Maternal respiratory viral infections during pregnancy and offspring's neurodevelopmental outcomes: a systematic review

Maternal infections during pregnancy, as cytomegalovirus and zika, have been consistently associated with severe newborn neurodevelopmental conditions, mainly related to vertical transmission and congenital infection. However, little is known about the neurodevelopmental consequences of maternal respiratory viral infections, which are the most prevalent infections during pregnancy. The recent COVID-19 pandemic has increased the interest in understanding the consequences of infections in offspring's development. This systematic review explores whether maternal gestational viral respiratory infections are associated with neurodevelopmental deviations in children below 10 years-old. The search was conducted in Pubmed, PsychInfo and Web of Science databases. 12 articles were revised, including information about maternal infection (Influenza, SARS-CoV-2 and unspecified respiratory infections) and offspring's neurodevelopment (global development, specific functions, temperament and behavioral/emotional aspects). Controversial results were reported regarding maternal respiratory infections during pregnancy and infants' neurodevelopment. Maternal infections seem to be associated with subtle alterations in some offspring's developmental subdomains, as early motor development, and attentional, behavioral/emotional minor problems. Further studies are needed to determine the impact of other psychosocial confounding factors

Salivary secretory immunoglobulin A as a potential biomarker of psychosocial stress response during the first stages of life: A systematic review

Mucosal secretory immunoglobulin A (s-IgA) has been recognized as a key component of human first line defense against infection. However, its reactivity to psychosocial stressors is poorly understood. This systematic review aimed to explore whether s-IgA levels changed after psychosocial stress in subjects under the age of 18. Fifteen articles were included. s-IgA basal levels are increased in children older than 9 years old exposed to stress. Furthermore, s-IgA seems to follow a circadian rhythm, which is altered under stress conditions. Finally, the collective evidence suggests that salivary s-IgA rapidly increases under acute stress after puberty. Overall, our review indicates that s-IgA could be considered a potential psychosocial stress biomarker of interest for pediatric and child-juvenile psychiatric population. Further studies are needed to validate the role of s-IgA circadian rhythm and basal levels as psychosocial stress biomarkers and disentangle the role of age and type of stressor

Secretory immunoglobulin A (s-IgA) reactivity to acute psychosocial stress in children and adolescents: The influence of pubertal development and history of maltreatment.

Background: Mucosal secretory immunoglobulin A (s-IgA) is an antibody protein-complex that plays a crucial role in immune first defense against infection. Although different immune biomarkers have been associated with stress-related psychopathology, s-IgA remains poorly studied, especially in youth. Objectives: The present study investigated how s-IgA behaves in front of acute psychosocial stress in children and adolescents, including possible variability associated with developmental stage and history of childhood maltreatment (CM). Methods: 94 children and adolescents from 7 to 17 years (54 with a current psychiatric diagnostic and 40 healthy controls) drawn from a larger Spanish study were explored (EPI-Young Stress Project). To assess biological reactivity, participants provided five saliva samples during an acute laboratory-based psychosocial stressor, the Trier Social Stress Test for Children (TSST-C). Samples were assayed for s-IgA, as well as for cortisol. Pubertal development was ascertained by Tanner stage and CM following TASSCV criteria. Results: We observed s-IgA fluctuations throughout the stressor, indicating the validity of TSST-C to stimulate s-IgA secretion (F(4,199) = 6.200, p <.001). Although s-IgA trajectories followed a reactivity and recovery pattern in adolescents, children exhibited no s-IgA response when faced with stress (F(4,197) = 3.406, p =.010). An interaction was found between s-IgA and CM (F(4,203) = 2.643, p =.035). Interestingly, an interaction between developmental stage, CM history and s-IgA reactivity was identified (F(12,343) = 2.036, p =.017); while children non-exposed to maltreatment exhibited no s-IgA changes to acute stress, children with a history of CM showed a similar response to adolescents, increasing their s-IgA levels after the psychosocial stressor. Conclusion: Acute psychosocial stress stimulates s-IgA secretion, but only after puberty. However, children with a history of maltreatment exhibited a response resembling that of adolescents, suggesting an early maturation of the immune system. Further studies are needed to clarify the validity of s-IgA as an acute stress biomarker, including additional measures during stress exposure. Keywords: Acute stress; Adolescents; Childhood maltreatment; Children; Developmental stage; TSST-C; secretory Immunoglobulin A (s-IgA)

