Skip to main content Accessibility help

Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3

  • A. B. Janssen (a1), L. E. Capron (a2), K. O'Donnell (a3), S. J. Tunster (a1), P. G. Ramchandani (a2), A. E. P. Heazell (a4), V. Glover (a5) and R. M. John (a1)...



Maternal prenatal stress during pregnancy is associated with fetal growth restriction and adverse neurodevelopmental outcomes, which may be mediated by impaired placental function. Imprinted genes control fetal growth, placental development, adult behaviour (including maternal behaviour) and placental lactogen production. This study examined whether maternal prenatal depression was associated with aberrant placental expression of the imprinted genes paternally expressed gene 3 (PEG3), paternally expressed gene 10 (PEG10), pleckstrin homology-like domain family a member 2 (PHLDA2) and cyclin-dependent kinase inhibitor 1C (CDKN1C), and resulting impaired placental human placental lactogen (hPL) expression.


A diagnosis of depression during pregnancy was recorded from Manchester cohort participants’ medical notes (n = 75). Queen Charlotte's (n = 40) and My Baby and Me study (MBAM) (n = 81) cohort participants completed the Edinburgh Postnatal Depression Scale self-rating psychometric questionnaire. Villous trophoblast tissue samples were analysed for gene expression.


In a pilot study, diagnosed depression during pregnancy was associated with a significant reduction in placental PEG3 expression (41%, p = 0.02). In two further independent cohorts, the Queen Charlotte's and MBAM cohorts, placental PEG3 expression was also inversely associated with maternal depression scores, an association that was significant in male but not female placentas. Finally, hPL expression was significantly decreased in women with clinically diagnosed depression (44%, p < 0.05) and in those with high depression scores (31% and 21%, respectively).


This study provides the first evidence that maternal prenatal depression is associated with changes in the placental expression of PEG3, co-incident with decreased expression of hPL. This aberrant placental gene expression could provide a possible mechanistic explanation for the co-occurrence of maternal depression, fetal growth restriction, impaired maternal behaviour and poorer offspring outcomes.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3
      Available formats


This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (, which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

Corresponding author

*Address for correspondence: R. M. John, Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK. (Email:


