Cinzia NioluAssociato di Psichiatria
Dipartimento di Medicina dei Sistemi Università di Roma “Tor Vergata”Responsabile UOS SPDC Fondazione Policlinico Tor Vergata
Responsabile Sportello SOS mamma Fondazione Policlinico Tor VergataPresidente Società Italiana Psichiatria SIP Lazio
Trasmissione intergenerazionale del trauma
Genetica dei disturbi mentali
Cluster genetici diversi danno origine a
traiettorie, percorsi fenotipici diversi
However, such relations are unable toexplain the vast majority of the inter-individual variation
in the population
Inter-individual variations in
physical, cognitive and
socioemotional growth have been
traditionally examined under
Gene-Environment interaction
traditionally examined under
the conceptual framework of
gene–environment (G x E)
interactions
(Dick et al., 2010; Gershon et al., 2011)
In che modo i fattori ambientali e sociali condizionano
l’espressione genica e lo sviluppo cellulare?
EPIGENETICSEPIGENETICS
Waddington's model of the epigenetic landscape
L'epigenetica è definita come lo studio dei
cambiamenti ereditabili nell'espressione genica
che non sono causati da cambiamenti nella
sequenza del DNA (Waterland & Michels, 2007).
O’Donnell KJ et al., 2017
Ipotesi: Status fetale meta-plastico che aumenta la vulnerabilità alle
influenze post-natali
Biological and social determinants of neurodevelopment across life course
The Lancet Commission on global mental health andsustainable development October 9, 2018
A major class of
epigenetic mechanism is
thought to involve
persistent
changes in chromatin
structure. Most, if not
all, transcriptional
CHROMATIN VARIATIONS and TRANSGENERATIONAL INHERITANCE
regulatory events cause
changes to chromatin
structure and
composition, which
result from the
recruitment of
chromatin-modifying
enzymes by transcription
factors and by the
transcriptional
machinery itself.
DNA methylation, histone modifications and non-coding RNAs are the three
known epigenetic marks that have been implicated in transgenerational
inheritance of the modified traits.
CHROMATIN VARIATIONS and TRANSGENERATIONAL INHERITANCE
Transgenerational and Intergenerational transmission
• Adult exposure
• In utero exposure
• Post-natal exposure
INTERGENERATIONAL
TRANSMISSION
TRANSGENERATIONAL
TRANSMISSION
Klengel et al, 2015
Parental stress can be transmitted via:
• GAMETES,
• GESTATIONAL UTERINE ENVIRONMENT,
From STRESS THEORY to the INTERGENERATIONAL TRANSMISSION of stress
Stress theory posits that organisms
will mount, and continue to express,
a biobehavioral response to an
environmental challenge as long as the challenge or stressor is present
(Selye, 1956)
LEVELS OF TRANSMISSIONLEVELS OF TRANSMISSION
• GESTATIONAL UTERINE ENVIRONMENT,
• EARLY POSTNATAL CARE
Stress effects that are inherited via an
‘intergenerational transmission’ mode
are reflected in offspring biological
changes, including neuroendocrine, epigenetic, and neuroanatomical
changes.
Bowers, Yehuda 2016
From STRESS THEORY to the INTERGENERATIONAL TRANSMISSION of stress
Yehuda et al., J Clin Endocrinol Metab. 2005 Jul;90(7):4115-8.
The influence on a child’s response to stress may begin before birth as a result of in utero exposure to maternal stress hormones – NOT their own experiences of
adversity
Women pregnant on 9/11 with PTSD had lower cortisol levels and so did their 7 month old infants
800PTSD- (n=46)PTSD+ (n=52)
0
200
400
600
Mothers Babies
Sal
ivar
y C
ortis
ol
Yehuda et al., J Clin Endocrinol Metab. 2005 Jul;90(7):4115-8.
