Depressione in gravidanza e

nel puerperio

Daniele La Barbera

Dipartimento di Biomedicina sperimentale e

Neuroscienze cliniche Sezione di Psichiatrica

Università di Palermo

Caltanissetta, 28 Settembre 2010

Il tempo

biologico e

psichico della

donna è un

tempo

ritmico.

Tutta la vita

psicobiologica

e sessuale

della donna è

inserita in una

dimensione

temporale

Aree cliniche di confine tra ginecologia

psicologia e psichiatria

• Sindrome premestruale

• Dismenorrea

• Pseudogravidanza psicogena

• Ipermenorrea, metrorragia

• Dolore pelvico

• Sterilità psicogena

• Aborto spontaneo

• Psicoprofilassi al parto

• Depressione in gravidanza

• Depressione puerperale

• Menopausa

Depressione Maggiore

• esordio: 3° decade di vita

• durata episodio: 20 settimane (mediana)

• frequenza episodi: 4 (mediana) nella vita

Depressione Maggiore

• 2 volte più frequente nelle donne:

15-54 anni donne 21%, uomini 12%

(Burt e Stein, J Clin Psychiatry 2002; 63 (suppl 7): 9-15)

• prevalenza attuale o nel corso della vita

rapporto uomo: donna di 2:1

(Kuehner, Acta Psychiatr Scand 2003; 108: 163-174)

Perché la Depressione Maggiore è più frequente nelle donne ?

• fattori genetici: non vi sono dati univoci (?);

• eventi traumatici nell’infanzia: bambine più a rischio di abusi fisici e più

sensibili al loro effetto;

• fluttuazioni ormonali: le donne presentano episodi depressivi in risposta a

fluttuazioni degli ormoni sessuali e soffrono maggiormente di disfunzioni tiroidee;

• disturbi d’ansia: le donne ne soffrono maggiormente;

• stile cognitivo: donne più inclini alla ruminazione e all’autocommiserazione;

• ruolo sociale: nella donna sono più frequenti ruoli frustranti (casalinga),

conflittuali o eccessivamente onerosi (casa-lavoro, discriminazione..);

• eventi stressanti: le donne presentano più frequentemente un episodio

depressivo dopo un evento negativo rilevante.

(Piccinelli e Wilkinson, Br J Psychiatry 2000; 177:486-492)

Depressione Maggiore Modello eziopatogenetico

Ereditarietà Eventi di perdita precoci Sesso

Personalità Eventi stressanti

Alterazione del funzionamento cerebrale

Depressione

Disturbi d’Ansia

Supporto sociale

?

Depressione Maggiore

eventi stressanti precoci grave compromissione delle cure

parentali: morte di un genitore, separazione-divorzio dei genitori,

violenza in famiglia, abusi fisici e sessuali.

(Piccinelli e Wilkinson, Br J Psychiatry 2000; 177:484-492)

Funzioni psicoendocrine

attività ipotalamo-ipofisi surrene Personalità

bassa autostima, senso di impotenza

Supporto sociale

Sistema ipotalamo-ipofisi-surrene

L’elevazione dei livelli di glucocorticoidi è una caratteristica

della risposta allo stress nei mammiferi.

Stress cronico persiste l’aumento dei glucocorticoidi, mentre si

riducono i livelli di NA, 5HT, DA, GABA

CRF nell’animale induce comportamenti “depressivi”.

Il riscontro di elevati livelli di glucocorticoidi si ritrova nel 20-

40% dei pazienti depressi ambulatoriali e nel 40-60% di quelli

ricoverati (più frequenti nella depressione melancolica).

In genere l’ipercortisolemia si risolve in seguito al trattamento;

se persiste indica un rischio elevato di ricaduta.

Depressione Maggiore e sesso femminile

eventi stressanti precoci

Abusi sessuali Maggior sensibilità

7-19% bambine 69% depressione da adulti 3-7% bambini 27%

Estrogeni aumentano l’attività ipotalamo-ipofisi-surrene in risposta allo stress

(Weiss et al, Am J Psychiatry 1999; 156:816-828;

Kuehner, Acta Psychiatr Scand 2003; 108: 163-174)

Nelle donne:

• maggior frequenza di scarsa autostima, insicurezza, senso di inadeguatezza, di impotenza e di disperazione; • maggior tendenza alla ruminazione, all’autocommiserazione, al pessimismo.

