Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Pregnancy and Childbirth
Published in: BMC Pregnancy and Childbirth 1/2019

Open Access 01-12-2019 | Antidepressant Drugs | Research article

The effect of antenatal depression and antidepressant treatment on placental tissue: a protein-validated gene expression study

Authors: Åsa Edvinsson, Charlotte Hellgren, Theodora Kunovac Kallak, Helena Åkerud, Alkistis Skalkidou, Elisabet Stener-Victorin, Romina Fornes, Olav Spigset, Susanne Lager, Jocelien Olivier, Inger Sundström-Poromaa

Published in: BMC Pregnancy and Childbirth | Issue 1/2019

Login to get access

Abstract

Background

Antenatal depression affects 10–20% of pregnant women. Around 2–4% of European pregnant women use antidepressant treatment, most commonly selective serotonin reuptake inhibitors (SSRIs). Poor pregnancy outcomes, such as preterm birth and low birth weight, have been described in women with antenatal depression and in pregnant women on SSRI treatment. However, the effects of antenatal depression and antidepressant treatment on the placenta are largely unknown. The aim of this work was to compare placental gene and protein expression in healthy women, women with untreated antenatal depression and women on antidepressant treatment during pregnancy.

Methods

Placental samples from 47 controls, 25 depressed and 45 SSRI-treated women were analysed by means of qPCR using custom-designed TaqMan low-density arrays (TLDAs) for 44 genes previously known to be involved in the pathophysiology of depression, and expressed in the placenta. Moreover, placental protein expression was determined by means of immunohistochemistry in 37 healthy controls, 13 women with untreated depression and 21 women on antidepressant treatment. Statistical comparisons between groups were performed by one-way ANOVA or the Kruskal–Wallis test.

Results

Nominally significant findings were noted for HTR1A and NPY2R, where women with untreated depression displayed higher gene expression than healthy controls (p < 0.05), whereas women on antidepressant treatment had similar expression as healthy controls. The protein expression analyses revealed higher expression of HTR1A in placentas from women on antidepressant treatment, than in placentas from healthy controls (p < 0.05).

