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Chittaranjan Andrade

1

ANTIDEPRESSANT DRUGS AND PREGNANCY

2-hour clinically-oriented

workshop.

Chittaranjan Andrade, MD

Professor in Psychopharmacology

National Institute of Mental

Health and Neurosciences Bangalore, India


2

CAVEAT

This workshop has been prepared with the best

available evidence and is regularly updated as

newer evidence becomes available.

Participants are nevertheless encouraged to

seek independent information sources and draw

their own conclusions.


3

IMPORTANCE

Women comprise about two-thirds of patients

with depression.

Most of them are in their childbearing years!

The discussion which follows thus applies to a

sizeable part of a psychiatrist’s clientele during

the first presentation as well as during every follow-up.


4

ISSUES AT STAKE

1. Pregnancy may trigger depression, or worsen

the course of preexisting depressive disorder [especially if medication was withdrawn].

2. Untreated depression may influence pregnancy

outcomes [due to maternal hormonal changes, maternal behavior].

3. Treated depression may influence pregnancy

outcomes [there is only one patient, but more than one person is

being treated].


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ISSUE 1: EFFECT OF PREGNANCY ON DEPRESSON

Mrs A is on treatment for

recurrent depressive disorder.

She wants to conceive.

Should she stop medication

before a planned pregnancy and resume during the second

trimester?


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EFFECT OF PREGNANCY ON DEPRESSION

It is a myth that pregnancy protects

against psychiatric illness.

Pregnancy is associated with

Emotional stress

Physical stress

Physiological stresses

Pregnancy can therefore trigger new-onset depression or depressive relapse.

What is the evidence?


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PREGNANCY AND RECURRENT DEPRESSIVE DISORDER: 1

In 65 women who stopped ADs before

conception, the relapse rate was 68%.

In 82 women who continued ADs all through pregnancy, the relapse rate was only 26%.

[Adjusted HR=5.0; 95% CI, 2.8-9.1]

In both groups, about half of the relapses

occurred during the 1st trimester [implications].

Women who stopped ADs relapsed earlier. (Cohen et al, JAMA 2006)


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PREGNANCY AND RECURRENT DEPRESSIVE DISORDER: 2

Reintroduction of ADs in women who stopped

ADs reduced the risk of relapse, but the risk

remained higher than in those who did not stop

at all [implications for reintroduction in 2nd trimester].

Women with a longer history of depressive illness and those with a larger number of previous

episodes were at higher risk of relapse. (Cohen et al, JAMA 2006)


9

IMPLICATION AND CAVEATS

In women with recurrent depressive disorder, it

may be better to continue ADs all through

pregnancy [especially when illness is more severe].

This study was conducted in the USA, where the

stress-support dimension is less favorable than in India. We do not know if the risk for relapse

is similar in Indian pregnancies which are not protected by antidepressants.


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ISSUE 2: EFFECT OF UNTREATED DEPRESSION ON PREGNANCY

Mrs B has depression but wants to

stop antidepressant medicines and

conceive.

Mrs C has developed depression

during the 1st trimester.

Each woman asks, “Can I suffer

through my depression so that my

unborn child is not exposed to potentially harmful medicines?


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EFFECT OF UNTREATED DEPRESSION ON PREGNANCY: 1

Increased risk of maternal mortality (Brettingham,

BMJ 2004).

Increased risk of poor weight gain, alcohol or

illicit drug use, pre-eclampsia, poor mother-child bonding (Kurki et al, Obstet Gynecol 2000; Nonacs and Cohen,

Psychiatr Clin North Am 2003; Davalos et al, Arch Womens Ment Health 2012).

Increased risk of preterm delivery, low birth

weight, operative delivery, neonatal ICU

admission (Chung et al, Psychosom Med 2001; Bonari et al, Can

J Psychiatry 2004; O’Keane and Marsh, BMJ 2007).


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EFFECT OF UNTREATED DEPRESSION ON PREGNANCY: 2

Meta-analysis of 29 prospective studies from 12

countries: Approximately 50% increased risk of

each of the following:

IUGR

Preterm birth

Low birth weight

(Grote et al, Arch Gen Psychiatry 2010)

(Grigoriadis et al, J Clin Psychiatry 2013)


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QUESTION

How might untreated depression affect the

pregnancy and the child?


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MECHANISMS OF HARM ASSOCIATED WITH UNTREATED DEPRESSION

Depression is associated with the following:

Neuroendocrinological changes

Immunological impairments

Abnormal eating patterns and nutritional disorders

Neglect of health

Poor adherence to medical regimes

Smoking, drinking, and illicit drug use

Impulsive behavior

Deliberate self-harm

These are confounds that are poorly measured or unavailable in observational research.