Disturbi depressivi e caratteristiche di personalità

(Piccinelli e Wilkinson, Br J Psychiatry 2000; 177:484-492

Kuehner, Acta Psychiatr Scand 2003; 108: 163-174)

Disturbi depressivi e alterata attività tiroidea

Il 5-10% dei pazienti depressi presentava prima del disturbo una disfunzione tiroidea subclinica.

Ipotiroidismo subclinico astenia, sonnolenza, rallentamento psico-motorio,

deficit di concentrazione e di memoria, depressione

Ipotiroidismo FT4 TSH basale TSH dopo TRH

Grado 1

“ 2 =

“ 3 = =

(Esposito et al, 1997)

Depressione Maggiore

Caratteristiche cliniche

Nelle donne più frequente:

• la comparsa nel periodo novembre-febbraio

• un maggior numero di sintomi

• ipersonnia, iperfagia, reattività umore, ipersensibilità al rifiuto

• tentativi di suicidio (suicidio nell’uomo)

(Burt e Stein, J Clin Psychiatry 2002; 63 (suppl 7): 9-15)

• pubertà

• fase premestruale

• puerperio

• peri-menopausa

• gravidanza e aborto

(Burt e Stein, J Clin Psychiatry 2002; 63 (suppl 7): 9-15)

Nelle donne (predisposte) la depressione maggiore

si manifesta più frequentemente nei periodi di

intense fluttuazioni degli ormoni sessuali:

Disturbi Depressivi del Puerperio

• Maternity Blues (Postpartum Blues, Baby Blues)

• Depressione Maggiore ad esordio nel

postpartum

• Psicosi puerperale

Maternity Blues

• Prevalenza: 50-85% donne.

• Esordio: entro pochi giorni dal parto (48 ore).

• Sintomi: tristezza, tendenza al pianto, sentimenti di

insufficienza e di incapacità, irritabilità, ansia, difficoltà

di concentrazione e di memoria, disturbi del sonno e

dell’appetito, cefalea, astenia.

• Remissione: entro 2 settimane. Durata protratta:

comparsa di depressione postpartum.

(Burt e Stein, J Clin Psychiatry 2002; 63 (suppl 7): 9-15

Steiner et al. J Affect Disord 2003;74:67-83)

Depressione Post-partum

- Esordio: primi tre mesi dal parto (primo mese).

- Prevalenza: 10-22%

- Sintomatologia : sovrapponibile alla Depressione Maggiore

- Effetti sullo sviluppo psichico del bambino: attaccamento insicuro e ambivalente, compromissione tono emozionale, sviluppo cognitivo e relazionale, manifestazioni psicopatologiche

- Prognosi: remissione entro 6-12 mesi

(Burt e Stein, J Clin Psychiatry 2002; 63 (suppl 7): 9-15

Steiner et al. J Affect Disord 2003;74:67-83)

Psicosi Post-partum

• Prevalenza: 0.1-0.3 % di puerpere.

• Esordio: prima settimana dopo il parto (48-72 ore).

• Sintomi: intense e rapide oscillazioni dello stato di coscienza, allucinazioni visive o uditive a contenuto triste o terrifico, temi deliranti di tipo persecutorio o depressivo e incentrati sulla relazione madre-bambino, ansia, agitazione; rischio di suicidio e di infanticidio.

• Prognosi: favorevole con remissione in 6-12 mesi nell’ 80% casi; tendenza alla ricorrenza nel postpartum (75-90%). 70% Disturbo Bipolare o Depressione Maggiore con aspetti psicotici

(Burt e Stein, J Clin Psychiatry 2002; 63 (suppl 7): 9-15

Steiner et al. J Affect Disord 2003;74:67-83)

• caduta ormoni placentari

• ipotiroidismo (in un sottogruppo)

• ambivalenza nei confronti del neonato

• stress connesso al ruolo materno

• esaurimento fisico; alterata attività asse ipotalamo-ipofisi-

surrene

•sonno insufficiente

• pregressi episodi di depressione o disturbo bipolare

• recenti eventi stressanti

• temperamento del neonato

• complicazioni perinatali

• scarso supporto familiare

Disturbi del puerperio

Eziologia

(Burt e Stein, J Clin Psychiatry 2002; 63 (suppl 7): 9-15

Steiner et al. J Affect Disord 2003;74:67-83)

