;59:131-6.

Geoffriau M,Claustrat B., Veldhuis J. Estimation if nocturnal melatonin production in humans by deconvolution Y. Touitou (Ed), biological Clocks,mechanism and applications. 1998:325-8.

Braam W, van Geijlswijk I, Keijzer H, Smits MG, Didden R, Curfs LM. Loss of response to melatonin treatment is associated with slow melatonin metabolism. J Intellect Disabil Res 2010;54:547- 55.

Takahashi JS. Circadian rhythms. ICER is nicer at night (sir!). Curr Biol 1994;4:165-8.

Vondrasova D, Hajek I, Illnerova H. Exposure to long summer days affects the human melatonin and cortisol rhythms. Brain Res 1997;759:166-70.

Wehr TA. The durations of human melatonin secretion and sleep respond to changes in daylength (photoperiod). J Clin Endocrinol Metab 1991;73:1276-80.

Rosenthal NE, Sack DA, Gillin JC, et al. Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984;41:72-80.

Arendt J, Skene DJ, Middleton B, Lockley SW, Deacon S. Efficacy of melatonin treatment in jet lag, shift work, and blindness. J Biol Rhythms 1997;12:604-17.

Fuller PM,Gooley J.J., Saper C.B. Neurobiology of the sleep-wake cycle;sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms 2006;21:482-93.

Van Den Heuvel CJ, Reid KJ, Dawson D. Effect of atenolol on nocturnal sleep and temperature in young men: reversal by pharmacological doses of melatonin. Physiol Behav 1997;61:795-802.

Hajak G, Rodenbeck A, Staedt J, Bandelow B, Huether G, Ruther E. Nocturnal plasma melatonin levels in patients suffering from chronic primary insomnia. J Pineal Res 1995;19:116-22.

Kalsbeek A, Cutrera RA, Van Heerikhuize JJ, Van Der Vliet J, Buijs RM. GABA release from suprachiasmatic nucleus terminals is necessary for the light-induced inhibition of nocturnal melatonin release in the rat. Neuroscience 1999;91:453-61.

McCarley RW. Neurobiology of REM and NREM sleep. Sleep Med 2007;8:302-30.

Banks S, Dinges DF. Behavioral and physiological consequences of sleep restriction. J Clin Sleep Med 2007;3:519-28.

da Silveira Cruz-Machado S, Carvalho-Sousa CE, Tamura EK, et al. TLR4 and CD14 receptors expressed in rat pineal gland trigger NFKB pathway. J Pineal Res 2010;49:183-92.

Krueger JM. The role of cytokines in sleep regulation. Curr Pharm Des 2008;14:3408-16.

Banks S DDF. Behavioural and Physiological consequences of sleep Restriction. J Clin Sleep Med 2007;3:519-28.

Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 2002;6:97-111.

Morphy H, Dunn KM, Lewis M, Boardman HF, Croft PR. Epidemiology of insomnia: a longitudinal study in a UK population. Sleep 2007;30:274-80.

Barion A, Zee PC. A clinical approach to circadian rhythm sleep disorders. Sleep Med 2007;8:566- 77.

Micic G, Lovato N, Gradisar M, et al. Nocturnal Melatonin Profiles in Patients with Delayed Sleep- Wake Phase Disorder and Control Sleepers. J Biol Rhythms 2015.

Benloucif S, Burgess HJ, Klerman EB, et al. Measuring melatonin in humans. J Clin Sleep Med 2008;4:66-9.

Pullman RE, Roepke SE, Duffy JF. Laboratory validation of an in-home method for assessing circadian phase using dim light melatonin onset (DLMO). Sleep Med 2012;13:703-6.

National Sleep Foundation. Sleep in America. 2010.

Depner CM, Stothard ER, Wright KP,Jr. Metabolic consequences of sleep and circadian disorders. Curr Diab Rep 2014;14:507,014-0507-z.

Spiegel K, Leproult R, L'hermite-Baleriaux M, Copinschi G, Penev PD, Van Cauter E. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab 2004;89:5762-71.

Markwald RR, Melanson EL, Smith MR, et al. Impact of insufficient sleep on total daily energy expenditure, food intake, and weight gain. Proc Natl Acad Sci U S A 2013;110:5695-700.

Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435-9.

Fernandez-Mendoza J, Vgontzas AN, Liao D, et al. Insomnia with objective short sleep duration and incident hypertension: the Penn State Cohort. Hypertension 2012;60:929-35.

Vgontzas AN, Bixler EO, Lin HM, et al. Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab 2001;86:3787-94.

Irwin M, Clark C, Kennedy B, Christian Gillin J, Ziegler M. Nocturnal catecholamines and immune function in insomniacs, depressed patients, and control subjects. Brain Behav Immun 2003;17:365-72.

Mallon L, Broman JE, Hetta J. Relationship between insomnia, depression, and mortality: a 12-year follow-up of older adults in the community. Int Psychogeriatr 2000;12:295-306.

Baglioni C,Spiegelhalder K., Lombardo C., Riemann D. Sleep and emotions:a focus on insomnia. Sleep Med Rev 2010;14:227-38.

Belenky G, Wesensten NJ, Thorne DR, et al. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. J Sleep Res 2003;12:1- 12.

Huang ZL, Zhang Z, Qu WM. Roles of adenosine and its receptors in sleep-wake regulation. Int Rev Neurobiol 2014;119:349-71.

Stutts JC, Wilkins JW, Scott Osberg J, Vaughn BV. Driver risk factors for sleep-related crashes. Accid Anal Prev 2003;35:321-31.

Fortier-Brochu E,Beaulieu-Bonneau S., Ivers H., Morin C.M. Relations between sleep, fatigue, and health-related quality of life in individuals with insomnia. J Psychosom Res 2010;69:475-83.

Kling RN,McLeod C.B., Koehoorn M. Sleep problems and workplace injuries in Canada. Sleep 2010;33:611-8.

Oomen CA, Bekinschtein P, Kent BA, Saksida LM, Bussey TJ. Adult hippocampal neurogenesis and its role in cognition. Wiley Interdiscip Rev Cogn Sci 2014;5:573-87.

Riemann D, Voderholzer U, Spiegelhalder K, et al. Chronic insomnia and MRI-measured hippocampal volumes: a pilot study. Sleep 2007;30:955-8.

Noh HJ, Joo EY, Kim ST, et al. The relationship between hippocampal volume and cognition in patients with chronic primary insomnia. J Clin Neurol 2012;8:130-8.

Fernandez-Mendoza J, Calhoun SL, Bixler EO, et al. Sleep misperception and chronic insomnia in the general population: role of objective sleep duration and psychological profiles. Psychosom Med 2011;73:88-97.

Baglioni C, Battagliese G, Feige B, et al. Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies. J Affect Disord 2011;135:10-9.

Riemann D, Spiegelhalder K, Feige B, et al. The hyperarousal model of insomnia: a review of the concept and its evidence. Sleep Med Rev 2010;14:19-31.

Buckley TM, Schatzberg AF. A pilot study of the phase angle between cortisol and melatonin in major depression - a potential biomarker? J Psychiatr Res 2010;44:69-74.

Pinho M, Sehmbi M, Cudney LE, et al. The association between biological rhythms, depression, and functioning in bipolar disorder: a large multi-center study. Acta Psychiatr Scand 2015.


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