Thesis

FROM MOTHER CHILD Transmission and Treatment of Mental Illness during Pregnancy Carlinde Wilhelmine Broeks to

Colophon: All rights reserved. No parts of this publication may be reproduced or transmitted in any form or by any means without the written permission of the author. The author gratefully acknowledges the financial support provided by Erasmus Medical Center and NPI/Arkin. Chapter 2 (Bright Up study) was funded by the ‘Light, Cognition, Behaviour and Health’ program of the Netherlands Organization for Health Research and Development (NWO), in collaboration with Signify Research (grant 058-14-003; NTR5476). Chapters 3, 5, and 6 (INCAS study) were supported by the Sophia Foundation for Scientific Research (SSWO; grant 570, 2012). Chapter 4 (STOP or GO study) received funding from ZonMw (grant 836021011), with additional support from Erasmus MC, Department of Psychiatry (NTR4694). Chapter 7 presents a pilot for the PROFILE study, a multicenter cohort project funded by Stichting tot Steun VCVGZ, in collaboration with NPI (Arkin) and Erasmus MC, focusing on peripartum treatment for women with personality disorders. The printing of this thesis was financially supported by: Erasmus Medical Center and NPI/Arkin Author: Carlinde Wilhelmine Broeks Cover design: Dirk Bakker / Noemi Tombeur Printed by: Ipskamp Printing ISBN: 978-94-6536-122-2

From Mother to Child Transmission and Treatment of Mental Illness during Pregnancy Van moeder op kind Overdracht en behandeling van psychiatrische aandoeningen tijdens de zwangerschap ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de Rector Magnificus Prof.dr.ir. A.J. Schuit en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op op woensdag 13 mei 2026 om 10:30 uur door Carlinde Wilhelmine Broeks geboren te Heerlen

Promotiecommissie Promotoren: Dr. M.P. Lambregtse-Van den Berg Prof. dr. W.J.G. Hoogendijk Copromotoren: Dr. A.M. Kamperman Dr. H.L. Van Beoordelingscommissie: Prof. dr. H. El Marroun Prof. dr. J.J. van Busschbach Dr. P.C.R. Mulders Paranimfen: Irene Sporre Sanne Wiltink

Voor mijn moeder Elisabeth Charlotte Wiemer 1955 - 2007

“Family dysfunction rolls from generation to generation like a fire in the woods taking down everything in its path, until one person, in one generation, has the courage to turn and face the flames. That person brings peace to his ancestors and spares the children that follow.” — Terry Real

11 29 31 55 79 109 123 125 145 177 Table of Contents Chapter 1 General introduction Part I: Exploring stress physiology in pathways of transgenerational transmission Chapter 2 Cortisol awakening response in pregnant women with depressive disorders: a potential marker of recovery status from pregnancy to postpartum Chapter 3 An exploratory study of perinatal hair cortisol concentrations in mother-infant dyads with severe psychiatric disorders versus healthy controls Chapter 4 Intergenerational impact of childhood trauma on hair cortisol concentrations in mothers and their young infants Chapter 5 Salivary cortisol reactivity in 6-month-old infants of mothers with severe psychiatric disorders: findings from the face-to-Face StillFace paradigm Part II: Intervention perspectives in the peripartum period Chapter 6 Attachment security and disorganization in infants of mothers with severe psychiatric disorder: exploring the role of comorbid personality disorder Chapter 7 A multi-modular group-based intervention for pregnant women with personality disorders and related psychiatric conditions Chapter 8 General discussion

203 204 208 212 214 216 218 222 Part III: Appendices Summary Nederlandse samenvatting List of publications PhD portfolio About the author Over de cover Dankwoord

Chapter 1

General Introduction

Chapter 1 12 General Introduction Plato argued in Meno (~ 385 BC) that “all learning is but recollection”, suggesting that human beings do not acquire knowledge solely from experience, but that something is already present at birth, waiting to be recalled (1). While modern science does not support the notion of innate metaphysical knowledge, evidence suggests that prenatal experiences can shape physiology in enduring ways, influencing how a child enters the world (2). A newborn may seem like a tabula rasa, a blank slate, but its body and mind already carry the imprint of past generations. Research on prenatal exposure to extreme stress, such as famine and war, has shown long-term consequences for metabolic health, cardiovascular function, and mental well-being (3). These findings indicate that the intrauterine environment can exert a profound influence on offspring, potentially altering stress regulation across the lifespan. Psychological distress during pregnancy, including maternal anxiety, depression, or other psychopathology, may likewise influence fetal development in ways that persist well beyond birth (4). While children of mothers with psychiatric disorders face higher risks for both physical and mental health issues (5), emerging research has begun to elucidate the biological and developmental mechanisms involved, including alterations in the fetal HPA axis. These early-life adaptations to adversity may contribute to long-term mental health vulnerability; but through what precise mechanisms? Beyond scientific curiosity, this line of research was also shaped by clinical experience. During my training as a psychiatrist, I became increasingly drawn to the field of peripartum psychiatry, where the urgency of care and the potential for early intervention come together. Working closely with pregnant women facing psychiatric challenges, I am often struck by how their personal histories reflect transgenerational patterns of adversity and vulnerability. Yet despite these difficulties, I encounter a deep determination in these women to break that cycle, for their own sake and that of their children. In many ways, they are (metaphorically) the person in the family story who, as Terry Real put it, chooses “to turn and face the flames”. This dissertation seeks to contribute to our understanding of how maternal psychiatric disorders during pregnancy shape the developing child, in ways that may heighten the risk of dysregulated stress responses and psychiatric symptoms (6,7). A key pathway that may underlie this transmission is the hypothalamus-pituitary-adrenal (HPA) axis, the