60
70
80
/day
)
High Risk High Risk GroupGroup
Urinary 24hr cortisol levels were lower in Holocaust offspring with parental PTSD
n=11n=15 n=14n=10
0
10
20
30
40
50
60
Comparison No ParentalPTSD; No
PTSD
Parental PTSD;PTSD
Parental PTSD;No PTSD
Co
rtis
ol (
ug/
day
)
GroupGroup
Yehuda et al., Am J Psychiatry. 2000
From STRESS THEORY to the INTERGENERATIONAL TRANSMISSION of stress
Several miRNAswere affected
<< Environmental conditions involving traumatic stress in early life in mice altered microRNAs
(miRNAs) expression, and behavioral and metabolic responses in the progeny >>
These results strongly suggest that sncRNAs are sensitive to environmental factors in early life, and contribute to the inheritance of trauma-induced phenotypes across generations.
Injection of sperm RNAs from these males into
fertilized wild-type oocytes
reproduced the behavioral and metabolic alterations in
the resulting offspring
• Serum of the traumatized animals,
• Serum of the traumatized animales’ progeny when adult
• Brain of the traumatized animals,
• Brain of the traumatized animales’ progeny when adult
• Sperm of traumatized males
F0F0
F1F1
F2F2
• On the elevated plus maze, F2 MSUS mice had a shorter
latency to first enter an open arm than F2 controls.
• They spent more time in the bright compartment of the
light-dark box, and had depressive-like behaviors on the
forced swim test.
• Since early stress can be a strong metabolic dysregulator,
glucose metabolism has been examined. Insulin in serum was
normal in F1 MSUS animals, but lower than controls in F2
MSUS progeny.
MSUS:maternal separation combined with unpredictable maternal stress
F2F2
Offspring effects may be mediated, in part, by epigenetic changes in parental germ cells resulting from acquired parental stress exposures throughout life. Germ cells in both females and males can be affected by
trauma exposure, but the critical periods for affecting
oocytes and sperm may differ.
Accordingly, the nature of the effects may differ in
oocytes and sperm in relation to trauma exposure.
Trauma e NutrizioneTrauma e Nutrizione
Trasmissione intergenerazionale del trauma: complicanze e aspetti correlati
Trauma e Uso di SostanzeTrauma e Uso di Sostanze
Trauma e Depressione PerinataleTrauma e Depressione Perinatale
Trauma e NutrizioneTrauma e Nutrizione
Trasmissione intergenerazionale del trauma: complicanze e aspetti correlati
Trauma e Uso di SostanzeTrauma e Uso di Sostanze
Trauma e Depressione PerinataleTrauma e Depressione Perinatale
TRAUMA E MALNUTRIZIONE:De HongerwinterUno dei più famosi “esperimenti naturali” in cui gli epidemiologi si
sono accorti di questi effetti è stato il cosiddetto traumatico inverno
della carestia in Olanda, nel 1944.
Sul finire della seconda guerra mondiale, quando l’esercito tedesco
bloccò l’accesso ai rifornimenti in alcuni territori dei Paesi Bassi, una
parte della popolazione, complice un inverno durissimo, patì
gravemente le fame, arrivando a un introito giornaliero di non più di
500 calorie.
Exposure of pregnant
womento a severe
famine
g0 Generation – exposed during pregnancy
g1 Generation – exposed in utero
TRAUMATC environmental factor: SEVERE FAMINE
� Higher risk for metabolic and
mental health diseases
g2 Generation – exposed by means of the
developing germ cells
g3 Generation?
mental health diseases
� Increased risk for metabolic
disorders but only in children
from at-risk F1 fathers
HIGH: 1°-2° trimester
LOW: 3° trimester
HIGH: 1°-2° trimester
LOW: 3° trimester
PERICONCEPTIONAL EXPOSURE TO FAMINE
lower methylation of the Insulin-like Growth Factor 2 (IGF2) locus
(key factor in human growth and development)
DNA methylation altered
when women were exposed
very early in pregnancy but
not in late gestation
60 years later
In particolare, in relazione al benessere e alla salute del
bambini, è stato studiato un programma di condizionamentobiologico, denominato Developmental Origins of Adult
Disease (DoHAD), che individua le origini delle malattiedell’adulto a partire dallo sviluppo infantile.