Biological mechanisms underlying psychosocial stress response: The consequences of prenatal maternal distress and childhood maltreatment on the endocrine and immune systems

Programa de Doctorat en Biomedicina[eng] During critical periods of development, psychosocial stress experiences may alter key neural networks of the human brain, with long-lasting effects on behavior and mental health. However, the specific biological mechanisms through which early life stress impacts on present and future mental health are still not well understood. Hypothalamic-pituitary-adrenal (HPA) axis is the principal sensor and regulator of stress response. Its modulation begins early in development through fetus-placental dialogue and continues during postnatal life, from childhood to adolescence, being especially sensitive to early life’s adversities. Thus, HPA axis programming during prepostnatal developmental periods is proposed as a plausible mechanism of early sensitization that undermine future HPA axis functioning and associated mental disorders. Moreover, it should not be forgotten that the HPA axis dialogues with the immune system, exhibiting a bidirectional interaction. In this framework, the present dissertation aimed to disentangle the impact of psychosocial stress exposure during early sensitive periods of pre-postnatal brain development on HPA axis and immunity system. Cortisol (the HPA axis ultimate effector) and secretory immunoglobulin A (s-IgA) (an immunoglobulin of the mucosal surfaces) were selected in this thesis, respectively, as putative biomarkers of the endocrine and immune response to early psychosocial stress exposure in early life. The study of two mother/infant dyad cohorts, the Intramural_Maternal_Epi_project cohort and the COGESCOV-19 cohort, enable us to explore the respectively effects of the maternal distress and SARS-CoV-2 infection during pregnancy on the newborn’s early stress reactivity. In Intramural_Maternal_Epi_project, we observed that the presence of depressive symptoms flattened the maternal cortisol circadian pattern, especially during the second trimester of pregnancy. Furthermore, elevated maternal cortisol levels in mid-late pregnancy were associated with poor birth outcomes, including prematurity and low weight percentile at birth. These results underscore the importance of early detection of depressive symptoms, which are often manifested as a subclinical condition during pregnancy. Another hypothesis we tested with this cohort was based on the premise that maternal distress during pregnancy could influence DNA methylation patterns in placenta. Specifically, we studied the DNA methylation of FKBP5, NR3C1 and HSD11B2 genes in two different placental layers: maternal decidua and chorionic villi. We observed that while maternal cortisol levels in early pregnancy were associated with an increase in DNA methylation of CpG islands of NR3C1 gene and a decrease in DNA methylation of CpG islands of FKBP5 gene in the chorionic villi, at the level of the maternal decidua it was the increase in DNA methylation (at specific CpG sites of FKBP5 gene) that was strongly associated with the lower gestational age of the newborn at birth. Thus, stress during the pregnancy, and its associated cortisol levels could influence placental epigenetic signatures differently depending on the time of exposure, the placental layer, and the gene of study. Complementarily, we could explore the putative consequences of maternal exposure to SARS-CoV-2 during pregnancy in the neurodevelopmental outcomes of offspring, thanks to the COGESCOV-19 cohort. In this regard, we observed that infants born to mothers exposed to SARS-CoV-2 (serologically positive) showed poorer responses in items related to regulation and motor system domains (NBAS-Brazelton scale) at seven weeks old. This effect was especially evident in infants whose mothers were infected in the third trimester. Considering the magnitude of COVID-19 pandemic, children born to mothers infected during pregnancy, particularly in late pregnancy, should undergo additional longitudinal screening for neurodevelopmental milestones. On the other hand, in this thesis, we had the opportunity to explore the effect of the most severe psychosocial stress condition for a child, such as exposure to maltreatment during their early years of life. Our research was made possible thanks to Epi_young_stress cohort, which consists of a representative number of children and adolescents from the general population (aged between 7 and 17 years). This cohort has been recruited through the collaboration of various child and adolescent psychiatry units nationwide and includes both children with a current psychiatric diagnosis and a control group. For all subjects, the history of childhood maltreatment was thoroughly examined, and the Trier Social Stress Test for children (TSST-C) was also administered to assess the reactivity of the HPA axis to acute stress in this population. Regarding the functioning of the HPA axis in this young population, although children with maltreatment showed higher basal cortisol levels compared to those not exposed to maltreatment, when subjected to the acute stressor (TSST-C), they exhibited a flattened cortisol response but