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

Grazie per l’attenzione

niolu@med.uniroma2.itniolu@med.uniroma2.it