Negli studi di Barker nei quali veniva notato come durante la
carestia olandese della Seconda Guerra Mondiale, quando la
fame era diffusa tra la popolazione, i bambini nascevano piùpiccoli per età gestazionale e da grandi avrebbero avuto un
DoHAD - Developmental Origins of Adult Disease
piccoli per età gestazionale e da grandi avrebbero avuto unrischio maggiore di sviluppare diabete di tipo II e sindromemetabolica.
David Barker, epidemiologist
L’ipotesi di Barker consisteva nel fatto che questi bambini, a causa delle cattive condizioni dietetiche, si erano abituati in utero a trattenere i nutrienti
come necessità adattativa all’ambiente altamente deficitario sul piano alimentare, creando una sorta di thrifty phenotype, “fenotipo risparmio”.
Questo fenotipo, ossia la tendenza a trattenere e conservare nel proprio corpo gli introiti calorici, determinava delle modificazioni metaboliche tali per
cui questi bambini, una volta divenuti adulti, erano a maggior rischio di obesità.
The Barker’s hypothesis – IL “FENOTIPO RISPARMIO”
<< Povertà di relazioni, povertà affettiva, vuoto di senso,
caduta dei valori, perdita del senso morale e religioso sono
gli indici di questa nuova forma di povertà che noi abbiamo
definito “vitale” e costituiscono un fattore di rischio, un
substrato di vulnerabilità psicopatologica. Ansia,
depressione, disturbi di adattamento, alcune reazioni
psicotiche possono trovare nella povertà vitale non un
elemento causale, ma un fattore di aggravamento
psicopatologico a causa delle condizioni di indebolimento
MADRI POVERE, UNA CATTIVA NUTRIZIONE IN
GRAVIDANZA SONO FATTORI DI SVANTAGGIO E
DI RISCHIO PER IL NASCITURO
psicopatologico a causa delle condizioni di indebolimento
generale delle risorse dell’individuo.>>
Siracusano A, Ribolsi M 2018
The incidence of posttraumatic stress disorder
(PTSD) and obesity are on the rise, and evidence
continues to support the observation that
individuals who have symptoms of PTSD are
more likely to develop obesity in their
lifetime.
TRAUMA AND OBESITY
lifetime.
The incidence of obesity in individuals with PTSD,
including war veterans, women, and children
exposed to trauma, is not solely attributable to
psychotropic medications, but actual
pathophysiologic mechanisms have not been fully
delineated.
• GENETIC MECHANISMS
(eg, telomere length)
• GROWTH AND INFLAMMATORY MEDIATORS
(eg, IL-6, BDNF)
• CELLULAR MECHANISMS
(eg, mitochondrial and endoplasmic reticulum function)
• ENDOCRINE MECHANISMS
(eg, glucocorticoid and RAAS pathways)
<< In addition to immediate implications for
pregnancy complications, increasing evidence
implicates maternal obesityas a major determinant of offspring health during
childhood and later adult life>>
(the Lancet 2016)
INTERGENERATIONAL TRANSMISSION OF OBESITY
Buon compleanno Mr Grape, Film 1993
Mother and child, Botero 1995
• OBESITY
• CORONARY HEART DISEASE
• STROKE
• TYPE 2 DIABETES
• ASTHMA
• POORER COGNITION
• HEDONIC BEHAVIORS
• NEURODEVELOPMENTAL DISORDERS
OBESE MOTHEROBESE MOTHER
OFFSPRING’S RISKOFFSPRING’S RISK
� changes in epigenetic processes
� alterations in the gut microbiome
GLOSSARY
Factors shapingthe neonatalmicrobiome
Tamburrini et al, Nature Medicine 2016
It was long believed that neonates are born with sterile gastrointestinal
tract (GIT) and the first microbial flora that colonizes humans’ GIT are
those from maternal vaginal canal, skin and large intestine
(Rook,Lowry, & Raison, 2014).