higher perceived anxiety. Noticeably, we also observed a dose-response relationship between the frequency and severity of the maltreatment and cortisol dysregulation. Furthermore, and in relation with putative immunity biomarkers in front psychosocial stress, we described that the acute exposure to the stress test was able to stimulate the secretion of s-IgA in young subjects after puberty. Additionally, concerning immune markers in response to acute stress, we found that exposure to the acute stressor (TSST-C) was able to stimulate the secretion of s-IgA in young subjects, but only after puberty. However, although s-IgA reactivity to acute stress was not observed in prepubescent children, when the presence of maltreatment was observed, these children had developed this immune response capability, suggesting that complex trauma could anticipates the immune maturation. Finally, considering our previous result that salivary s-IgA quickly rises after acute stress exposure, we wanted to know if salivary s-IgA could be a new promising biomarker of psychosocial stress reactivity in young population. A systematic review of the available scientific literature revealed that s-IgA can be considered a reliable biomarker of acute stress in under 18 population. However, further research is needed to specifically determine how psychosocial stress impacts on s-IgA circadian rhythm and basal levels. Together, the results of this thesis support the notion that psychosocial stress during prenatal and child-juvenile periods could alter endocrine and immune systems regulation, modifying early behavioral dimensions and the reactivity to stress, which might increase the risk of future mental health problems.[spa] Durante los periodos más precoces y sensibles del desarrollo del sistema nervioso central (SNC), la exposición al estrés psicosocial puede alterar los sistemas biológicos para el futuro funcionamiento adaptativo del sujeto. El cortisol (último efector del eje Hipotalámico Hipofisario Adrenal (HHA)) y la inmunoglobulina A secretora (s-IgA) se seleccionaron en esta tesis, respectivamente, como posibles biomarcadores de respuesta al estrés psicosocial en las primeras etapas de la vida. Se pudo estudiar el papel del distrés materno durante el embarazo, y su posible asociación con en el comportamiento y la reactividad ante el estrés del recién nacido, gracias a dos cohortes de diadas madre/niño seguidas durante el embarazo y hasta las primeras semanas postnatales: la cohorte del Intramural_Maternal_Epi_project y la cohorte COGESTCOV-19. En primer lugar, pudimos constatar que el patrón diurno de cortisol estaba desregulado en mujeres con síntomas de depresión, especialmente durante en el segundo trimestre del embarazo. Así mismo se observó que altos niveles de cortisol en esta etapa del embarazo se asociaban con prematuridad y bajo peso al nacer. Por otra parte, se pudo comprobar que los niveles altos de cortisol materno al principio del embarazo podrían asociarse con un perfil de metilación del ADN específico en genes placentarios implicados en la regulación del cortisol, incrementando el riesgo de un parto adelantado. Finalmente, se estudiaron las consecuencias de la infección materna por SARS-COV-2 durante el embarazo en las respuestas motoras y de regulación ante los estímulos del test de Brazelton en los niños a las 7 semanas de vida, constatando un mayor efecto si la infección afectaba al último trimestre de embarazo. Por otro lado, el estudio de una cohorte de niños/as y adolescentes con y sin patología mental (cohorte del proyecto Epi_young_stress) nos permitió analizar el papel del maltrato infantil en la posible sensibilización temprana del eje HHA y del sistema inmunitario de los sujetos expuestos. Para testar esta posible sensibilización, en este estudio se indujo estrés psicosocial agudo a todos los sujetos de la cohorte, mediante un protocolo de laboratorio cuasi experimental: el test de estrés psicosocial Trier para niños (TSST-C). Los niños/as y adolescentes expuestos a maltrato mostraron mayores niveles de cortisol basales y una hiporreactividad del eje HHA al TSST-C, a pesar de mostrar una mayor percepción de ansiedad ante estrés psicosocial agudo comparados con los niños no expuestos a maltrato. También se observó una relación dosis-efecto entre la exposición y severidad del maltrato y la desregulación del eje HHA. Además, el estrés psicosocial estimuló la secreción de s-IgA, pero sólo después de la pubertad. Sin embargo, los niños/as expuestos a maltrato infantil mostraron secreción de la s-IgA ante estrés psicosocial de forma similar a los adolescentes, sugiriendo una anticipación de la maduración del sistema inmune en los niños maltratados. El uso de la s-IgA como posible biomarcador de estrés agudo y crónico en etapas tempranas de la vida fue estudiado y discutido mediante una revisión sistemática. En conjunto, los resultados de esta tesis sostienen que la exposición al estrés psicosocial durante los periodos tempranos del desarrollo del SNC (prenatal, infancia y adolescencia) podrían alterar la respuesta al estrés de los sistemas endocrino e inmune, modificando algunos rasgos de la conducta temprana en el recién nacido y aumentando el riesgo de futuros problemas de salud mental