Depressione Maggiore in gravidanza

Rischi se la depressione non è trattata:

• scarsa igiene della gravidanza

• rischio suicida

• impulsività

• alterazioni neuro-endocrine (ipercortisolemia)

• stress materno prenatale -->minor peso e minore età gestazionale

Nell’animale lo stress materno --> aborto, basso peso, ipossia,

ipotensione, ritardo di crescita, difficoltà di apprendimento

(Wisner et al, 2000)

Prevalenza: 9% primo episodio in gravidanza

14% ricaduta

What are the signs of depression during pregnancy? Women with depression usually experience some of the following symptoms for 2 weeks or more:

•Persistent sadness

•Difficulty concentrating

•Sleeping too little or too much

•Loss of interest in activities that you usually enjoy

•Recurring thoughts of death, suicide, or hopelessness

•Anxiety

•Feelings of guilt or worthlessness

•Change in eating habits

What are possible triggers of depression during pregnancy? •Relationship problems

•Family or personal history of depression

•Infertility treatments

•Previous pregnancy loss

•Stressful life events

•Complications in pregnancy

What can happen if depression is not treated?

Untreated depression can hurt the mother and her baby. Some

women with depression have a hard time caring for themselves

during pregnancy. They may:

Eat poorly

Not gain enough weight

Have trouble sleeping

Miss prenatal visits

Not follow medical instructions

Use harmful substances, like tobacco, alcohol, or illegal drugs

Depression during pregnancy can raise the risk of:

Problems during pregnancy or delivery

Having a low-birth-weight baby

Premature birth

Aborto

Entro 6 mesi dall’aborto :

• Depressione Maggiore - 11% primo episodio

- 54% se episodi pregressi

- rischio 5 volte maggiore in assenza

di figli

• Gravidanza entro 1 anno: aumenta il rischio di depressione

dopo 1 anno: non aumenta il rischio di depressione

(Burt e Stein, J Clin Psychiatry 2002; 63 (suppl 7): 9-15)

Le classi di psicofarmaci con i più intensi effetti teratogeni

sono i Sali di litio e gli anticonvulsivanti

Gli SSRI sono i farmaci antidepressivi più comunemente

prescritti, per la loro efficacia e per il miglior profilo di tollerabilità

e sicurezza, rispetto ai più vecchi antidepressivi.

Tuttavia studi hanno dimostrato che l’esposizione ai farmaci SSRI

nella fase tardiva della gravidanza è associata a complicanze di

breve periodo nei neonati, tra cui il distress respiratorio lieve,

irritabilità, problemi di alimentazione, ittero e convulsioni.

Vol. 279 No. 8, February 25, 1998

Nathalie A. Kulin,; Anne Pastuszak, & coll.

Context Although a large number of women of reproductive age use

new selective serotonin reuptake inhibitors (SSRIs) and half of all

pregnancies are unplanned, no data exist on the safety of these agents

for the human fetus. Objective To assess fetal safety and risk of fluvoxamine, paroxetine,

and sertraline.

Design A prospective, multicenter, controlled cohort study.

Setting Nine Teratology Information Service centers in the United

States and Canada.

Patients All women who were counseled during pregnancy following

exposure to a new SSRI and followed up by the participating centers.

Controls were randomly selected from women counseled after

exposure to nonteratogenic agents.

Vol. 279 No. 8, February 25, 1998

Nathalie A. Kulin,; Anne Pastuszak, & coll.

Main Outcome Measures Rates of major congenital malformations.

Results A total of 267 women exposed to an SSRI and 267 controls

were studied. Exposure to SSRIs was not associated with either

increased risk for major malformations (9/222 live births [4.1%] vs

9/235 live births [3.8%] in the controls, relative risk, 1.06, 95%

confidence interval, 0.43-2.62) or higher rates of miscarriage,

stillbirth, or prematurity. Mean (SD) birth weights among SSRI users

(3439 [505] g) were similar to the controls (3445 [610] g) as were the

gestational ages (39.4 [1.7] weeks vs 39.4 [1.9] weeks).