MICROBIOMEMICROBIOME
NUTRITIONNUTRITION
EPIGENOMEEPIGENOME
INFLAMMATIONINFLAMMATION
RECENT STUDIES SHOWED THAT HUMANS START TO
Microbiome, inflammation, epigenetic alterations, and mental diseases: a fatidical interplay
Like viruses, bacterial elements may pass through the
maternal digestive tract or other internal mucosa to colonize the
embryo’s digestive tract.
RECENT STUDIES SHOWED THAT HUMANS START TO ACQUIRE GUT BACTERIA WHILE THEY ARE IN UTERO
THE ACQUISITION OF GI FLORA IS INFLUENCED BY
MATERNAL DIET AND LIFESTYLE AND MAY BE
LINKED TO DEVELOPMENTAL DISORDERS IN NEONATES
“These altered hedonic behaviors are associated with reduced
striatal dopamine levels, suggesting that a hypodopaminergic state of the mesolimbic reward system may be responsible for the higher
vulnerability to develop addictive-like behaviors and altered
metabolic phenotypes in the offspring”
Maternal overnutrition and hedonic behaviorsMATERNAL TRAUMA MATERNAL OBESITY HEDONIC BEHAVIORS HEDONIC BEHAVIORS
IN OFFSPRING
MATERNAL
HIGH FAT
DIET
MATERNAL
HIGH FAT
DIET
Hypothalamic appetite regulatory system
Hypothalamic appetite regulatory system
Mesolimbic reward systemMesolimbic reward system
HYPERPHAGIAHYPERPHAGIA
FOOD
PREFERENCE
FOOD
PREFERENCE
EDONIC
BEHAVIORS
EDONIC
BEHAVIORS
Trauma e NutrizioneTrauma e Nutrizione
Trasmissione intergenerazionale del trauma: complicanze e aspetti correlati
Trauma e Uso di SostanzeTrauma e Uso di Sostanze
Trauma e Depressione PerinataleTrauma e Depressione Perinatale
There is a strong, bidirectional link
between substance abuse and traumatic experiences.
Patients, teens in particular, with
cooccurring substance use disorders(SUDs) and
TRAUMA AND SUBSTANCE ABUSE
cooccurring substance use disorders(SUDs) and
posttraumatic stress disorder (PTSD) have significant
functional and psychosocial impairment.
Common neurobiological foundations point to the
reinforcing cycle of trauma
symptoms, substance withdrawal, and substance use.
Effetti multigenerazionali dell’uso di sostanze
Epigenetic transgenerational inheritance may
YOHN et al, 2015
provide a means by which parental drug use
can influence several generations of offspring.
Recent evidence suggests that parental drug
exposure produces behavioral, biochemical, and
neuroanatomical changes in future
generations.
BEHAVIORAL EFFECTSBEHAVIORAL EFFECTS
YOHN et al, 2015
NEUROCHEMICAL EFFECTSNEUROCHEMICAL EFFECTS
STUCTURAL PHYSIOLOGICAL
EFFECTS
STUCTURAL PHYSIOLOGICAL
EFFECTS
YOHN et al, 2015
Trauma e NutrizioneTrauma e Nutrizione
Trasmissione intergenerazionale del trauma: complicanze e aspetti correlati
Trauma e Uso di SostanzeTrauma e Uso di Sostanze
Trauma e Depressione PerinataleTrauma e Depressione Perinatale
Women are MORE THAN TWICE as susceptible
to depression as men;
Perinatal depression is highly prevalent:
10-20%
Perinatal Depression Depression during pregnancy is an
emerging field in terms of understanding
the pathophysiology of the disease and
determining adequate treatment
10-20%• First trimester: 7.4%
• Second trimester: 12.8%
• Third trimester: 12.0%
• Postpartum: 13% at 3 months postpartum
Philippe et al 2016, ACOG 2015
1 out of 5 pregnant women will have a mental health problem during their
pregnancy, and in the year after they have a baby
5 out of 100 women will develop a serious mental health problem
4out of 1000 women who have a baby will need admission to
hospital for their mental health problems
How big is the problem?