Conclusion

The differentially expressed HTR1A, both at the gene and the protein level that was revealed in this study, suggests the involvement of HTR1A in the effect of antenatal depression on biological mechanisms in the placenta. More research is needed to elucidate the role of depression and antidepressant treatment on the placenta, and, further, the effect on the fetus.
Appendix
Available only for authorised users
Literature
1.
Woody CA, Ferrari AJ, Siskind DJ, Whiteford HA, Harris MG. A systematic review and meta-regression of the prevalence and incidence of perinatal depression. J Affect Disord. 2017;219:86–92.CrossRefPubMed
2.
Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T. Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol. 2005;106(5 Pt 1):1071–83.CrossRefPubMed
3.
Andersson L, Sundstrom-Poromaa I, Bixo M, Wulff M, Bondestam K. aStrom M. point prevalence of psychiatric disorders during the second trimester of pregnancy: a population-based study. Am J Obstet Gynecol. 2003;189(1):148–54.CrossRefPubMed
4.
Gorman LL, O'Hara MW, Figueiredo B, Hayes S, Jacquemain F, Kammerer MH, et al. Adaptation of the structured clinical interview for DSM-IV disorders for assessing depression in women during pregnancy and post-partum across countries and cultures. Br J Psychiatry Suppl. 2004;46:s17–23.CrossRefPubMed
5.
Melville JL, Gavin A, Guo Y, Fan MY, Katon WJ. Depressive disorders during pregnancy: prevalence and risk factors in a large urban sample. Obstet Gynecol. 2010;116(5):1064–70.CrossRefPubMedPubMedCentral
6.
Patkar AA, Bilal L, Masand PS. Pharmacotherapy of depression in pregnancy. Ann Clin Psychiatry. 2004;16(2):87–100.CrossRefPubMed
7.
The National Board of Health and Welfare. Sweden 2016. (www.socialstyrelsen.se).
8.
Huybrechts KF, Palmsten K, Mogun H, Kowal M, Avorn J, Setoguchi-Iwata S, et al. National trends in antidepressant medication treatment among publicly insured pregnant women. Gen Hosp Psychiatry. 2013;35(3):265–71.CrossRefPubMedPubMedCentral
9.
Kieler H. The Nordic health registers - an important source when evaluating the safety of antidepressants during pregnancy. Clin Epidemiol. 2010;2:205–7.CrossRefPubMedPubMedCentral
10.
El Marroun H, Jaddoe VW, Hudziak JJ, Roza SJ, Steegers EA, Hofman A, et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry. 2012;69(7):706–14.CrossRefPubMed
11.
Petersen I, Peltola T, Kaski S, Walters KR, Hardoon S. Depression, depressive symptoms and treatments in women who have recently given birth: UK cohort study. BMJ Open. 2018;8(10):e022152.CrossRefPubMedPubMedCentral
12.
Charlton RA, Jordan S, Pierini A, Garne E, Neville AJ, Hansen AV, et al. Selective serotonin reuptake inhibitor prescribing before, during and after pregnancy: a population-based study in six European regions. BJOG. 2015;122(7):1010–20.CrossRefPubMed
13.
Furu K, Kieler H, Haglund B, Engeland A, Selmer R, Stephansson O, et al. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design. BMJ. 2015;350:h1798.CrossRefPubMedPubMedCentral
14.
Olivier JD, Akerud H, Kaihola H, Pawluski JL, Skalkidou A, Hogberg U, et al. The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on offspring. Front Cell Neurosci. 2013;7:73.CrossRefPubMedPubMedCentral
15.
Prady SL, Hanlon I, Fraser LK, Mikocka-Walus A. A systematic review of maternal antidepressant use in pregnancy and short- and long-term offspring's outcomes. Arch Womens Ment Health. 2018;21(2):127–40.
16.
Wang YZ, S. Chapter 3, structure of the placenta. In: Vascular biology of the placenta. Morgan & Claypool Life Sciences: San Rafael (CA); 2010.CrossRef
17.
Audette MC, Kingdom JC. Screening for fetal growth restriction and placental insufficiency. Semin Fetal Neonatal Med. 2018;23(2):119–25.CrossRefPubMed
18.
Hodyl NA, Aboustate N, Bianco-Miotto T, Roberts CT, Clifton VL, Stark MJ. Child neurodevelopmental outcomes following preterm and term birth: what can the placenta tell us? Placenta. 2017;57:79–86.CrossRefPubMed
19.
Sultana Z, Maiti K, Dedman L, Smith R. Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction? Am J Obstet Gynecol. 2018;218(2S):S762–S73.CrossRefPubMed
20.
Reijnders IF, Mulders A, Koster MPH. Placental development and function in women with a history of placenta-related complications: a systematic review. Acta Obstet Gynecol Scand. 2018;97(3):248–57.CrossRefPubMed