Conclusion The new SSRIs, fluvoxamine, paroxetine, and

sertraline, do not appear to increase the teratogenic risk when used

in their recommended doses

Volume 193, Issue 6, December 2005

Anna Sivojelezova

Citalopram use in pregnancy: Prospective comparative

evaluation of pregnancy and fetal outcome

Objective Citalopram is a selective serotonin reuptake inhibitor indicated for depression.

The safety of this medication in pregnancy has not been fully established. The purpose

of this study was to investigate whether citalopram is associated with an increased

incidence of adverse pregnancy outcomes.

Study design Pregnant women who contacted the Motherisk Program, a Teratogen Information

Center in Toronto, Ontario, with regard to the safety of citalopram in pregnancy were

enrolled in the study. The exposed women were matched to a disease-matched group

of women and a nonteratogenic group.

All women were matched for age (± 2 years) and gestational age at time of first call

to the Motherisk (± 2 weeks). A structured telephone follow-up interview was

conducted following the expected date of confinement.

Volume 193, Issue 6, December 2005

Results The total number of pregnant women enrolled in this study was 396 (132 women in

each group). A total of 125 women took citalopram at least in the first trimester.

Seventy-one (54%) women continued to take the drug throughout pregnancy.

One hundred fourteen women (86%) had live births, 14 (11%) had spontaneous

abortions, 2 (1.5%) had elective terminations, and 2 (1.5%) experienced stillbirths.

Fetal survival rates, mean birth weights, and duration of pregnancy were not

statistically different among the 3 groups. Of 108 live-born infants whose mothers

were exposed to citalopram in the first trimester, there was 1 (0.9%) male infant

born with a major malformation. There was a relative risk of 4.2 (95% confidence

interval 1.71-10.26) in neonates exposed to citalopram close to term to be admitted

to special-care nurseries as compared with the unexposed infants.

Conclusion Citalopram use during the period of embryogenesis in pregnancy is not associated

with an apparent major teratogenic risk. Late pregnancy use of citalopram is associated

with increased risk of poor neonatal adaptation syndrome, recently described with

other selective serotonin reuptake inhibitors.

Neonatal Adaptation Syndrome

In recent years there has been increasing recognition of a set of

neurobehavioral signs in infants born to mothers taking antidepressants.

This ‘syndrome’ has been given a number of names including Neonatal

Adaptation Syndrome, Neonatal Abstinence Syndrome, Neonatal

Withdrawal Syndrome and Neonatal Serotonergic Syndrome.

.

Newborn babies exposed to antidepressants in utero may manifest:

Insomnia or somnolence

Agitation , tremors, jitteriness, shivering and/ or altered tone

Restlessness, irritability &constant crying

Poor feeding, vomiting or diarrhoea

Poor temperature control, hypoglycaemia

Tachypnoea, respiratory distress, nasal congestion or cyanosis

Seizures

Reports of incidence suggest 30% of SSRI exposed full term

babies show poor neonatal adaptation – this compares with

approximately 10% of non exposed babies .

It is usually short lived with a median duration of 3 days, and

75 % complete resolution by 5 days. However there have been

reports of adaptation signs lasting up to 4 weeks.

Premature babies are more vulnerable to NAS, and are more

likely to develop signs, which may be more severe. One study

reported 100% of exposed babies born before 37 weeks

developed signs of NAS. Premature babies have been found to

require 4 times as long in NICU compared to an age controlled

non exposed group.

Symptoms can vary greatly in severity from mild transitory

symptoms to more severe symptoms including seizures and

dehydration.

Jul 2010

.

Use of antidepressants during pregnancy and the

risk of spontaneous abortion Hamid Reza Nakhai-Pour, MD PhD, Perrine Broy, BSc and Anick Bérard, PhD

Background: The risk of relapse of depression or the diagnosis of some other psychiatric disorders

during pregnancy necessitates the use of antidepressants despite possible adverse effects. Whether such

use increases the risk of spontaneous abortion is still being debated. We evaluated the risk of

spontaneous abortion in relation to the use of antidepressants during pregnancy.

Methods: Using a nested case–control study design, we obtained data from the

Quebec Pregnancy Registry for 5124 women who had a clinically detected

spontaneous abortion. For each case, we randomly selected 10 controls from the

remaining women in the registry who were matched by the case’s index date (date of

spontaneous abortion) and gestational age at the time of spontaneous abortion.