The Royal College of Psychiatrists, 2015
Ilnostrostudio
Valutazione dei Fattori di Rischio e Stratificazione - TRAUMA
Studio pr omosso dall ’Associazione Volontar i per PTV onlus che ha gent i lmente autor izzato l ’ut i l izzo dei dat i . �
Patr ocinato dalla Società I taliana di Psichiat r ia Regione Lazio. �U.O.C. Psichiat r ia, Fondazione PTV, Dir et tor e: Pr of. A. Sir acusano�
In collabor azione con: UOS Igiene Mentale delle r elazioni affet t ive e del post - par tum, Policlinico Umber to I di Roma, Univer sità La Sapienza, Roma.�
U.O.C. Ginecologia, Fondazione Policlinico Tor Ver gata Roma, Dir et tor e: Pr of. E. Piccione. �Dipar t imento di Medicina di Labor ator io, Fondazione PTV, Dir et tor e: Pr of. S. Ber nar dini �
Ilnostrostudio
“Ruolodeilifestressevents,resilienzaelivellidicitochineproinfiammatorie:unostudiopilota”
“ GRUPPIDIRICERCAINTERUNIVERSITARISULLAPSICOPATOLOGIAPERINATALE
DELLADIADEMADRE-BAMBINO”
Valutazione dei Fattori di Rischio e Stratificazione - TRAUMA
Metodi
Cara eris chedelcampione:
80DONNE
20DPN,LSE
20DPN,nLSE40DPNStudio pr omosso dall ’Associazione Volontar i per PTV onlus che ha gent i lmente autor izzato l’ut i l izzo dei dat i. �
Pat r ocinato dalla Società I tal iana di Psichiat r ia Regione Lazio. �U.O.C. Psichiat r ia, Fondazione PTV, Dir et tor e: Pr of. A. Sir acusano�
In col labor azione con: UOS Igiene Mentale delle r elazioni affet t ive e del post - par tum,
Ilnostrostudio
“Ruolodeilifestressevents,resilienzaelivellidicitochineproinfiammatorie:unostudiopilota”
Obiettivi
1- Indagare la relazione esistente tra eventi traumatici e sintomi depressivi perinatali (DPN);
2-Indagare relazione tra resilienza, DPN e indici biologici;
3- Indagare relazione tra indici biologici, DPN e eventi traumatici
20HSingravidanza
20HSnoningravidanza
40HSPoliclinico Umber to I di Roma, Univer si tà La Sapienza, Roma.�
U.O.C. Ginecologia, Fondazione Policlinico Tor Ver gata Roma, Dir et tor e: Pr of. E. Piccione. �Dipar t imento di Medicina di Labor ator io, Fondazione PTV, Di r et tor e: Pr of. S. Ber nar dini �
Valutazione dei Fattori di Rischio e Stratificazione - TRAUMA
Le pazienti con diagnosi di DPN che avevano in
anamnesi uno o più eventi traumatici presentavano
una sintomatologia depressiva più severa
I traumi più rappresentati nel campione di donne con
diagnosi di DPN erano le esperienze di Abuso
psicologico, Abuso sessuale, Emotional Neglect
Valutazione dei Fattori di Rischio e Stratificazione - TRAUMA
Le pazienti con diagnosi di DPN che avevano in
anamnesi uno o più eventi traumatici presentavano
punteggi più bassi di resilienza.
Le pazienti con diagnosi di DPN si differenziavano dal
gruppo di controllo in termini di indici biologici
(VES e TNFa)
Risultati 6: Resilienza come fattore protettivo
P< 0.05
I livelli sierici di BDNF erano direttamente proporzionali ai
punteggi di resilienza
Valutazione dei Fattori di Rischio e Stratificazione - TRAUMA
Niolu et al Unpublished data
TRAUMA E DEPRESSIONE PERINATALE
DISREGOLAZIONE INFIAMMATORIAIMPATTO SUL
NEONATO IL-1, IL-2, IL-6, IL-17, TNFa, IFNb,
cortisolo, PCR, VES
• Disregolazione infiammatoria
• Dist del neurosviluppo
• Basso peso alla nascita
• Ridotta aspettativa di vita
Figli di donne sane e donne con depressione in gravidanza seguiti fino ai 25aa
- Link tra depressione pre-natale e alterazione dei
parametri immunologici (CICATRICE BIOLOGICA) nella parametri immunologici (CICATRICE BIOLOGICA) nella
prole all’età di 25 aa (effetto persistente e
indipendente da episodi depressivi o traumi life-time)
- livelli più alti di hs-CRP: rischio cardiovascolare
Origini fetali della salute e del rischio di malattia
• Neonates’ functional connectivity patterns
predicted the degree to which their mother predicted the degree to which their mother
experienced inflammation while pregnant.