Hide All
Abou-Saleh, MT, Ghubash, R, Karim, L, Krymski, M, Bhai, I (1998). Hormonal aspects of postpartum depression. Psychoneuroendocrinology 23, 465475.
Apostolidou, S, Abu-Amero, S, O'Donoghue, K, Frost, J, Olafsdottir, O, Chavele, K, Whittaker, J, Loughna, P, Stanier, P, Moore, G (2007). Elevated placental expression of the imprinted PHLDA2 gene is associated with low birth weight. Journal of Molecular Medicine 85, 379387.
Asher, I, Kaplan, B, Modai, I, Neri, A, Valevski, A, Weizman, A (1995). Mood and hormonal changes during late pregnancy and puerperium. Clinical and Experimental Obstetrics and Gynecology 22, 321325.
Blakeley, PM, Capron, LE, Jensen, AB, O'Donnell, KJ, Glover, V (2013). Maternal prenatal symptoms of depression and down regulation of placental monoamine oxidase A expression. Journal of Psychosomatic Research 75, 341345.
Bridges, RS, DiBiase, R, Loundes, DD, Doherty, PC (1985). Prolactin stimulation of maternal behavior in female rats. Science 227, 782784.
Bridges, RS, Freemark, MS (1995). Human placental lactogen infusions into the medial preoptic area stimulate maternal behavior in steroid-primed, nulliparous female rats. Hormones and Behaviour 29, 216226.
Bridges, RS, Grattan, DR (2003). Prolactin-induced neurogenesis in the maternal brain. Trends in Endocrinology and Metabolism 14, 199201.
Bridges, RS, Numan, M, Ronsheim, PM, Mann, PE, Lupini, CE (1990). Central prolactin infusions stimulate maternal behavior in steroid-treated, nulliparous female rats. Proceedings of the National Academy of Sciences USA 87, 80038007.
Bridges, RS, Robertson, MC, Shiu, RP, Sturgis, JD, Henriquez, BM, Mann, PE (1997). Central lactogenic regulation of maternal behavior in rats: steroid dependence, hormone specificity, and behavioral potencies of rat prolactin and rat placental lactogen I. Endocrinology 138, 756763.
Broad, KD, Keverne, EB (2011). Placental protection of the fetal brain during short-term food deprivation. Proceedings of the National Academy of Sciences USA 108, 1523715241.
Champagne, FA, Curley, J, Swaney, W, Hasen, N, Keverne, EB (2009). Paternal influence on female behavior: the role of Peg3 in exploration, olfaction, and neuroendocrine regulation of maternal behavior of female mice. Behavioral Neuroscience 123, 469480.
Chiavegatto, S, Sauce, B, Ambar, G, Cheverud, JM, Peripato, AC (2012). Hypothalamic expression of Peg3 gene is associated with maternal care differences between SM/J and LG/J mouse strains. Brain and Behavior 2, 365376.
Cleal, JK, Day, P, Hanson, MA, Lewis, RM (2009). Measurement of housekeeping genes in human placenta. Placenta 30, 10021003.
Cleal, JK, Day, PL, Hanson, MA, Lewis, RM (2010). Sex differences in the mRNA levels of housekeeping genes in human placenta. Placenta 31, 556557.
Clifton, VL (2010). Review: Sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta 31 (Suppl.), S33S39.
Cox, JL, Chapman, G, Murray, D, Jones, P (1996). Validation of the Edinburgh Postnatal Depression Scale (EPDS) in non-postnatal women. Journal of Affective Disorders 39, 185189.
Cox, JL, Holden, JM, Sagovsky, R (1987). Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. British Journal of Psychiatry 150, 782786.
Curley, JP, Pinnock, SB, Dickson, SL, Thresher, R, Miyoshi, N, Surani, MA, Keverne, EB (2005). Increased body fat in mice with a targeted mutation of the paternally expressed imprinted gene Peg3 . FASEB Journal 19, 13021304.
de Tychey, C, Briancon, S, Lighezzolo, J, Spitz, E, Kabuth, B, de Luigi, V, Messembourg, C, Girvan, F, Rosati, A, Thockler, A, Vincent, S (2008). Quality of life, postnatal depression and baby gender. Journal of Clinical Nursing 17, 312322.
Diplas, AI, Lambertini, L, Lee, M-J, Sperling, R, Lee, YL, Wetmur, JG, Chen, J (2009). Differential expression of imprinted genes in normal and IUGR human placentas. Epigenetics 4, 235240.
Dutton, PJ, Warrander, LK, Roberts, SA, Bernatavicius, G, Byrd, LM, Gaze, D, Kroll, J, Jones, RL, Sibley, CP, Froen, JF, Heazell, AE (2012). Predictors of poor perinatal outcome following maternal perception of reduced fetal movements – a prospective cohort study. PLOS ONE 7, e39784.
Feng, W, Marquez, RT, Lu, Z, Liu, J, Lu, KH, Issa, JP, Fishman, DM, Yu, Y, Bast, RC Jr. (2008). Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation. Cancer 112, 14891502.
Fritz, MS, Mackinnon, DP (2007). Required sample size to detect the mediated effect. Psychological Science 18, 233239.
Gerardin, P, Wendland, J, Bodeau, N, Galin, A, Bialobos, S, Tordjman, S, Mazet, P, Darbois, Y, Nizard, J, Dommergues, M, Cohen, D (2011). Depression during pregnancy: is the developmental impact earlier in boys? A prospective case–control study. Journal of Clinical Psychiatry 72, 378387.