Use of antidepressants was defined by filled prescriptions and was compared with

nonuse. We also studied the classes, types and doses of antidepressants.

Results: A total of 284 (5.5%) of the women who had a spontaneous abortion

had at least one prescription for an antidepressant filled during the pregnancy, as

compared with 1401 (2.7%) of the matched controls (odds ratio [OR] 2.09, 95%

confidence interval [CI] 1.83–2.38).. When we looked at antidepressant use by

type versus no use, paroxetine use alone (OR 1.75, 95% CI 1.31–2.34) and

venlafaxine use alone (OR 2.11, 95% CI 1.34–3.30) were associated with an

increased risk of spontaneous abortion.

Interpretation: The use of antidepressants, especially paroxetine,

venlafaxine or the combined use of different classes of

antidepressants, during pregnancy was associated with an increased

risk of spontaneous abortion

• Fluoxetine promotes gliogenesis during neural differentiation

in mouse embryonic stem cells

Kusakawa S, Nakamura K, Miyamoto Y,

Sanbe A, Torii T, Yamauchi J, Tanoue A

Sept. 2010

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for treatment of mood

disorders and depression, even during pregnancy and lactation. SSRIs are thought to be much safer than

tricyclic antidepressants, with a low risk of embryonic toxicity. Several recent studies, however, have

reported that fetal exposure to SSRIs increases the risk of adverse effects during fetal and neonatal

development. This is consistent with our previous finding that fluoxetine, a prototypical SSRI,

profoundly affected the viability of cultured embryonic stem (ES) cells as well as their ability to

differentiate into cardiomyocytes. Furthermore, we found that fluoxetine induced fluctuations in

ectodermal marker gene expression during ES cell differentiation, which suggests that fluoxetine may

affect neural development. In the present study, we investigated the effects of fluoxetine on the process

of differentiation from ES cells into neural cells using the stromal cell-derived inducing activity (SDIA)

method. Fluoxetine treatment was found to enhance the expression of glial marker genes following

neural differentiation, as observed by immunocytochemical analysis or quantitative RT-PCR. The

promoter activity of glial marker genes was also significantly enhanced when cells were treated with

fluoxetine, as observed by luciferase reporter assay. The expression of neuronal markers during ES

cell differentiation into neural cells, on the other hand, was inhibited by fluoxetine treatment. In

addition, FACS analysis revealed an increased population of glial cells in the differentiating ES cells

treated with fluoxetine. These results suggest that fluoxetine could facilitate the differentiation of

mouse ES cells into glial cell lineage, which may affect fetal neural development

Citalopram Risks: Has been associated with a rare

but serious newborn lung problem (persistent

pulmonary hypertension of the newborn, or PPHN)

when taken during the last half of pregnancy; has been

associated with septal heart defects; has been

associated with a birth defect that affects the brain and

skull (anencephaly), a birth defect that affect sutures on

the head (craniosynostosis) and a birth defect that

affects the abdominal organs (omphalocele)

Recommendation: Consider as an option during

pregnancy

Fluoxetine Risks: Has been associated with PPHN

when taken during the last half of pregnancy

Recommendation: Consider as an option during

pregnancy

Paroxetine Risks: Has been associated with fetal

heart defects when takenduring the first three months

of pregnancy; has been associated with PPHN when

taken during the last half of pregnancy; has been

associated with anencephaly, craniosynostosis and

omphalocele

Recommendation: Avoid during pregnancy

Sertraline Risks: Has been associated with PPHN

when taken during the last half of pregnancy; has been

associated with septal heart defects; has been

associated with omphalocele

Recommendation: Consider as an option during

pregnancy

Amitriptyline Risks: Suggested risk of limb

malformation in early studies, but not confirmed by

newer studies

Recommendation: Consider as an option during

pregnancy

Nortriptilina Risks: Suggested risk of limb

malformation in early studies, but not confirmed by

newer studies

Recommendation: Consider as an option during

pregnancy

• Some studies associate the use of antidepressants

during pregnancy with preterm birth, but other studies

don't support this link.

• Use of more than one type of SSRI during the first

trimester of pregnancy has been associated with an

increased prevalence of septal heart defects.

Grazie per

l’attenzione