•
• Systemic maternal inflammation during
pregnancy,operationalized as IL-6 level, predicted
these children’s performance on a memory game
at age two
SVILUPPERÀ UNO STILE DI
ATTACCAMENTO INSICURO
Arch Womens Ment Health. 2016 Oct;19(5):927-35.
DISTURBO DELLA RELAZIONE
MADRE-BAMBINO
DEPRESSIONEMATERNA
• Donne con attaccamento evitante e sintomi depressivi: rischio di ritardo dello sviluppo nella prole
• Donne con stile di attaccamento sicuro in gravidanza: assenza di ritardo di sviluppo nella prole
Alhusen JL et al., 2013
L’attaccamento insicuro si trasmette di madre in fi glio e media la trasmissione transgenerazionale della depre ssione
What about the mother-fetus bonding?
<< Bonding increases significantly through pregnancy, in quality and
intensity. Regression analyses indicate that stronger antenatal bonding
at all time points (trimesters 1 through 3) predicted strong postnatal
bonding>>
A accamentoMaterno-Fetale:Impa oabreve,medioelungotermine
SUCOSAINCIDEUNASCARSAQUALITÁDIATTACCAMENTOMATERNO-FETALE?
• Dist.D’Ansia
• Dist.Dell’Umore(Depressione,Irritabilità)
• Comportamen diabusosulfeto
• A accamentomadre-bambinoinsicuro/
disorganizzato
• Ritardodisviluppo
• S ledivitasanoingravidanza(usoditabacco,alcol,
sostanze)
• Eserciziofis
i
c o
• Ricercadiinformazionisugravidanza,partoecuradel
neonato
DIATTACCAMENTOMATERNO-FETALE?
Alhusenetal2009
MAAS-Fa oripsicopatologici/Depressione
Laqualitàdell’a accamento
Materno-fetalecorrelainversamente
conlagravitàdellasintomatologia
depressivapresente
r=-0,786
P<0.0001
0 20 40 60 80 1000
10
20
30
MAAS
EP
DS
MAAS:MaternalAntenatalA achmentScale
EPDS:EdinburghPerinatalDepressionScale
MAAS-Relazionedonnaingravidanza/figuramaternainepocainfan le
Laqualitàdell’a accamento
Materno-fetalecorrelainversamente
conipunteggi“MotherAnthipathy”e
“MotherNeglect”CECA-Q
r=-0,354
P<0.05
r=-0,339
P<0.05
0 20 40 60 80 1000
5
10
15
20
25
MAAS
MO
TH
ER
AN
THIP
ATH
Y
0 20 40 60 80 1000
5
10
15
20
MAAS
MO
THE
R N
EG
LEC
TMAAS:MaternalAntenatalA achmentScale
La qualità dell’attaccamento Materno-
fetale (MAAS) è correlata, non solo al
livello di Depressione Perinatale (EPDS),
ma alla qualità della relazione che la donna ha avuto con la propria figura
materna (CECA-Q).