General Introduction 13 1 body’s central stress response system, for which there is growing evidence of altered functioning in mothers affected by depression, anxiety, and trauma-related disorders and their offspring (8). The first part of this dissertation explores the potential role of HPA axis dysregulation in peripartum psychopathology and its impact on infants and young children. Building on these biological insights, the second part of the dissertation shifts focus to the clinical implications of maternal psychopathology. Specifically, it examines the quality of the attachment relationship between mother and child, particularly in mothers with and without comorbid personality disorder, and evaluates a group-based clinical intervention for pregnant women facing personality disorders and related psychiatric pathology. These studies reflect the notion that the peripartum period offers a window of opportunity: a time when positive, strength-based interventions can make a lasting difference in the lives of both mother and child (9,10). Together, they seek to contribute to a better integration of fundamental research and clinical care. Thus, while this dissertation primarily explores mechanisms of risk, it also considers how clinical interventions may support protective processes during this sensitive period. The HPA axis: orchestrating the body’s response to stress The hypothalamic-pituitary-adrenal (HPA) axis is the body’s central neuroendocrine system for regulating stress and maintaining homeostasis (11). Sensing threat, the hypothalamus, the brain’s central regulator of homeostasis, initiates the stress response by releasing corticotropin-releasing factor (CRF) and arginine vasopressin (AVP). These signaling molecules act synergistically to stimulate the pituitary gland, which responds by secreting adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH then travels to the adrenal glands, located atop the kidneys, triggering the release of glucocorticoid hormones, primarily cortisol (12). In response to increased cortisol levels, the hypothalamus and pituitary gland are inhibited through a negative feedback mechanism, reducing the release of CRF and ACTH. This feedback loop helps to regulate the body’s stress response and maintain homeostasis (Figure 1).

Chapter 1 14 Cortisol plays an important role in sustaining the body’s response to stress by mobilizing energy reserves, modulating immune function, and fine-tuning physiological processes to optimize survival. Under normal conditions, cortisol follows a diurnal rhythm (high in the morning, gradually declining throughout the day) with acute spikes in response to stressors (13,14). Cortisol levels rise in response to immediate psychological and social stressors, such as social evaluation, loneliness, or threat, but are also sensitive to prolonged stress Figure 1 – The hypothalamic–pituitary–adrenal (HPA) axis and negative feedback regulation under stress. Adapted from Mennesson, M., & Revest, J.-M. (2023). Glucocorticoid-Responsive Tissue Plasminogen Activator (tPA) and Its Inhibitor Plasminogen Activator Inhibitor-1 (PAI-1): Relevance in Stress-Related Psychiatric Disorders. International Journal of Molecular Sciences, 24(5), 4496.

General Introduction 15 1 conditions, including poverty, family conflict, and caregiving burden (15). Beyond its role in stress regulation, cortisol has widespread effects throughout the body and brain, influencing immune responses, metabolism, and neural systems involved in cognition and emotion (16). Consequently, alterations in cortisol regulation have been proposed as a key mechanism linking environmental stress exposure to long-term developmental and mental and physical health outcomes, specifically when stress is experienced during sensitive periods such as pregnancy or early life (17-19). The HPA axis is not a static system, but a flexible and dynamic regulator of homeostasis, responding to internal and external cues (20,21). Because the system is designed to absorb and adjust to repeated perturbations, it can be difficult to define what constitutes “pathological” dysregulation (22). Alterations may reflect maladaptive overactivation, exhaustion, or even compensatory downregulation depending on timing, chronicity, and context; except in cases of clearly defined pathology, such as persistently elevated cortisol despite dexamethasone suppression (Cushing’s syndrome) or insufficient cortisol response to ACTH stimulation (Addison’s disease). The HPA axis during pregnancy and postpartum During pregnancy, the hypothalamic-pituitary-adrenal (HPA) axis undergoes profound endocrine adaptations, largely driven by placental corticotropin-releasing hormone (pCRH) (23). Unlike hypothalamic CRH, pCRH amplifies maternal cortisol levels via a positive feedback loop, leading to a two- to fivefold increase in circulating cortisol concentrations, with the steepest rise in late pregnancy (24,25). Elevated maternal cortisol plays a crucial role in fetal organ maturation, including lung development and glucose metabolism, while the placenta regulates fetal exposure through 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts cortisol into its inactive form, cortisone (26). Despite these adaptations, pregnancy itself attenuates the acute stress response, likely due to central changes in glucocorticoid receptor (GR) sensitivity and alterations in CRH-binding protein (CRH-BP) concentrations, which decline by ~50% in late pregnancy (23). During labor, cortisol levels peak (particularly in vaginal delivery), which potentially aids neonatal adaptation and pulmonary surfactant production (27). See figure 2. After birth, the abrupt loss of placental CRH (pCRH) triggers a rapid decline in maternal cortisol levels, occurring within hours to days. This drop, together with the restoration