Glover, V, Hill, J (2012). Sex differences in the programming effects of prenatal stress on psychopathology and stress responses: an evolutionary perspective. Physiology and Behavior 106, 736740.
Glynn, LM, Sandman, CA (2011). Prenatal origins of neurological development: a critical period for fetus and mother. Current Directions in Psychological Science 20, 384389.
Green, BB, Kappil, M, Lambertini, L, Armstrong, DA, Guerin, DJ, Sharp, AJ, Lester, BM, Chen, J, Marsit, CJ (2015). Expression of imprinted genes in placenta is associated with infant neurobehavioral development. Epigenetics 10, 834841.
Groer, MW, Morgan, K (2007). Immune, health and endocrine characteristics of depressed postpartum mothers. Psychoneuroendocrinology 32, 133139.
Gude, NM, Roberts, CT, Kalionis, B, King, RG (2004). Growth and function of the normal human placenta. Thrombosis Research 114, 397407.
Haig, D (2008). Placental growth hormone-related proteins and prolactin-related proteins. Placenta 29 (Suppl. A), S36S41.
Hayes, A (2013). Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-based Approach. Guilford Press: New York.
Ingram, J, Greenwood, R, Woolridge, M (2003). Hormonal predictors of postnatal depression at 6 months in breastfeeding women. Journal of Reproductive and Infant Psychology 21, 6168.
Janssen, AB, Kertes, DA, McNamara, GI, Braithwaite, EC, Creeth, HD, Glover, VI, John, RM (2016). A role for the placenta in programming maternal mood and childhood behavioural disorders. Journal of Neuroendocrinology. Published online 2 February 2016. doi:10.1111/jne.12373.
Janssen, AB, Tunster, SJ, Savory, N, Holmes, A, Beasley, J, Parveen, SA, Penketh, RJ, John, RM (2015). Placental expression of imprinted genes varies with sampling site and mode of delivery. Placenta 36, 790795.
Jensen, AB, Tunster, SJ, John, RM (2014). The significance of elevated placental PHLDA2 in human growth restricted pregnancies. Placenta 35, 528532.
Jensen Pena, C, Monk, C, Champagne, FA (2012). Epigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain. PLOS ONE 7, e39791.
John, RM (2013). Epigenetic regulation of placental endocrine lineages and complications of pregnancy. Biochemical Society Transactions 41, 701709.
Khashan, AS, McNamee, R, Abel, KM, Pedersen, MG, Webb, RT, Kenny, LC, Mortensen, PB, Baker, PN (2008). Reduced infant birthweight consequent upon maternal exposure to severe life events. Psychosomatic Medicine 70, 688694.
Kim, J, Frey, WD, He, H, Kim, H, Ekram, MB, Bakshi, A, Faisal, M, Perera, BP, Ye, A, Teruyama, R (2013). Peg3 mutational effects on reproduction and placenta-specific gene families. PLOS ONE 8, e83359.
Lagerberg, D, Magnusson, M (2012). Infant gender and postpartum sadness in the light of region of birth and some other factors: a contribution to the knowledge of postpartum depression. Archives of Women's Mental Health 15, 121130.
Lefebvre, L, Viville, S, Barton, SC, Ishino, F, Keverne, EB, Surani, MA (1998). Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest . Nature Genetics 20, 163169.
Li, J, Olsen, J, Vestergaard, M, Obel, C (2010). Attention-deficit/hyperactivity disorder in the offspring following prenatal maternal bereavement: a nationwide follow-up study in Denmark. European Child and Adolescent Psychiatry 19, 747753.
Li, LL, Keverne, EB, Aparicio, SA, Ishino, F, Barton, SC, Surani, MA (1999). Regulation of maternal behavior and offspring growth by paternally expressed Peg3 . Science 284, 330334.
Liu, Y, Murphy, SK, Murtha, AP, Fuemmeler, BF, Schildkraut, J, Huang, Z, Overcash, F, Kurtzberg, J, Jirtle, R, Iversen, ES, Forman, MR, Hoyo, C (2012). Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements. Epigenetics 7, 735746.
Livak, KJ, Schmittgen, TD (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 25, 402408.
Mairesse, J, Lesage, J, Breton, C, Breant, B, Hahn, T, Darnaudery, M, Dickson, SL, Seckl, J, Blondeau, B, Vieau, D, Maccari, S, Viltart, O (2007). Maternal stress alters endocrine function of the feto-placental unit in rats. American Journal of Physiology. Endocrinology and Metabolism 292, E1526E1533.
McNamara, GI, Isles, AR (2014). Influencing the social group: the role of imprinted genes. Advances in Genetics 86, 107134.
Meller, M, Vadachkoria, S, Luthy, DA, Williams, MA (2005). Evaluation of housekeeping genes in placental comparative expression studies. Placenta 26, 601607.