Attaccamento Madre-bambino/Padre-
bambino
TRAUMATRAUMA
DEPRESSIONEDEPRESSIONE
Trasmissione transgenerazionale della Relazione di Attaccamento
Attaccamento Materno-fetale
Attaccamento Madre-bambinoTRASMISSIONE
TRANSGENERAZIONALE
Il progetto SOS MOOD“MOOD of MOthers and Offspring
Development”:linee di ricerca e risultati preliminari
UOC Neuropsichiatria Infantile - Direttore Prof. Paolo Curatolo
UOC Psichiatria e Psicologia Clinica - Direttore Prof. Alberto Siracusano
Policlinico “Tor Vergata”
Università degli studi di Roma “Tor Vergata”
Progetto promosso da: Volontari Policlinico “Tor Vergata”
OBJECTIVES (1)
1) to longitudinally evaluate possible
long-term effects of maternal perinataldepression on socio-communicativeand behavioral phenotype of theand behavioral phenotype of the
offspring with a specific focus on theincrease of ASD risk.
OBJECTIVES (2)
2) to characterize the CLINICAL PHENOTYPE of: Offspring of Perinatal Offspring of Perinatal
Depressed women
pharmacologically
Treated during
pregnancy
(O-PND*Treat) (O-PND*Treat)
Offspring NOT
exposed to drug
treatment
(O-PND*NonTreat).
Methods: MOTHERS• 30 mothers enrolled
• Sportello “SOS Mamma” Policlinico Tor Vergata –
open from April 2012
• Psychiatric clinical evaluation of the women was
performed performed
PRENATAL PERIOD
II TRIMESTER OF PREGNANCY
PRENATAL PERIOD
II TRIMESTER OF PREGNANCY
EPDS Edinburgh Perinatal
Depression ScaleCox et al, 1987
EPDS Edinburgh Perinatal
Depression ScaleCox et al, 1987
EPDS ≥ 12: Perinatal Depression
EPDS 9-11: Probable Depression
10 item10 item
16 womenMean age: 37 yrs
NO
N 4 N 4
YES Pharmacological
Treatment
N 7 N 7 Preliminary Sample: Mothers
EPDS ≥ 12: N 11 women
EPDS < 12: N 5 women No PNDNo PND
NO Pharmacological
TreatmentPNDPND
Methods: Offspring
CHILD EVALUATION:
o Griffiths III/Wechsler Scale (WPPSI-III;
WISC-IV)
PARENTAL QUESTIONNAIRES:o Social Responsiveness Scale (SRS)
o Behavioural features (Conners’ Parents; Child Behaviour
Standardized clinical assessment of the children at a mean age of 5 years:
o Autism Diagnostic Observation
Schedule Second Edition (ADOS-2)
o Behavioural features (Conners’ Parents; Child Behaviour Checklist)
o Parental Stress Index (PSI)
16 womenMean age: 37 yrs
16 childrenMean age: 5 yrs
Results (1)
EPDS ≥ 12: N 11 women
EPDS < 12: N 5 women
PNDPND
No PNDNo PND
2 ASD2 ASD
1 ASD
EPDS ≥ 12: N 11 women
16 womenMean age: 37 yrs (DS…)
NO Pharmacological
Treatment
N 4 N 4 PNDPND
7 Children EXPOSED to medication (5 M 2 F)
mean age 4 yrs
YES Pharmacological
Treatment
N 7 N 7
Results (2)
EPDS < 12: N 5 women
Treatment
4 Children NON-EXPOSED to medication (5 M 2 F)
mean age 4 yrs
4 Children NON-EXPOSED to medication (5 M 2 F)
mean age 4 yrs
2 ASD2 ASD
1 ASDNo PNDNo PND
Results OFFSPRING O-PND vs O-No-PND
1516
No significant statistical difference emerged, between the
offspring of PND (O-PND) and the children of No-PND (O-No
PND), in the level of Autistic Symptoms (ADOS-2) and
Socio-Communicative Difficulties (SRS)
Results (3): O-PND vs O-No-PND
ADOS-2SRS
90
0123456789
101112131415
ADOSTotalScore(meanscore)
O-NoPND
O-PND
• Mean ADOS Total Score: O-PND 4,00 vs O-No PND 3,00
• Mean ADOS Calibrated Severity Score CSS : 2,11 O-PND vs 2,20 O-
No PND
• Mean SRS Total Score: O-PND 58,50 vs O-No PND 52,60
30
45