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EXAMPLES OF CONFOUNDING BY INDICATION

[Meaning of confounding by indication]

E.g.:

Antidepressant-treated women were older, had higher BMI, smoked more, and were more likely to

be primiparous in a study of women who used

SNRI/NRI drugs during pregnancy. (Lennestai and Kallen, J Clin Psychopharmacol 2007)

Antidepressant-treated women were more likely to

smoke, consume alcohol, or abuse substances. (Ferreira et al, Pediatrics 2007)


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IMPLICATIONS AND CAVEATS

It may be better to treat depression during

pregnancy than to leave it untreated.

We do not have Indian data to know whether

harmful maternal behavior and harmful maternal internal environment associated with untreated

depression would result in the same harmful

outcomes.


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ISSUE 3: EFFECT OF TREATED DEPRESSION ON PREGNANCY

What effects might

untreated depression or

antidepressant drugs have

on pregnancy outcomes?


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EFFECT OF DRUG-TREATED DEPRESSION ON PREGNANCY: 1

1. Planned abortion

2. Spontaneous abortion

3. Preterm labour

4. Morphological teratogenicity

a) Major, e.g. cardiac defects

b) Minor, e.g. minor finger, toe, or ear defects

c) Qualitative, e.g. cleft palate

d) Quantitative, e.g. small head circumference


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EFFECT OF DRUG-TREATED DEPRESSION ON PREGNANCY: 2

5. Neonatal toxicity (because of immature liver)

6. Neonatal withdrawal (e.g. SSRIs, BDZP)

7. Physiological teratogenicity (e.g. persistent

pulmonary hypertension with SSRIs)

8. Behavioral teratogenicity (e.g. low IQ, behavioral or

personality problems in later life, autism)

9. Maternal adverse outcomes

Extra weight gain

Pregnancy-induced hypertension


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IS PSYCHOTHERAPY A VIABLE ALTERNATIVE TO DRUGS?


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PSYCHOTHERAPY: NEGATIVES

May not be available.

May not be accessible.

May not be affordable.

May not be acceptable.

May not be appropriate.

(e.g. poor motivation, severe

depression).

Onset of efficacy may be delayed.


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PSYCHOTHERAPY: POSITIVES

Treats only the mother.

Can be used to augment drug

management and hence:

Improve efficacy of drugs.

Reduce the need for polypharmacy.

Reduce the need for higher doses.

Note: Involve family in therapy [e.g. for support and stress management].


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SSRIs AND AUTISM SPECTRUM DISORDER (ASD)

This is one of the best researched areas with regard to research design.

Well over a dozen cohort and case-control studies

have been published.

Most other pregnancy outcomes have not been as well studied.

The methods and conclusions considered here apply to other pregnancy outcomes, as well.


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SSRIs AND RISK OF ASD: 1 (Andrade, J Clin Psychiatry 2017 a & b)

Findings of 6 meta-analyses (2016-17) and 4

subsequent studies (2017) on the risk of ASD

following gestational exposure to antidepressant

drugs:

1. There is a small increase in ASD risk in children

exposed to antidepressant drugs in utero.

This may be due to the SSRI, or to poorly measured,

unmeasured, or unknown confounds

These were listed in a previous slide.

These include shared genes between depression and ASD.


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2. The risk of ASD is reduced after adjusting for

confounding variables

And may no longer be statistically significant after

adjusting for maternal psychiatric illness.

3. The risk is as high in unexposed as in exposed

siblings.

4. The risk is as high after paternal exposure as

after maternal exposure.


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5. Antidepressant exposure is associated with an

increased risk of ASD in the offspring even when

the exposure is limited to the preconception period

When there is no way in which the drugs can have a physiological effect on the fetus.

Putting these findings together, it appears that

maternal mental illness [or environmental toxicity]

may explain much or all of the risk of ASD associated with antidepressant exposure during

pregnancy.


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COUNSELLING WOMEN ABOUT RISKS

Simple guidelines to

be adopted for all

depressed women


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IMPORTANT DOs: 1

At first contact, discuss with woman, family:

Effect of pregnancy on illness

Effect of untreated illness on pregnancy

Role of psychotherapy

Effect of drug-treated illness on pregnancy

Need for planned pregnancy

Involve woman, family in decision-making.

Review discussion, especially during wellness.

Document decision-making processes.