Biological mechanisms underlying psychosocial stress response: The consequences of prenatal maternal distress and childhood maltreatment on the endocrine and immune systems

[eng] During critical periods of development, psychosocial stress experiences may alter key neural networks of the human brain, with long-lasting effects on behavior and mental health. However, the specific biological mechanisms through which early life stress impacts on present and future mental health are still not well understood. Hypothalamic-pituitary-adrenal (HPA) axis is the principal sensor and regulator of stress response. Its modulation begins early in development through fetus-placental dialogue and continues during postnatal life, from childhood to adolescence, being especially sensitive to early life’s adversities. Thus, HPA axis programming during prepostnatal developmental periods is proposed as a plausible mechanism of early sensitization that undermine future HPA axis functioning and associated mental disorders. Moreover, it should not be forgotten that the HPA axis dialogues with the immune system, exhibiting a bidirectional interaction. In this framework, the present dissertation aimed to disentangle the impact of psychosocial stress exposure during early sensitive periods of pre-postnatal brain development on HPA axis and immunity system. Cortisol (the HPA axis ultimate effector) and secretory immunoglobulin A (s-IgA) (an immunoglobulin of the mucosal surfaces) were selected in this thesis, respectively, as putative biomarkers of the endocrine and immune response to early psychosocial stress exposure in early life. The study of two mother/infant dyad cohorts, the Intramural_Maternal_Epi_project cohort and the COGESCOV-19 cohort, enable us to explore the respectively effects of the maternal distress and SARS-CoV-2 infection during pregnancy on the newborn’s early stress reactivity. In Intramural_Maternal_Epi_project, we observed that the presence of depressive symptoms flattened the maternal cortisol circadian pattern, especially during the second trimester of pregnancy. Furthermore, elevated maternal cortisol levels in mid-late pregnancy were associated with poor birth outcomes, including prematurity and low weight percentile at birth. These results underscore the importance of early detection of depressive symptoms, which are often manifested as a subclinical condition during pregnancy. Another hypothesis we tested with this cohort was based on the premise that maternal distress during pregnancy could influence DNA methylation patterns in placenta. Specifically, we studied the DNA methylation of FKBP5, NR3C1 and HSD11B2 genes in two different placental layers: maternal decidua and chorionic villi. We observed that while maternal cortisol levels in early pregnancy were associated with an increase in DNA methylation of CpG islands of NR3C1 gene and a decrease in DNA methylation of CpG islands of FKBP5 gene in the chorionic villi, at the level of the maternal decidua it was the increase in DNA methylation (at specific CpG sites of FKBP5 gene) that was strongly associated with the lower gestational age of the newborn at birth. Thus, stress during the pregnancy, and its associated cortisol levels could influence placental epigenetic signatures differently depending on the time of exposure, the placental layer, and the gene of study. Complementarily, we could explore the putative consequences of maternal exposure to SARS-CoV-2 during pregnancy in the neurodevelopmental outcomes of offspring, thanks to the COGESCOV-19 cohort. In this regard, we observed that infants born to mothers exposed to SARS-CoV-2 (serologically positive) showed poorer responses in items related to regulation and motor system domains (NBAS-Brazelton scale) at seven weeks old. This effect was especially evident in infants whose mothers were infected in the third trimester. Considering the magnitude of COVID-19 pandemic, children born to mothers infected during pregnancy, particularly in late pregnancy, should undergo additional longitudinal screening for neurodevelopmental milestones. On the other hand, in this thesis, we had the opportunity to explore the effect of the most severe psychosocial stress condition for a child, such as exposure to maltreatment during their early years of life. Our research was made possible thanks to Epi_young_stress cohort, which consists of a representative number of children and adolescents from the general population (aged between 7 and 17 years). This cohort has been recruited through the collaboration of various child and adolescent psychiatry units nationwide and includes both children with a current psychiatric diagnosis and a control group. For all subjects, the history of childhood maltreatment was thoroughly examined, and the Trier Social Stress Test for children (TSST-C) was also administered to assess the reactivity of the HPA axis to acute stress in this population. Regarding the functioning of the HPA axis in this young population, although children with maltreatment showed higher basal cortisol levels compared to those not exposed to maltreatment, when subjected to the acute stressor (TSST-C), they exhibited a flattened cortisol response but higher perceived