60
75
90
SRSSocialResponsiveness
Scale(meantotTscore)
O-NoPND
O-PND
Results OFFSPRING O-PND*NoTreat vs O-PND*Treat
0123456789
10111213141516
ADOSTotalScore(mean
O-PND*Treat
O-PND*NonTreat
Children of mothers with PND who did not
received pharmacological treatment during
pregnancy (O-PND*NoTreat) scored higher
compared to offspring of pharmacologically
treated women (O-PND*Treat) on ADOS Total
Score (mean: OPD-NT 6,00 vs OPD-T2,86) and on
Results (4): O-PND*NoTreat vs O-PND*Treat
ADOSTotalScore(meanscore)
Score (mean: OPD-NT 6,00 vs OPD-T2,86) and on
CSS (mean: 3,67 OPD-NT vs 1,33 OPD-T)
O-PND-NoTreat scored higher on ADOS TOTAL and adosCSS
1
2
3
4
5
6
7
8
9
10
CSS(meanscore)
O-PND*Treat
O-PND*NonTreat
ADOS2
Children of mothers with PND who did not receive
pharmacological treatment during pregnancy
(O-PND*NoTreat) scored higher compared to
offspring of pharmacologically treated women
(O-PND*Treat) on SRS total score (mean: 64,00
OPD-NT vs 56,14 OPD-T)
Results (5): O-PND*NoTreat vs O-PND*Treat
90
SRS
OPD-NT vs 56,14 OPD-T)
30
45
60
75
SRS(meantotalscore)
O-PND*Treat
O-PND*NonTreat
Children of mothers with PND who
did not receive pharmacological
treatment during pregnancy (O-
PND*NoTreat) scored higher
compared to offspring of
pharmacologically treated women
Results (6): O-PND*NoTreat vs O-PND*Treat
CONNERS parents
65
70
75
80
85
90
95
100
pharmacologically treated women
(O-PND*Treat) on Defiant (mean:
53,67 OPD-NT vs 46,71 OPD-T)
Hyperkinetic behaviours (mean:
63,33 OPD-NT vs 52,00 OPD-T) and
Inattention score of Conners’ (mean
68,00 OPD-NT vs 48,57 OPD-T)
35
40
45
50
55
60
65
Conners'Hyperkine cbehavioursscore(meanT
score)
Conners'Defiantscore(meanTscore)
Conners'Ina en onscore(meanTscore)
O-PND*Treat
O-PND*NonTreat
Results: Parental Stress Indexpnd -treat vs pnd -no treat
Mothers with PND who received pharmacological
treatment during pregnancy (O-PND*Treat) scored
higher compared to offspring of pharmacologically not
treated women (O-PND*NoTreat) on PSI Total score
Results (7): pnd-treat vs pnd-no treat
Parental STRESS Index
76
96
116
136
PND*Treat
PND*NonTreat
treated women (O-PND*NoTreat) on PSI Total score
(mean: 46,3 OPD-NT vs 81,43 OPD-T)
PND-Treat mothers reported more PARENTAL STRESS INDEX
36
56
76
ParentalStressIndex
CONCLUSIONS on Preliminary results
• Not a significant increased risk of autism in the children of women affected by Perinatal
Depression compared to offspring of healthy control mothers
CONCLUSIONS on Preliminary results
• A different clinical phenotype came out within the offspring of women affected by Perinatal Depression
and exposed to psychotropic medications during pregnancy compared to offspring not prenatally
exposed to pharmacotherapy:
o lower sub-threshold autistic symptoms and less defiant-inattentive-hyperkinetic behaviours
emerged within offspring exposed to psychotropic medications in pre-natal period.
CONCLUSIONS on Preliminary results
• Women pharmacologically treated during pregnancy, later reported higher
Parental Stress Index
• Paucity of the Sample
• Hypothesis: medication as a regulator of the inflammation related to
Depression?
• Importance of Perinatal Depression Treatment
• Analysis of Confounding Factors
CONCLUSIONS on Preliminary results
• Analysis of Confounding Factors