Chapter 1 16 of negative feedback sensitivity, contributes to postpartum HPA axis reorganization, which may influence maternal mood, stress regulation, and vulnerability to peripartum psychiatric disorders (23). Variability in postpartum cortisol trajectories has been linked to postpartum depression, though the underlying neuroendocrine mechanisms remain not completely understood. There is also emerging evidence that HPA axis alterations may play a role in the onset of postpartum manic or psychotic episodes (28). Additionally, mode of delivery, parity, and feeding type (breastfeeding vs. bottle feeding) can further modulate postpartum cortisol dynamics (29). Given the prevalence of psychiatric disorders in the peripartum period, the interaction between HPA axis adaptations and peripartum mental health is an important focus of research (32-34). To study these dynamic stress processes in peripartum women and their offspring, various methods have been developed to quantify HPA axis functioning. Figure 2 – Maternal, fetal, and placental HPA axis interactions during pregnancy. The placenta produces CRH, which amplifies maternal and fetal cortisol levels via a positive feedback loop. Maternal cortisol can cross the placenta and influence fetal HPA axis activity.

General Introduction 17 1 Measuring HPA axis functioning To assess HPA axis functioning, several methods are used, each capturing different aspects of cortisol dynamics. These methods can be broadly divided into those measuring short-term responses, long-term output, and the reactivity of the HPA axis to external stressors. 1. Short-term measurements: Cortisol has traditionally been measured in saliva, blood serum, or urine, reflecting momentary or short-term systemic levels (35). These methods are particularly useful for evaluating acute responses or daily fluctuations of cortisol. One such measure, the cortisol awakening response (CAR), captures the rapid increase in cortisol within the first hour after waking. It is considered a marker of the diurnal rhythm and anticipatory stress sensitivity (36). 2. Long-term measures: More recently, hair cortisol concentrations (HCCs) have gained popularity as a biomarker of long-term systemic cortisol output. HCCs offer a retrospective view of cumulative HPA axis activity over weeks to months (37,38). This method provides insight into chronic cortisol production, which may coexist with other alterations in cortisol dynamics. 3. Stress reactivity and feedback mechanisms: To assess how the HPA axis responds to external challenges, stress reactivity paradigms, such as the Trier Social Stress Test (TSST) in adults and the Face-to-Face Still-Face (FFSF) paradigm in infants, are commonly used (39,40). These paradigms evaluate cortisol changes in response to stressors and capture the capacity of the HPA axis to recover from stress. Additionally, suppression tests, like the dexamethasone suppression test (DST), assess the negative feedback mechanisms within the HPA axis (41). In addition to these methods, other biomarkers, such as cortisol extracted from fingernails, have been used to assess HPA axis activity (42,43). However, these are not employed in the present dissertation. This dissertation primarily focuses on salivary cortisol measurements in both basal and stress-reactive paradigms, as well as hair cortisol concentrations (HCCs). These

Chapter 1 18 measures are particularly relevant to exploring peripartum HPA axis functioning in mothers and infants. While these methods are interrelated, they each provide distinct physiological insights. For example, high chronic cortisol output (as indexed by HCC) may coexist with blunted reactivity and altered CAR. Thus, interpreting these markers in context is crucial (and difficult), especially in populations undergoing major endocrine transitions, such as during pregnancy and postpartum. HPA axis and psychopathology Dysregulation of the HPA axis has emerged as a shared, though non-specific, biological feature across a wide range of psychiatric disorders. Altered cortisol dynamics, such as elevated basal levels, flatter diurnal slopes, and blunted reactivity, have been identified in both internalizing and externalizing conditions (40,44,45). In major depressive disorder (MDD), elevated hair cortisol concentrations (HCC) have been consistently reported, particularly in melancholic subtypes, reflecting impaired feedback sensitivity of the HPA axis (46-48). In contrast, post-traumatic stress disorder (PTSD) is often associated with lower cortisol levels and increased glucocorticoid receptor sensitivity (49,50). These differences indicate that HPA axis dysregulation is not uniform across disorders; its direction and magnitude appear to depend on psychiatric classification, symptom severity, chronicity, and comorbidities (51,52). Traumatic experiences, especially in early life, seem to play a particularly strong role in modulating HPA axis functioning and may even outweigh psychiatric classifications in predicting cortisol alterations. Several studies have linked childhood maltreatment to long-term reductions in cortisol levels, both in traditional measures and in hair cortisol concentrations (53,54). Certain meta-analyses support these findings, suggesting that early neglect and abuse are associated with blunted HPA responses and lower HCC in adulthood (55,56). However, this is not universally the case, as some studies report inconsistent results. In contrast, recent or acute trauma may elevate cortisol levels, particularly in the early aftermath of the traumatic event (57). Together, these findings highlight the complex and heterogeneous nature of HPA axis functioning in psychopathology. While cortisol dysregulation is a common feature across psychiatric disorders, its clinical significance and direction are shaped by