anxiety. Noticeably, we also observed a dose-response relationship between the frequency and severity of the maltreatment and cortisol dysregulation. Furthermore, and in relation with putative immunity biomarkers in front psychosocial stress, we described that the acute exposure to the stress test was able to stimulate the secretion of s-IgA in young subjects after puberty. Additionally, concerning immune markers in response to acute stress, we found that exposure to the acute stressor (TSST-C) was able to stimulate the secretion of s-IgA in young subjects, but only after puberty. However, although s-IgA reactivity to acute stress was not observed in prepubescent children, when the presence of maltreatment was observed, these children had developed this immune response capability, suggesting that complex trauma could anticipates the immune maturation. Finally, considering our previous result that salivary s-IgA quickly rises after acute stress exposure, we wanted to know if salivary s-IgA could be a new promising biomarker of psychosocial stress reactivity in young population. A systematic review of the available scientific literature revealed that s-IgA can be considered a reliable biomarker of acute stress in under 18 population. However, further research is needed to specifically determine how psychosocial stress impacts on s-IgA circadian rhythm and basal levels. Together, the results of this thesis support the notion that psychosocial stress during prenatal and child-juvenile periods could alter endocrine and immune systems regulation, modifying early behavioral dimensions and the reactivity to stress, which might increase the risk of future mental health problems.[spa] Durante los periodos más precoces y sensibles del desarrollo del sistema nervioso central (SNC), la exposición al estrés psicosocial puede alterar los sistemas biológicos para el futuro funcionamiento adaptativo del sujeto. El cortisol (último efector del eje Hipotalámico Hipofisario Adrenal (HHA)) y la inmunoglobulina A secretora (s-IgA) se seleccionaron en esta tesis, respectivamente, como posibles biomarcadores de respuesta al estrés psicosocial en las primeras etapas de la vida. Se pudo estudiar el papel del distrés materno durante el embarazo, y su posible asociación con en el comportamiento y la reactividad ante el estrés del recién nacido, gracias a dos cohortes de diadas madre/niño seguidas durante el embarazo y hasta las primeras semanas postnatales: la cohorte del Intramural_Maternal_Epi_project y la cohorte COGESTCOV-19. En primer lugar, pudimos constatar que el patrón diurno de cortisol estaba desregulado en mujeres con síntomas de depresión, especialmente durante en el segundo trimestre del embarazo. Así mismo se observó que altos niveles de cortisol en esta etapa del embarazo se asociaban con prematuridad y bajo peso al nacer. Por otra parte, se pudo comprobar que los niveles altos de cortisol materno al principio del embarazo podrían asociarse con un perfil de metilación del ADN específico en genes placentarios implicados en la regulación del cortisol, incrementando el riesgo de un parto adelantado. Finalmente, se estudiaron las consecuencias de la infección materna por SARS-COV-2 durante el embarazo en las respuestas motoras y de regulación ante los estímulos del test de Brazelton en los niños a las 7 semanas de vida, constatando un mayor efecto si la infección afectaba al último trimestre de embarazo. Por otro lado, el estudio de una cohorte de niños/as y adolescentes con y sin patología mental (cohorte del proyecto Epi_young_stress) nos permitió analizar el papel del maltrato infantil en la posible sensibilización temprana del eje HHA y del sistema inmunitario de los sujetos expuestos. Para testar esta posible sensibilización, en este estudio se indujo estrés psicosocial agudo a todos los sujetos de la cohorte, mediante un protocolo de laboratorio cuasi experimental: el test de estrés psicosocial Trier para niños (TSST-C). Los niños/as y adolescentes expuestos a maltrato mostraron mayores niveles de cortisol basales y una hiporreactividad del eje HHA al TSST-C, a pesar de mostrar una mayor percepción de ansiedad ante estrés psicosocial agudo comparados con los niños no expuestos a maltrato. También se observó una relación dosis-efecto entre la exposición y severidad del maltrato y la desregulación del eje HHA. Además, el estrés psicosocial estimuló la secreción de s-IgA, pero sólo después de la pubertad. Sin embargo, los niños/as expuestos a maltrato infantil mostraron secreción de la s-IgA ante estrés psicosocial de forma similar a los adolescentes, sugiriendo una anticipación de la maduración del sistema inmune en los niños maltratados. El uso de la s-IgA como posible biomarcador de estrés agudo y crónico en etapas tempranas de la vida fue estudiado y discutido mediante una revisión sistemática. En conjunto, los resultados de esta tesis sostienen que la exposición al estrés psicosocial durante los periodos tempranos del desarrollo del SNC (prenatal, infancia y adolescencia) podrían alterar la respuesta al estrés de los sistemas endocrino e inmune, modificando algunos rasgos de la conducta temprana en el recién nacido y aumentando el riesgo de futuros problemas de salud mental