Record LMP


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IMPORTANT DOs: 2

At every follow-up:

Record date of LMP

Ask about adherence to contraceptive measures

Be proactive in suspecting pregnancy


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ISSUES RELATED TO CONTRACEPTION

Oral contraceptives can diminish

lamotrigine levels by 50%.

St. John’s wort can diminish the efficacy of oral contraceptives.

SSRIs may increase the blood

levels of gynecological drugs.

Liaise with gynecologist.


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QUESTION

Mrs D is on antidepressant

medication. She discovers

that she is pregnant. She

asks whether she should stop her medication.

How would you analyze her

case to best advise her?


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DISCONTINUING MEDICATION DURING PREGNANCY?

Consider the following in the patient’s

past history, if available:

Frequency and severity of episodes

Time to relapse after noncompliance

Speed and magnitude of response to drug

therapy after relapse

Course of illness during pregnancy and the postpartum period.


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QUESTION

What dosing strategy

would you follow during

pregnancy?


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OTHER GUIDANCE FOR MANAGEMENT DURING PREGNANCY

Do not use lowest historically-effective doses (these may be ineffective during the stressful period that is pregnancy; the whole point in treatment is to treat

EFFECTIVELY).

In this regard, note that drug metabolism or

excretion is upregulated as pregnancy progresses.

E.g. With lithium, lamotrigine

Administer drugs in divided doses to lower dosage

peaks.

Avoid polypharmacy.


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QUESTION

How might you further

reduce the risk of relapse

during pregnancy?


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ANSWER

Supplement with psychotherapy

Supplement with social support.

Lower stress exposure

Ensure adequate sleep.

Involve the family in these measures.


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GENERAL CAVEAT

With drugs of known, marked risks, consider

tapering and withdrawing the drugs, if possible

during the period of risk; e.g. the first trimester.

E.g. Valproate, topiramate [not used as antidepressants, though!] [so far, no antidepressant has been associated with

serious risk]


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BEFORE PREGNANCY

Provide antenatal

psychiatric counselling

Liaise with gynecologist.

Supplement with folate

(0.4-4.0 mg/day) months

in advance.

Enlist family supervision.


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FIRST TRIMESTER

Consider ECT (for severe depression).

Prefer monotherapy.

Do not use lowest historically effective doses!

Administer in divided doses to

lower peak drug levels.

Prescribe folate: 0.4-4.0

mg/day.


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SECOND AND THIRD TRIMESTERS

Do ultrasound, fetal echocardiography by

week 16-18.

Raise drug doses to compensate for increased blood volume, hepatic

metabolism, renal clearance (e.g. with

lamotrigine).

Monitor drug levels (especially for lithium).


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QUESTION

What medication advice

would you provide a

woman a week before

delivery?


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PUERPERIUM

Shortly before delivery, consider lowering

drug doses because the neonatal liver is not

mature for metabolism of maternal drugs.

Maintain pre-pregnancy doses after delivery.

Monitor drug levels, if possible.


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TERATOGENICITY


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QUESTION

What is the baseline rate of major congenital

malformations in healthy women who have not

been exposed to medications during pregnancy?


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ANSWER

Most epidemiological studies find

a base rate of about 2-3% for

major congenital malformations in

the general population.

In a USA study of nearly 1.8

million pregnancies, Huybrechts et

al (JAMA Psychiatry 2018) obtained a

rate of 3.5%.


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QUESTION

If exposure to a drug during pregnancy is

associated with a 5-7% rate of major

congenital malformations, would you consider

that the drug is responsible for teratogenicity?


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ANSWER 1: NOT NECESSARILY!

Confounding by indication: Incompletely treated

illness behavior may be responsible for behaviors

that increase the risk of malformations

E.g. Antidepressant-treated women were older, had higher BMI, smoked more, and were more likely to be

primiparous in a study of 732 women who used SNRI/NRI drugs during pregnancy.

(Lennestai and Kallen, J Clin Psychopharmacol 2007)

E.g. Antidepressant-treated women were more likely to smoke, consume alcohol, or abuse substances. (Ferreira et al, Pediatrics 2007)


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ANSWER 2: POSSIBLY

1. If there is specificity

E.g. cardiovascular defects with paroxetine.

2. If the risk is elevated relative to other drugs in

the same category

E.g. paroxetine relative to SSRIs

(confounding by indication is still present because paroxetine may be preferred for women with anxiety who

hence need more medication; but confounding here may be reduced in magnitude).