General Introduction 19 1 a range of interacting factors, including the timing of trauma, the type of disorder, and the chronicity of symptoms (58,59). Further research is needed to clarify these mechanisms, particularly in women during the peripartum period, which itself involves significant physiological endocrine transitions. Effect of peripartum psychopathology on offspring Through which prenatal programming mechanisms could maternal stress and psychopathology during pregnancy shape the development of the offspring? One hypothesis is that maternal stress and psychopathology during pregnancy may influence the development of the offspring through alterations in the maternal HPA axis, with cortisol as a central mediator (60-63). Although the placenta provides partial protection against maternal cortisol via 11β-HSD2 (as described in the context of pregnancy-related HPA axis adaptations) this barrier diminishes toward the end of pregnancy (23,26,64). Consequently, fetal exposure to maternal cortisol follows a nonlinear trajectory, depending on timing and severity. Fetal HPA axis development and timing sensitivity Fetal HPA axis development is shaped by maternal glucocorticoid levels, particularly in early pregnancy when the fetus does not yet produce its own cortisol (8,65). The setpoint of the fetal HPA axis, reflecting how sensitively it responds to stress and how tightly it is regulated, is thought to develop progressively, with structural differentiation occurring in the first and second trimester (including the hypothalamus, pituitary, and adrenal glands) and functional feedback mechanisms developing in the third (see Figure 3). Excess maternal cortisol may downregulate fetal cortisol production and alter longterm HPA set points (66,67). Placental corticotropin-releasing hormone (pCRH), which increases in response to maternal cortisol, may further amplify this effect (68). This forms a feedforward loop: elevated maternal cortisol stimulates placental CRH, which in turn promotes further maternal cortisol production. Under normal conditions, this loop is buffered by maternal negative feedback sensitivity. However, in the context of peripartum psychopathology, this regulation may be impaired, leading to prolonged or excessive fetal glucocorticoid exposure. Elevated pCRH has indeed been linked to adverse neurodevelopmental outcomes, although not consistently (64,69,70). Timing and neurodevelopmental outcomes Some evidence supports the idea that timing matters: early elevations in maternal

Chapter 1 20 cortisol have been associated with poorer infant cognitive outcomes, particularly during periods of rapid brain development in the first and early second trimester (71). In contrast, cortisol elevations later in pregnancy may support adaptive maturation of fetal systems, including the HPA axis itself. Additionally, maternal and infant cortisol levels are often correlated postpartum (7274), though this synchrony may be altered in the context of maternal trauma or severe psychopathology (75). Transgenerational influences and long-term consequences Trauma exposure, particularly in early life, can alter HPA axis regulation (54,59). In the context of pregnancy, such preconception experiences in a mother’s life may influence maternal cortisol in ways that affect fetal development, even independent of current Figure 3 – Developmental timeline of the fetal hypothalamic-pituitary-adrenal (HPA) axis. This figure illustrates the sequential maturation of the fetal HPA axis across gestation, including the differentiation and functional activation of the hypothalamus, pituitary gland, and adrenal cortex, as well as the rise in placental CRH and 11β-HSD2 expression. Adapted from Howland, M. A., Sandman, C. A., & Glynn, L. M. (2017). Developmental origins of the human hypothalamic-pituitary-adrenal axis. Expert Review of Endocrinology & Metabolism, 12(5), 321–339 (65).

General Introduction 21 1 psychiatric symptoms. These transgenerational effects may be mediated by persistent changes in HPA sensitivity and stress responsivity, as well as epigenetic mechanisms such as reduced glucocorticoid receptor expression and methylation of stress-related genes (e.g., NR3C1, FKBP5) (59,76-81). These alterations in HPA axis functioning can have lasting consequences because the HPA axis is involved in regulating brain development, emotional reactivity, and physiological stress responses. Disruptions in cortisol signaling during critical periods of gestation may interfere with neurogenesis, synaptic pruning, and the maturation of brain regions such as the amygdala, hippocampus, and prefrontal cortex; areas essential for emotion regulation, memory, and executive functioning (82-84). Furthermore, altered fetal programming of the HPA axis may result in heightened stress sensitivity or maladaptive cortisol rhythms postnatally, increasing the risk for anxiety, depression, or behavioral dysregulation later in life (60-62). Together, these findings suggest that pregnancy may be a sensitive window during which maternal HPA axis dysregulation, shaped by stress, trauma and psychopathology, could influence the neurodevelopmental trajectory of the child and contribute to transgenerational transmission of vulnerability. At the same time, this developmental plasticity offers an opportunity to identify and strengthen protective factors, including timely therapeutic interventions that may help moderate these risks. Towards clinical application: attachment and intervention While the first part of this dissertation explores biological pathways linking maternal psychopathology to offspring outcomes, the second part takes a more exploratory step toward clinical practice. In particular, it focuses on the impact of maternal personality pathology on the early mother-infant relationship, and evaluates a psychotherapeutic intervention for pregnant women with (comorbid) personality disorders. Previous work has shown that personality disorders are associated with impaired reflective functioning and a higher risk of insecure attachment in offspring (85, 86). These relational disruptions may serve as a key mechanism through which maternal psychopathology affects child development. To address this, a one-day-a-week group-based treatment program was developed for pregnant women with personality disorders and related psychiatric conditions (87).