Childhood maltreatment disrupts HPA-axis activity under basal and stress conditions in a dose-response relationship in children and adolescents

Abstract Background. This study investigates the impact of childhood maltreatment (CM) on hypothalamic- pituitary-adrenal (HPA)-axis functioning and on anxiety perception. Moreover, the influence of CM severity and frequency was also explored. Methods. In total, 187 participants aged 7-17 were assessed for CM history using validated questionnaires and ad hoc interviews to be classified according to the criteria of the Tool for Assessing the Severity of Situations in which Children are Vulnerable (TASSCV). Psychopathology was ascertained using the K-SADS-PL5. To assess HPA-axis functioning, salivary cortisol samples were collected throughout a normal day and during an acute psychosocial stressor, the Trier Social Stress Test for children (TSST-C). Subjective anxiety was evaluated using STAI/-C. Results. Youth with a CM history had higher overall diurnal cortisol levels ( p = 0.001), blunted cortisol response to acute psychosocial stress ( p = 0.002) and greater perceived anxiety ( p = 0.003), than those without CM. Specifically, participants exposed to moderate/severe or often/frequent CM showed the greater diurnal cortisol output ( pseverity = 0.002; pfrequency = 0.003), and blunted cortisol response during the TSST-C ( pseverity = 0.006; pfrequency = 0.008). Meanwhile, youth with low CM severity/frequency exhibited a similar cortisol response to those without CM. However, perceived anxiety was higher in those exposed to CM ( p < 0.001), regardless of its severity/frequency. Conclusions. Disturbances in HPA-axis functioning are already evident early after CM exposure, while psychological and physiological responses to an acute stressor are dissociated in youth exposed to CM. The dose-response relationship described in this paper highlights the need to comprehensively evaluate CM so that vulnerable children can be identified and assigned to proper interventions

Supplementary Materials

Supplementary materials for " Serial Diurnal Salivary Cortisol Profiles in 667 pregnant women – Association with Cardiometabolic Complications"</p

Complex post-traumatic stress disorder (CPTSD) of ICD-11 in youths with childhood maltreatment: Associations with age of exposure and clinical outcomes.

Background: Exposure to childhood maltreatment (CM) increases the risk of psychiatric morbidity in youths. The new Complex Post-Traumatic Stress Disorder (CPTSD) diagnosis captures the heterogeneity and complexity of clinical outcomes observed in youths exposed to CM. This study explores CPTSD symptomatology and its association with clinical outcomes, considering the impact of CM subtypes and age of exposure. Methods: Exposure to CM and clinical outcomes were evaluated in 187 youths aged 7-17 (116 with psychiatric disorder; 71 healthy controls) following the Tools for Assessing the Severity of Situations in which Children are Vulnerable (TASSCV) structured interview criteria. CPTSD symptomatology was explored by confirmatory factor analysis, considering four subdomains: post-traumatic stress symptoms, emotion dysregulation, negative self-concept and interpersonal problems. Results: Youths exposed to CM (with or without psychiatric disorders) showed greater internalizing, externalizing and other symptomatology, worse premorbid adjustment and poorer overall functioning. Youth with psychiatric disorder and exposed to CM reported more CPTSD symptomatology, psychiatric comorbidity and polypharmacy and earlier onset of cannabis use. Different subtypes of CM and the developmental stage of exposure differentially impact CPTSD subdomains. Limitations: Small percentage of resilient youths was studied. It was not possible to explore specific interactions between diagnostic categories and CM. Direct inference cannot be assumed. Conclusions: Gathering information on type and age of exposure to CM is clinically useful to understand the complexity of psychiatric symptoms observed in youths. Inclusion of the CPTSD diagnosis should increase the implementation of early specific interventions, improving youths' functioning and reducing the severity of clinical outcomes