21.
Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D. Placental passage of antidepressant medications. Am J Psychiatry. 2003;160(5):993–6.CrossRefPubMed
22.
Loughhead AM, Fisher AD, Newport DJ, Ritchie JC, Owens MJ, DeVane CL, et al. Antidepressants in amniotic fluid: another route of fetal exposure. Am J Psychiatry. 2006;163(1):145–7.CrossRefPubMed
23.
Cikos S, Fabian D, Makarevich AV, Chrenek P, Koppel J. Biogenic monoamines in preimplantation development. Hum Reprod. 2011;26(9):2296–305.CrossRefPubMed
24.
Oufkir T, Arseneault M, Sanderson JT, Vaillancourt C. The 5-HT 2A serotonin receptor enhances cell viability, affects cell cycle progression and activates MEK-ERK1/2 and JAK2-STAT3 signalling pathways in human choriocarcinoma cell lines. Placenta. 2010;31(5):439–47.CrossRefPubMed
25.
Charnock-Jones DS, Burton GJ. Placental vascular morphogenesis. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14(6):953–68.CrossRefPubMed
26.
Bhuiyan M, Petropoulos S, Gibb W, Matthews SG. Sertraline alters multidrug resistance phosphoglycoprotein activity in the mouse placenta and fetal blood-brain barrier. Reprod Sci. 2012;19(4):407–15.CrossRefPubMed
27.
Bonnin A, Goeden N, Chen K, Wilson ML, King J, Shih JC, et al. A transient placental source of serotonin for the fetal forebrain. Nature. 2011;472(7343):347–50.CrossRefPubMedPubMedCentral
28.
Gentile S, Fusco ML. Placental and fetal effects of antenatal exposure to antidepressants or untreated maternal depression. J Matern Fetal Neonatal Med. 2017;30(10):1189–99.CrossRefPubMed
29.
Kaihola H, Olivier J, Poromaa IS, Akerud H. The effect of antenatal depression and selective serotonin reuptake inhibitor treatment on nerve growth factor signaling in human placenta. PLoS One. 2015;10(1):e0116459.CrossRefPubMedPubMedCentral
30.
Olivier JD, Akerud H, Skalkidou A, Kaihola H, Sundstrom-Poromaa I. The effects of antenatal depression and antidepressant treatment on placental gene expression. Front Cell Neurosci. 2014;8:465.PubMed
31.
Kumsta R, Hummel E, Chen FS, Heinrichs M. Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience. Front Neurosci. 2013;7:83.CrossRefPubMedPubMedCentral
32.
Simons RL, Lei MK, Beach SRH, Cutrona CE, Philibert RA. Methylation of the oxytocin receptor gene mediates the effect of adversity on negative schemas and depression. Dev Psychopathol. 2017;29(3):725–36.CrossRefPubMed
33.
Galbally M, Ryan J. Van IM, Watson SJ, Spigset O, Lappas M, et al. maternal depression, antidepressant use and placental oxytocin receptor DNA methylation: findings from the MPEWS study. Psychoneuroendocrinology. 2018;90:1–8.CrossRefPubMed
34.
Janssen AB, Capron LE, O'Donnell K, Tunster SJ, Ramchandani PG, Heazell AE, et al. Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3. Psychol Med. 2016;46(14):2999–3011.CrossRefPubMedPubMedCentral
35.
Capron LE, Ramchandani PG, Glover V. Maternal prenatal stress and placental gene expression of NR3C1 and HSD11B2: the effects of maternal ethnicity. Psychoneuroendocrinology. 2018;87:166–72.CrossRefPubMed
36.
Togher KL, Treacy E, O'Keeffe GW, Kenny LC. Maternal distress in late pregnancy alters obstetric outcomes and the expression of genes important for placental glucocorticoid signalling. Psychiatry Res. 2017;255:17–26.CrossRefPubMed
37.
Seth S, Lewis AJ, Saffery R, Lappas M, Galbally M. Maternal prenatal mental health and placental 11beta-HSD2 gene expression: initial findings from the mercy pregnancy and emotional wellbeing study. Int J Mol Sci. 2015;16(11):27482–96.CrossRefPubMedPubMedCentral
38.
Reynolds RM, Pesonen AK, O'Reilly JR, Tuovinen S, Lahti M, Kajantie E, et al. Maternal depressive symptoms throughout pregnancy are associated with increased placental glucocorticoid sensitivity. Psychol Med. 2015;45(10):2023–30.CrossRefPubMed
39.
O'Donnell KJ, Bugge Jensen A, Freeman L, Khalife N, O'Connor TG, Glover V. Maternal prenatal anxiety and downregulation of placental 11beta-HSD2. Psychoneuroendocrinology. 2012;37(6):818–26.CrossRefPubMed
40.
Zhang W, Finik J, Dana K, Glover V, Ham J, Nomura Y. Prenatal depression and infant temperament: the moderating role of placental gene expression. Infancy. 2018;23(2):211–31.CrossRefPubMed
41.
Lahti-Pulkkinen M, Cudmore MJ, Haeussner E, Schmitz C, Pesonen AK, Hamalainen E, et al. Placental morphology is associated with maternal depressive symptoms during pregnancy and toddler psychiatric problems. Sci Rep. 2018;8(1):791.CrossRefPubMedPubMedCentral