Chapter 1 22 The intervention integrates mentalization-based therapy, psychomotor treatment, partner involvement, and psychiatric care. The included studies examine both maternal functioning (including depressive symptoms, attachment representations, and bonding) and child-related outcomes. Outline of this thesis The dissertation is structured in two parts: the first examines stress physiology in the peripartum period, focusing on cortisol-related HPA axis functioning in both mothers and infants. The second part shifts to the clinical domain, addressing the impact of maternal psychiatric disorders on the mother-infant relationship and evaluating a group-based intervention in a peripartum treatment setting. Chapters 2 to 5 explore different aspects of HPA axis functioning in the context of maternal psychopathology. Chapter 2 focuses on the cortisol awakening response (CAR) in pregnant women with depressive disorders, examining the CAR as a marker for persistent depressive symptoms postpartum. Chapter 3 explores long-term cortisol output by measuring hair cortisol concentrations (HCCs) in mother-infant dyads, comparing psychiatric and control groups. Chapter 4 builds on this by investigating if maternal childhood trauma is associated with altered maternal and infant HCCs, addressing potential intergenerational effects of early adversity in the life of the mother. Chapter 5 turns to infant stress reactivity, using the Face-to-Face Still-Face paradigm to assess whether maternal psychopathology is related to altered cortisol responses in infants. Chapters 6 and 7 focus more explicitly on maternal-infant interaction and treatment. Chapter 6 examines the relationship of maternal personality pathology with infant attachment patterns. Chapter 7 evaluates a multi-component, group-based intervention for pregnant women with personality disorders and related conditions, assessing effects on maternal mental health, reflective functioning, and bonding outcomes. The final chapter (chapter 8) integrates findings across studies, considering their theoretical and clinical implications. It also outlines directions for future research, including the need for longitudinal, biopsychosocial models to better understand and intervene in peripartum psychiatry.

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General Introduction 25 1 45. Koumantarou Malisiova E, Mourikis I, Darviri C, Nicolaides NC, Zervas IM, Papageorgiou C, Chrousos GP. Hair cortisol concentrations in mental disorders: A systematic review. Physiol Behav. 2021;229:113244. 46. Stetler C, Miller GE. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med. 2011;73(2):114-26. 47. Herane-Vives A, de Angel V, Papadopoulos A, Wise T, Chua K-C, Strawbridge R, et al. Short-term and long-term measures of cortisol in saliva and hair in atypical and non-atypical depression. Acta Psychiatrica Scandinavica. 2018;137(3):216-30. 48. Juruena MF, Bocharova M, Agustini B, Young AH. Atypical depression and non-atypical depression: Is HPA axis function a biomarker? A systematic review. Journal of Affective Disorders. 2018;233:45-67. 49. Morris MC, Compas BE, Garber J. Relations among posttraumatic stress disorder, comorbid major depression, and HPA function: A systematic review and meta-analysis. Clinical Psychology Review. 2012;32(4):301-15. 50. Pan X, Wang Z, Wu X, Wen SW, Liu A. Salivary cortisol in post-traumatic stress disorder: a systematic review and meta-analysis. BMC Psychiatry. 2018;18(1):324. 51. Booij SH, Bouma EM, de Jonge P, Ormel J, Oldehinkel AJ. Chronicity of depressive problems and the cortisol response to psychosocial stress in adolescents: the TRAILS study. Psychoneuroendocrinology. 2013;38(5):659-66. 52. Juruena MF, Eror F, Cleare AJ, Young AH. The Role of Early Life Stress in HPA Axis and Anxiety. Adv Exp Med Biol. 2020;1191:141-53. 53. Steudte S, Kirschbaum C, Gao W, Alexander N, Schönfeld S, Hoyer J, Stalder T. Hair Cortisol as a Biomarker of Traumatization in Healthy Individuals and Posttraumatic Stress Disorder Patients. Biological Psychiatry. 2013;74(9):639-46. 54. Hinkelmann K, Muhtz C, Dettenborn L, Agorastos A, Wingenfeld K, Spitzer C, et al. Association Between Childhood Trauma and Low Hair Cortisol in Depressed Patients and Healthy Control Subjects. Biological Psychiatry. 2013;74(9):e15-e7. 55. Bunea IM, Szentágotai-Tătar A, Miu AC. Early-life adversity and cortisol response to social stress: a meta-analysis. Transl Psychiatry. 2017;7(12):1274. 56. Oresta S, Vinkers CH, van Rossum EFC, Penninx B, Nawijn L. How childhood trauma and recent adverse events are related to hair cortisol levels in a large adult cohort. Psychoneuroendocrinology. 2021;126:105150. 57. Luo H, Hu X, Liu X, Ma X, Guo W, Qiu C, et al. Hair Cortisol Level as a Biomarker for Altered Hypothalamic-Pituitary-Adrenal Activity in Female Adolescents with Posttraumatic Stress Disorder After the 2008 Wenchuan Earthquake. Biological Psychiatry. 2012;72(1):65-9. 58. Staufenbiel SM, Penninx BW, Spijker AT, Elzinga BM, van Rossum EF. Hair cortisol, stress exposure, and mental health in humans: a systematic review. Psychoneuroendocrinology. 2013;38(8):1220-35. 59. Steudte-Schmiedgen S, Kirschbaum C, Alexander N, Stalder T. An integrative model linking traumatization, cortisol dysregulation and posttraumatic stress disorder: Insight from recent hair cortisol findings. Neuroscience & Biobehavioral Reviews. 2016;69:124-35. 60. Kapoor A, Dunn E, Kostaki A, Andrews MH, Matthews SG. Fetal programming of hypothalamopituitary-adrenal function: prenatal stress and glucocorticoids. J Physiol. 2006;572(Pt 1):31-44. 61. Glover V. Prenatal stress and its effects on the fetus and the child: possible underlying biological mechanisms. Adv Neurobiol. 2015;10:269-83. 62. Glover V, O’Connor TG, O’Donnell K. Prenatal stress and the programming of the HPA axis. Neurosci Biobehav Rev. 2010;35(1):17-22. 63. Bowers ME, Yehuda R. Intergenerational Transmission of Stress in Humans. Neuropsychopharmacology. 2016;41(1):232-44. 64. O’Keane V, Lightman S, Marsh M, Pawlby S, Papadopoulos AS, Taylor A, et al. Increased pituitary-adrenal activation and shortened gestation in a sample of depressed pregnant women: a pilot study. J Affect Disord. 2011;130(1-2):300-5.