Murthi, P, Fitzpatrick, E, Borg, AJ, Donath, S, Brennecke, SP, Kalionis, B (2008). GAPDH, 18S rRNA and YWHAZ are suitable endogenous reference genes for relative gene expression studies in placental tissues from human idiopathic fetal growth restriction. Placenta 29, 798801.
Newbern, D, Freemark, M (2011). Placental hormones and the control of maternal metabolism and fetal growth. Current Opinion in Endocrinology, Diabetes and Obesity 18, 409416.
O'Donnell, K, O'Connor, TG, Glover, V (2009). Prenatal stress and neurodevelopment of the child: focus on the HPA axis and role of the placenta. Developmental Neuroscience 31, 285292.
O'Donnell, KJ, Bugge Jensen, A, Freeman, L, Khalife, N, O'Connor, TG, Glover, V (2012). Maternal prenatal anxiety and downregulation of placental 11β-HSD2. Psychoneuroendocrinology 37, 818826.
Pearson, RM, Melotti, R, Heron, J, Joinson, C, Stein, A, Ramchandani, PG, Evans, J (2012). Disruption to the development of maternal responsiveness? The impact of prenatal depression on mother–infant interactions. Infant Behavior and Development 35, 613626.
Radford, EJ, Isganaitis, E, Jimenez-Chillaron, J, Schroeder, J, Molla, M, Andrews, S, Didier, N, Charalambous, M, McEwen, K, Marazzi, G, Sassoon, D, Patti, ME, Ferguson-Smith, AC (2012). An unbiased assessment of the role of imprinted genes in an intergenerational model of developmental programming. PLoS Genetics 8, e1002605.
Reynolds, RM, Pesonen, AK, O'Reilly, JR, Tuovinen, S, Lahti, M, Kajantie, E, Villa, PM, Laivuori, H, Hamalainen, E, Seckl, JR, Raikkonen, K (2015). Maternal depressive symptoms throughout pregnancy are associated with increased placental glucocorticoid sensitivity. Psychological Medicine 45, 20232030.
Roh, CR, Budhraja, V, Kim, HS, Nelson, DM, Sadovsky, Y (2005). Microarray-based identification of differentially expressed genes in hypoxic term human trophoblasts and in placental villi of pregnancies with growth restricted fetuses. Placenta 26, 319328.
Rondo, PHC, Ferreira, RF, Nogueira, F, Ribeiro, MCN, Lobert, H, Artes, R (2003). Maternal psychological stress and distress as predictors of low birth weight, prematurity and intrauterine growth retardation. European Journal of Clinical Nutrition 57, 266272.
Shingo, T, Gregg, C, Enwere, E, Fujikawa, H, Hassam, R, Geary, C, Cross, JC, Weiss, S (2003). Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 299, 117120.
Smith, FM, Garfield, AS, Ward, A (2006). Regulation of growth and metabolism by imprinted genes. Cytogenetic and Genome Research 113, 279291.
Steer, RA, Scholl, TO, Hediger, ML, Fischer, RL (1992). Self-reported depression and negative pregnancy outcomes. Journal of Clinical Epidemiology 45, 10931099.
Surani, MA (1998). Imprinting and the initiation of gene silencing in the germ line. Cell 93, 309312.
Talge, NM, Neal, C, Glover, V (2007). Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? Journal of Child Psychology and Psychiatry 48, 245261.
Torner, L, Toschi, N, Pohlinger, A, Landgraf, R, Neumann, ID (2001). Anxiolytic and anti-stress effects of brain prolactin: improved efficacy of antisense targeting of the prolactin receptor by molecular modeling. Journal of Neuroscience 21, 32073214.
Tunster, SJ, Jensen, AB, John, RM (2013). Imprinted genes in mouse placental development and the regulation of fetal energy stores. Reproduction 145, R117R137.
Van den Bergh, BR, Mulder, EJ, Mennes, M, Glover, V (2005). Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms. A review. Neuroscience and Biobehavioral Reviews 29, 237258.
van Os, J, Selten, JP (1998). Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. British Journal of Psychiatry 172, 324326.
Vidal, AC, Benjamin Neelon, SE, Liu, Y, Tuli, AM, Fuemmeler, BF, Hoyo, C, Murtha, AP, Huang, Z, Schildkraut, J, Overcash, F, Kurtzberg, J, Jirtle, RL, Iversen, ES, Murphy, SK (2014). Maternal stress, preterm birth, and DNA methylation at imprint regulatory sequences in humans. Genetics and Epigenetics 6, 3744.
Walker, TL, Vukovic, J, Koudijs, MM, Blackmore, DG, Mackay, EW, Sykes, AM, Overall, RW, Hamlin, AS, Bartlett, PF (2012). Prolactin stimulates precursor cells in the adult mouse hippocampus. PLOS ONE 7, e44371.
Warrander, LK, Batra, G, Bernatavicius, G, Greenwood, SL, Dutton, P, Jones, RL, Sibley, CP, Heazell, AE (2012). Maternal perception of reduced fetal movements is associated with altered placental structure and function. PLOS ONE 7, e34851.


Related content

Powered by UNSILO

Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3

  • A. B. Janssen (a1), L. E. Capron (a2), K. O'Donnell (a3), S. J. Tunster (a1), P. G. Ramchandani (a2), A. E. P. Heazell (a4), V. Glover (a5) and R. M. John (a1)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.