42.
Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item Edinburgh postnatal depression scale. Br J Psychiatry. 1987;150:782–6.CrossRefPubMed
43.
Rubertsson C, Borjesson K, Berglund A, Josefsson A, Sydsjo G. The Swedish validation of Edinburgh postnatal depression scale (EPDS) during pregnancy. Nord J Psychiatry. 2011;65(6):414–8.CrossRefPubMed
44.
Bergink V, Kooistra L. Lambregtse-van den berg MP, Wijnen H, Bunevicius R, van Baar a, et al. validation of the Edinburgh depression scale during pregnancy. J Psychosom Res. 2011;70(4):385–9.CrossRefPubMed
45.
Ponder KL, Salisbury A, McGonnigal B, Laliberte A, Lester B, Padbury JF. Maternal depression and anxiety are associated with altered gene expression in the human placenta without modification by antidepressant use: implications for fetal programming. Dev Psychobiol. 2011;53(7):711–23.CrossRefPubMedPubMedCentral
46.
Hannerfors AK, Hellgren C, Schijven D, Iliadis SI, Comasco E, Skalkidou A, et al. Treatment with serotonin reuptake inhibitors during pregnancy is associated with elevated corticotropin-releasing hormone levels. Psychoneuroendocrinology. 2015;58:104–13.CrossRefPubMed
47.
Cottrell EC, Seckl JR, Holmes MC, Wyrwoll CS. Foetal and placental 11beta-HSD2: a hub for developmental programming. Acta Physiol (Oxf). 2014;210(2):288–95.CrossRef
48.
Hellgren C, Akerud H, Skalkidou A, Backstrom T, Sundstrom-Poromaa I. Low serum allopregnanolone is associated with symptoms of depression in late pregnancy. Neuropsychobiology. 2014;69(3):147–53.CrossRefPubMed
49.
Hellgren C, Comasco E, Skalkidou A, Sundstrom-Poromaa I. Allopregnanolone levels and depressive symptoms during pregnancy in relation to single nucleotide polymorphisms in the allopregnanolone synthesis pathway. Horm Behav. 2017;94:106–13.CrossRefPubMed
50.
Andersen CL, Jensen JL, Orntoft TF. Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res. 2004;64(15):5245–50.CrossRefPubMed
51.
Hirsch FR, Varella-Garcia M, Bunn PA Jr, Di Maria MV, Veve R, Bremmes RM, et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21(20):3798–807.CrossRefPubMed
52.
John T, Liu G, Tsao MS. Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors. Oncogene. 2009;28(Suppl 1):S14–23.CrossRefPubMed
53.
Reis M, Aamo T, Spigset O, Ahlner J. Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database. Ther Drug Monit. 2009;31(1):42–56.CrossRefPubMed
54.
Huang WQ, Zhang CL, Di XY, Zhang RQ. Studies on the localization of 5-hydroxytryptamine and its receptors in human placenta. Placenta. 1998;19(8):655–61.CrossRefPubMed
55.
Velasquez JC, Goeden N, Bonnin A. Placental serotonin: implications for the developmental effects of SSRIs and maternal depression. Front Cell Neurosci. 2013;7:47.CrossRefPubMedPubMedCentral
56.
St-Pierre J, Laurent L, King S, Vaillancourt C. Effects of prenatal maternal stress on serotonin and fetal development. Placenta. 2016;48(Suppl 1):S66–71.CrossRefPubMed
57.
Paquette AG, Lesseur C, Armstrong DA, Koestler DC, Appleton AA, Lester BM, et al. Placental HTR2A methylation is associated with infant neurobehavioral outcomes. Epigenetics. 2013;8(8):796–801.CrossRefPubMedPubMedCentral
58.
Beck SG, Choi KC, List TJ. Comparison of 5-hydroxytryptamine1A-mediated hyperpolarization in CA1 and CA3 hippocampal pyramidal cells. J Pharmacol Exp Ther. 1992;263(1):350–9.PubMed
59.
Hamon M, Lanfumey L, el Mestikawy S, Boni C, Miquel MC, Bolanos F, et al. The main features of central 5-HT1 receptors. Neuropsychopharmacology. 1990;3(5–6):349–60.PubMed
60.
Riad M, Garcia S, Watkins KC, Jodoin N, Doucet E, Langlois X, et al. Somatodendritic localization of 5-HT1A and preterminal axonal localization of 5-HT1B serotonin receptors in adult rat brain. J Comp Neurol. 2000;417(2):181–94.CrossRefPubMed
61.
Hjorth S, Bengtsson HJ, Kullberg A, Carlzon D, Peilot H, Auerbach SB. Serotonin autoreceptor function and antidepressant drug action. J Psychopharmacol. 2000;14(2):177–85.CrossRefPubMed
62.
Briley M, Moret C. Neurobiological mechanisms involved in antidepressant therapies. Clin Neuropharmacol. 1993;16(5):387–400.CrossRefPubMed
63.
Artigas F. Serotonin receptors involved in antidepressant effects. Pharmacol Ther. 2013;137(1):119–31.CrossRefPubMed
64.
Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, et al. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci. 2003;23(25):8788–99.CrossRefPubMedPubMedCentral
65.
Anttila S, Huuhka K, Huuhka M, Rontu R, Hurme M, Leinonen E, et al. Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. J Neural Transm (Vienna). 2007;114(8):1065–8.CrossRef
66.
Albert PR, Lemonde S. 5-HT1A receptors, gene repression, and depression: guilt by association. Neuroscientist. 2004;10(6):575–93.CrossRefPubMed
67.
Olivier JD, Valles A, van Heesch F, Afrasiab-Middelman A, Roelofs JJ, Jonkers M, et al. Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring. Psychopharmacology. 2011;217(3):419–32.CrossRefPubMed
68.
Leung K. [(18)F]Y1–973. Molecular Imaging and Contrast Agent Database (MICAD). Bethesda (MD)2004.
69.
Ortiz AA, Milardo LF, DeCarr LB, Buckholz TM, Mays MR, Claus TH, et al. A novel long-acting selective neuropeptide Y2 receptor polyethylene glycol-conjugated peptide agonist reduces food intake and body weight and improves glucose metabolism in rodents. J Pharmacol Exp Ther. 2007;323(2):692–700.CrossRefPubMed
70.
Paiva SP, Veloso CA, Campos FF, Carneiro MM, Tilan JU, Wang H, et al. Elevated levels of neuropeptide Y in preeclampsia: a pilot study implicating a role for stress in pathogenesis of the disease. Neuropeptides. 2016;55:127–35.CrossRefPubMed
71.
Beloosesky R, Gayle DA, Amidi F, Ahanya SN, Desai M, Ross MG. Ontogenic expression of putative feeding peptides in the rat fetal brain and placenta. Nutr Neurosci. 2006;9(1–2):33–40.CrossRefPubMed
72.
Roseboom PH, Nanda SA, Fox AS, Oler JA, Shackman AJ, Shelton SE, et al. Neuropeptide Y receptor gene expression in the primate amygdala predicts anxious temperament and brain metabolism. Biol Psychiatry. 2014;76(11):850–7.CrossRefPubMed
73.
El Marroun H, White T, Verhulst FC, Tiemeier H. Maternal use of antidepressant or anxiolytic medication during pregnancy and childhood neurodevelopmental outcomes: a systematic review. Eur Child Adolesc Psychiatry. 2014;23(10):973–92.CrossRefPubMed
74.
Lupattelli A, Spigset O, Bjornsdottir I, Hameen-Anttila K, Mardby AC, Panchaud A, et al. Patterns and factors associated with low adherence to psychotropic medications during pregnancy--a cross-sectional, multinational web-based study. Depress Anxiety. 2015;32(6):426–36.CrossRefPubMed
75.
Zoega H, Kieler H, Norgaard M, Furu K, Valdimarsdottir U, Brandt L, et al. Use of SSRI and SNRI antidepressants during pregnancy: a population-based study from Denmark, Iceland, Norway and Sweden. Plos One. 2015;10(12):e0144474.CrossRefPubMedPubMedCentral
76.
Hellgren C, Edvinsson A, Olivier JD, Fornes R, Stener-Victorin E, Ubhayasekera SJ, et al. Tandem mass spectrometry determined maternal cortisone to cortisol ratio and psychiatric morbidity during pregnancy-interaction with birth weight. Psychoneuroendocrinology. 2016;69:142–9.CrossRefPubMed
Metadata
Title
The effect of antenatal depression and antidepressant treatment on placental tissue: a protein-validated gene expression study
Authors
Åsa Edvinsson
Charlotte Hellgren
Theodora Kunovac Kallak
Helena Åkerud
Alkistis Skalkidou
Elisabet Stener-Victorin
Romina Fornes
Olav Spigset
Susanne Lager
Jocelien Olivier
Inger Sundström-Poromaa
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Pregnancy and Childbirth / Issue 1/2019
Electronic ISSN: 1471-2393
DOI
https://doi.org/10.1186/s12884-019-2586-y

Other articles of this Issue 1/2019

BMC Pregnancy and Childbirth 1/2019 Go to the issue

Research article

Women’s recall of health care provider counselling on gestational weight gain (GWG): a prospective, population-based study

Research article

Quality of maternal and newborn healthcare services in two public hospitals of Bangladesh: identifying gaps and provisions for improvement

Research article

Prevalence and profile of adverse drug reactions in high-risk pregnancy: a cohort study

Research article

Acceptability of a text message-based intervention for obesity prevention in infants from Hawai‘i and Puerto Rico WIC

Research article

Antenatal care as a means to increase participation in the continuum of maternal and child healthcare: an analysis of the poorest regions of four Mesoamérican countries

Research article

Seasonality, temperature and pregnancy oral glucose tolerance test results in Australia