Chapter 1 26 65. Howland MA, Sandman CA, Glynn LM. Developmental origins of the human hypothalamicpituitary-adrenal axis. Expert Rev Endocrinol Metab. 2017;12(5):321-39. 66. Van der Voorn B, Hollanders JJ, Kieviet N, Dolman KM, de Rijke YB, van Rossum EFC, et al. Maternal Stress During Pregnancy Is Associated with Decreased Cortisol and Cortisone Levels in Neonatal Hair. Horm Res Paediatr. 2018:1-9. 67. Romero-Gonzalez B, Caparros-Gonzalez RA, Gonzalez-Perez R, Delgado-Puertas P, PeraltaRamirez MI. Newborn infants’ hair cortisol levels reflect chronic maternal stress during pregnancy. PLoS One. 2018;13(7):e0200279. 68. Thomson M. The physiological roles of placental corticotropin releasing hormone in pregnancy and childbirth. J Physiol Biochem. 2013;69(3):559-73. 69. Sandman CA, Wadhwa P, Glynn L, Chicz-Demet A, Porto M, Garite TJ. Corticotrophin-releasing hormone and fetal responses in human pregnancy. Ann N Y Acad Sci. 1999;897:66-75. 70. Meltzer-Brody S. New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum. Dialogues Clin Neurosci. 2011;13(1):89-100. 71. Davis EP, Sandman CA. The timing of prenatal exposure to maternal cortisol and psychosocial stress is associated with human infant cognitive development. Child Dev. 2010;81(1):131-48. 72. Davis M, West K, Bilms J, Morelen D, Suveg C. A systematic review of parent-child synchrony: It is more than skin deep. Dev Psychobiol. 2018;60(6):674-91. 73. Sethre-Hofstad L, Stansbury K, Rice MA. Attunement of maternal and child adrenocortical response to child challenge. Psychoneuroendocrinology. 2002;27(6):731-47. 74. Karlen J, Frostell A, Theodorsson E, Faresjo T, Ludvigsson J. Maternal Influence on Child HPA Axis: A Prospective Study of Cortisol Levels in Hair. Pediatrics. 2013;132(5):E1333-E40. 75. Slopen N, Roberts AL, LeWinn KZ, Bush NR, Rovnaghi CR, Tylavsky F, Anand KJS. Maternal experiences of trauma and hair cortisol in early childhood in a prospective cohort. Psychoneuroendocrinology. 2018;98:168-76. 76. Steudte-Schmiedgen S, Stalder T, Schönfeld S, Wittchen H-U, Trautmann S, Alexander N, et al. Hair cortisol concentrations and cortisol stress reactivity predict PTSD symptom increase after trauma exposure during military deployment. Psychoneuroendocrinology. 2015;59:12333. 77. Matthews SG, McGowan PO. Developmental programming of the HPA axis and related behaviours: epigenetic mechanisms. Journal of Endocrinology. 2019;242(1):T69-T79. 78. Liu PZ, Nusslock R. How Stress Gets Under the Skin: Early Life Adversity and Glucocorticoid Receptor Epigenetic Regulation. Curr Genomics. 2018;19(8):653-64. 79. van der Knaap LJ, Riese H, Hudziak JJ, Verbiest MMPJ, Verhulst FC, Oldehinkel AJ, van Oort FVA. Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study. Translational Psychiatry. 2014;4(4):e381-e. 80. Linda M. Bierer MD, Heather N. Bader BS, Nikolaos P. Daskalakis MDPD, Amy Lehrner PD, Nadine Provençal PD, Tobias Wiechmann MS, et al. Intergenerational Effects of Maternal Holocaust Exposure on FKBP5 Methylation. American Journal of Psychiatry.0(0):appi. ajp.2019.19060618. 81. Khoury JE, Bosquet Enlow M, Plamondon A, Lyons-Ruth K. The association between adversity and hair cortisol levels in humans: A meta-analysis. Psychoneuroendocrinology. 2019;103:10417. 82. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10(6):434-45. 83. Gunnar M, Quevedo K. The neurobiology of stress and development. Annu Rev Psychol. 2007;58:145-73. 84. Buss C, Davis EP, Shahbaba B, Pruessner JC, Head K, Sandman CA. Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proc Natl Acad Sci U S A. 2012;109(20):E1312-9.