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COMMENT

Only large, randomized, double-blind, placebo-

controlled trials can describe the true risk of

teratogenicity with different drugs.

Such studies, for ethical reasons, cannot and will

not be conducted.


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QUESTION

What is the risk period

during pregnancy when exposure to psychotropic

medications can result in teratogenicity?


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RISK PERIODS

Weeks 5-7: Neural tube defects

Weeks 6-10: Cardiac defects

Weeks 8-11: Lip and palate defects

Weeks 10-22: Craniofacial anomalies

(Anytime after week 12: Behavioral teratogenicity) Wisner et al, Am J Psychiatry 2000


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RISK PERIODS: IMPLICATIONS

If a woman wants to stop medicines, by the

time she discovers that she is pregnant it

may be too late.

Risk also continues beyond the first trimester.


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ANTIDEPRESSANTS AND RISKS DURING PREGNANCY


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GENERAL NOTES: 1

In textbooks, older antidepressants (TCA) are

widely recommended for use during pregnancy

because ‘after half a century of use, there are no

reports of adverse outcomes’.

The ‘no reports’ only testify to

The absence of specific teratogenicity

The absence of obviously elevated (other) risks


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GENERAL NOTES: 1

There are no epidemiological data to document the

absence of small elevations in risks with TCA use.

The ‘no reports’ will not testify to safety with regard to:

Spontaneous abortion

Preterm labour

Small head circumference, low birth weight

Neonatal withdrawal syndrome

Neurodevelopmental delays and syndromes.

Etc.etc.etc.


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SSRIs AND PREGNANCY

SSRIs: the most commonly used antidepressants.

Recommended as first choice antidepressants

during pregnancy in Denmark (Nielsen et al, Ugeskr Laeger

2007) and ‘many other countries’ (Lund et al, Arch Pediatr

Adolesc Med 2009).

Epidemiological data on use provided by Tuccori et

al (Clin Ther 2009).

There are more data for SSRIs in pregnancy than

for any other drug or group of drugs in the pharmacopoeia.


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SSRIs AND PREGNANCY

Teratogenicity

Fetal growth


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SSRIs AND TERATOGENICITY

SSRIs marginally increase the risk of certain

specific major malformations

Gao et al (BMC Med 2018)

Paroxetine increases the risk of certain cardiac

malformations

Berard et al (Br J Clin Pharmacol 2016)


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FIRST TRIMESTER SSRI EXPOSURE (examples)

Case control studies:

Louik et al (NEJM 2007)

9849 cases, 5860 controls

Alwan et al (NEJM 2007)

9622 cases, 4092 controls


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LOUIK (2007) AND ALWAN (2007): IMPORTANT FINDINGS

Overall, SSRIs did not increase the risk of birth

defects.

SSRIs, however, doubled to trebled the risk of certain rare defects such as anencephaly,

omphalocele, and craniosynostosis.

Specific SSRIs increased the risk of certain specific

defects; however, the absolute risk was small.


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Pedersen et al (BMJ 2009)

Retrospective population-based, Danish cohort

study.

SSRI-exposed infants, n=1370

SSRI-unexposed infants, n=493,113

Exposure: -28 to +112 days of gestation


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Pedersen et al (BMJ 2009)

Major malformations (4%), NS

Minor malformations (1.5%), NS

Doubled risk of septal heart defects with SSRIs (significant only for citalopram and sertraline).

[NNH, 246]

Cardiac malformations and septal heart defects risk

increased in women who used >1 SSRI.


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SSRIs AND PREGNANCY

Neonatal issues

unrelated to

teratogenicity

Functional outcomes


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PREGNANCY LOSS: 1

Pooled analysis of 267 SSRI users vs 267 nonusers (Kulin et al, JAMA 1998):

Spontaneous abortion, 11.2% vs 7.9% (NS)

Meta-analysis of 9 studies with 2999 pregnancies (Rahimi et al, Reprod Toxicol 2006):

OR for pregnancy loss with SRIs = 1.7 (95% CI, 1.28-2.24).

Meta-analysis of 6 studies of 1534 antidepressant

users vs 2033 nonusers (Hemels et al, Ann Pharmacother 2005):

Spontaneous abortion RR=1.45 (95% CI, 1.19-1.77)


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PREGNANCY LOSS: 2

Nakhai-Pour et al (CMAJ 2010)

5124 women with a spontaneous abortion matched

1: 10 with controls.

Antidepressant drugs were associated with an approximately doubled risk of spontaneous

abortion after early gestational exposure.