General Introduction 27 1 85. Lyons-Ruth K, Jacobvitz D. Attachment disorganization: Genetic factors, parenting contexts, and developmental transformation from infancy to adulthood. Handbook of attachment: Theory, research, and clinical applications, 2nd ed. New York, NY, US: The Guilford Press; 2008. p. 666-97. 86. Lyons-Ruth K, Riley C, Patrick MPH, Hobson RP. Disinhibited attachment behavior among infants of mothers with borderline personality disorder, depression, and no diagnosis. Personality Disorders: Theory, Research, and Treatment. 2019;10(2):163-72. 87. Van Ravesteyn LM, Kamperman AM, Schneider TAJ, Raats ME, Steegers EAP, Tiemeier H, et al. Group-based multicomponent treatment to reduce depressive symptoms in women with co-morbid psychiatric and psychosocial problems during pregnancy: A randomized controlled trial. J Affect Disord. 2018;226:36-44.

Part I: Exploring stress physiology in pathways of transgenerational transmission

Chapter 2

Cortisol awakening response in pregnant women with depressive disorders: a potential marker of recovery status from pregnancy to postpartum Carlinde W. Broeks, Babette Bais, Rien Van, Hilmar H. Bijma, Elisabeth F.C. van Rossum, Witte J.G. Hoogendijk, Mijke P. Lambregtse-Van den Berg, Astrid M. Kamperman In: Comprehensive Psychoneuroendocrinology 23 (2025) 100297

Chapter 2 32 Abstract Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to peripartum depression, potentially contributing to symptom persistence. This study examines the relationship between the cortisol awakening response (CAR) during pregnancy and depressive symptom reduction postpartum. Pregnant women with a current depressive episode were included in this study, part of a larger randomized controlled trial on bright light therapy. At baseline (12–32 weeks of pregnancy), participants provided saliva samples at awakening, and at 30 and 60 minutes postawakening. The CAR was assessed using area under the curve relative to ground (AUCg), area under the curve relative to increase (AUCi), and peak reactivity. Depressive symptoms were measured using the Hamilton Depression Rating Scale (HAM-D) at baseline and two months postpartum. Linear regression models examined the association between CAR measures and change in depressive symptoms. The study included 55 pregnant women (mean age: 32.3 years). Mean HAM-D scores decreased from 16.7 at baseline to 5.7 postpartum. Higher AUCi and peak cortisol reactivity were significantly associated with less reduction in depressive symptoms, while AUCg showed no significant association. These findings suggest that heightened cortisol reactivity to awakening during pregnancy may reflect a vulnerability to persistent depressive symptoms in the postpartum period. Stress reactivity may be more relevant than basal cortisol output in predicting recovery, warranting further investigation into CAR as a potential biomarker for peripartum depression prognosis.

Cortisol awakening response in pregnant women with depressive disorders: a potential marker of recovery status from pregnancy to postpartum 33 2 Introduction Depressive disorders during pregnancy and postpartum pose significant risks for both mother and child, affecting maternal well-being, child outcomes, and early mother-infant interactions [1]. Emerging evidence implicates the endocrine system, specifically the hypothalamic-pituitary-adrenal (HPA) axis, in the onset and persistence of depressive disorders during pregnancy and postpartum [2]. Dysregulation of the HPA axis, including basal cortisol levels and stress reactivity, has been associated with both active and remitted depression [3,4]. During pregnancy, the maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes significant adaptations, leading to increased circulating cortisol levels while simultaneously showing signs of blunted negative feedback regulation [5]. These changes are driven by rising levels of placental corticotropin-releasing hormone (CRH), increased corticosteroid-binding globulin (CBG), and alterations in CRH-binding protein (CRH-BP), which modulate CRH bioavailability throughout gestation, leading to a two- to threefold rise in maternal plasma cortisol [6,7]. Given that elevated and decreased cortisol levels have been associated with depression in non-pregnant populations, it has been hypothesized that these pregnancy-related hormonal changes may contribute to depression. However, not all women with peripartum depression show clear HPA axis dysregulation, which can manifest at different levels. Some individuals exhibit elevated cortisol levels due to increased HPA axis activation, while others show impaired regulatory feedback, leading to altered cortisol reactivity rather than consistently high levels [8,9]. Importantly, not all women with peripartum depression display clear markers of HPA axis dysfunction, highlighting the complexity of its role in perinatal mental health. A potential marker of stress regulation is the Cortisol Awakening Response (CAR), which represents the natural rise in cortisol levels within 20-30 minutes after awakening. This increase in cortisol upon waking is thought to prepare the body for the anticipated demands of the day, making it a key indicator of the body’s ability to mobilize energy and cope with stress [10]. The CAR reflects HPA axis reactivity and has been widely studied in stress-related disorders, including depression [11]. Clinically, CAR has been proposed as a biomarker of an individual’s ability to regulate stress and adapt to challenges [5,12,13]. The CAR is generally considered a stable and reliable measure in healthy populations, with several studies demonstrating its stability over short- and

Chapter 2 34 long-term intervals [14]. Recent evidence from Wang et al. (2024) indicates that depressed individuals tend to exhibit an elevated CAR, with sex-specific differences showing higher CAR responses in depressed females compared to males [11]. In healthy pregnant women, the overall circadian rhythm and awakening response of cortisol are preserved [15,16], although the CAR might decrease in later pregnancy [17,18]. Several studies have evaluated the relationship between CAR and peripartum depression, suggesting a potential role for CAR in understanding HPA-axis alterations during this period. Some research has reported that pregnant women with major depressive disorder (MDD) exhibit lower awakening cortisol levels [19-21], while others have found an increased CAR in this population [22,23]. Although some studies have not observed significant differences between depressed and non-depressed pregnant women [24,25], such variability may reflect methodological differences or sample characteristics. Despite this variability in findings, CAR appears to be a valuable biomarker for investigating peripartum depression and its underlying biological mechanisms. Given the mixed findings regarding the relationship between the CAR and peripartum depression, there remains a critical need to clarify how CAR during pregnancy correlates with depressive symptoms. Identifying a biological marker that can be used as a marker to predict the course of symptoms and guide treatment for peripartum depression would offer significant clinical value. This study examines the relationship between the CAR during pregnancy, before treatment, and depressive symptoms postpartum. The sample consists of pregnant women with depressive disorder from a randomized controlled trial (RCT) on bright light therapy [26]. While both treatment and placebo groups showed significant symptom reduction - suggesting spontaneous remission, placebo effects, or behavioral changes - our study focuses on CAR as a potential marker for symptom change. We hypothesize that in women with depression during pregnancy, a more pronounced CAR - characterized by a steeper increase and/or higher peak in cortisol levels after awakening - may be related to a smaller reduction in depressive symptoms after delivery. Elevated CAR has been linked to heightened stress reactivity and persistent depressive symptoms in other populations [27-29]. However, this relationship remains understudied in pregnancy, where hypercortisolism and HPA axis adaptations may further modulate CAR dynamics. We therefore explore how specific CAR measures - area under the curve with respect to ground (AUCg) and increase (AUCi), and peak reactivity - relate to symptom change in pregnant women.

Cortisol awakening response in pregnant women with depressive disorders: a potential marker of recovery status from pregnancy to postpartum 35 2 Given the impact of peripartum depression on maternal and infant health, identifying potential biomarkers like CAR could support early intervention strategies. Hormonal fluctuations play a key role in peripartum depression [30,31], and studies suggest CAR variations may indicate depression risk [28,29]. This study employs longitudinal cortisol assessments to explore the potential role of CAR in peripartum mental health. Materials and methods Study Design This study was part of a randomized controlled trial (RCT), in which pregnant women were randomly allocated to treatment with either bright light therapy (BLT) or a placebo condition with dim red light therapy (DRLT) during 6 weeks [26,32]. The original sample consisted of 67 women diagnosed with a depressive disorder during pregnancy. Although different studies in small samples found positive effects of BLT on antepartum depression [33-36], our RCT showed no statistically significant differences in symptom change scores between BLT and DRLT. Symptoms significantly improved in both treatment arms, with HDRS scores decreasing from a mean of 16.7 (SD 5.3) to 5.7 (SD 5.6) two months postpartum, corresponding to an average symptom reduction of 65.7%. The Medical Ethical Committee of the Erasmus Medical Center, Rotterdam, The Netherlands, approved this research project (MEC-2015-731). Participants Participants were included between week 12 and 32 of pregnancy (gestational age confirmed by first-trimester ultrasound). Diagnosis of a depressive disorder was established through a structured clinical interview for DSM disorders (SCID) conducted by a trained assessor, following the Diagnostic and Statistical Manual of Mental Disorders. Recruitment took place in the Netherlands from 2016 to 2019. Details on recruitment and in- and exclusion criteria are outlined elsewhere [26]. For the current analysis, additional exclusion criteria included the use of locally administered or systemic corticosteroids and obstetric complications (e.g. preterm birth) (n = 0), as these factors could be related to cortisol levels. However, no participants in the study experienced preterm birth (n = 0), so this criterion did not lead to any exclusions. Out of the original 67 women included in the study, 10 were excluded due to missing cortisol measurements and 2 were excluded for corticosteroid use, leaving 55 women in the final sample.

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