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OBERLANDER ET AL: 1 (Arch Gen Psychiatry 2006)

119,547 live births

SSRI exposure, n=1451

Depression without SSRI exposure, n=14,234

No depression, no SSRI exposure, n=92,192

Propensity matching:

Depression with SSRI exposure, n=817

Depression with no SSRI exposure, n=805


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SSRIs increased the risk of premature labor late in

pregnancy.

But mean gestational age was just 2-3 days shorter.

SSRIs increased the risk of low birth weight.

But mean birth weight was just 30-50 g less.

SSRIs increased the risk of cesarean birth.


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SSRIs increased the risk of a neonatal

withdrawal syndrome.

SSRIs increase the risk of respiratory distress in the neonate (14% vs 8%).

And the risk of neonatal jaundice

(9.4% vs 7.5%).

And the risk of feeding problems

(3.9% vs 2.4%).


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After matching for severity of maternal

depression, SSRI exposure was associated with

lower birth weight (including smallness for

gestational age) and more respiratory distress in the neonate than untreated maternal depression.

These data seem to challenge the

recommendation that depression in pregnancy

should be treated! But propensity matching cannot eliminate unknown/unmeasured confounds.

(Oberlander et al, Arch Gen Psychiatry 2006)


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Lund et al (Arch Pediatr Adolesc Med 2009)

Prospective Danish cohort study.

Group 1: SSRI-treated pregnancies (n=329)

[mostly sertraline, citalopram]

Group 2: Psychiatrically ill, but SSRI-unexposed

pregnancies (n=4902)

Group 3: Pregnancies uncomplicated by psychiatric

illness or drugs (n=51,770)


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(SSRI group) vs (illness group) vs (no illness, no

drug group)

Preterm delivery: 9% vs 5% vs 5%

NICU admission: 16% vs 9% vs 7%

5’ Apgar <8: 5% vs 1% vs 1%

Birth weight <2.5 kg: NS


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Mean gestational age about 5 days less in the SSRI

group relative to the other two groups.

No significant difference in mean birth weight.

No significant difference in mean head

circumference.

These data appear to challenge the suggestion that

depression in pregnancy should be treated.

BUT, there may have been confounding by indication in the SSRI-treated women.


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Ross et al (JAMA Psychiatry 2013)

Meta-analysis of 23 studies:

Antidepressant exposure during pregnancy is

associated with:

Shorter duration of gestation (by 3 days)

Increased risk of preterm delivery (by 55%)

Lower birth weight (by 75 g)

Lower 1- and 5-min Apgar scores (by <0.4 points).

Antidepressant exposure is not associated with an

increased risk of spontaneous abortion.

What is statistically significant is not clinically significant.


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POOR NEONATAL ADAPTATION SYNDROME (PNAS)

Cause: AD withdrawal, AD toxicity, both

Starts hours to days after delivery; self-limiting,

and ends days to (rarely) weeks later.

Clinical features: lethargy, hypoactivity, shaking,

shivering, tremors, excessive crying, jitteriness,

irritability agitation, poor feeding, excessive weight

loss, rapid respiration, respiratory distress,

hypothermia, hypoglycemia, increased or decreased muscle tone, and seizures

(Grigoriadis et al, J Clin Psychiatry 2013).


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PNAS

SSRIs treble the risk of a mild,

self-limiting neonatal behavioral

syndrome characterized by

nonspecific motor, respiratory, gastrointestinal, and CNS

symptoms.

The syndrome is best managed

supportively. Moses-Kolko et al, JAMA 2005


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PNAS IN NEONATES

A mild to severe SSRI withdrawal syndrome develops in about 30% of

neonates after prolonged exposure

to the drug in utero.

The withdrawal syndrome peaks in

severity during the first two days

after birth; in some cases, however,

the peak may not occur until the fourth day of life.

(Levinson-Castiel et al, Arch Ped Adol Med 2006)


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SSRIs/VENLAFAXINE WITHDRAWAL IN NEONATES

76 women treated with SSRIs/venlafaxine during the 3rd trimester vs 90 untreated controls.

Exposed infants were more likely to exhibit CNS (63%) and respiratory (41%) symptoms.

These appeared within a day and lasted a median of 3-4 days.

In 75%, these resolved within 3-5 days (longer in premature infants).

Median hospital stay, 15 vs 4 days in exposed vs unexposed infants.

Ferreira et al, Pediatrics 2007)


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SSRIs AND PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

PPHN: Failure of the baby to adapt to breathing

after birth; adverse consequences relate to anoxia.

Ventilatory support is required.

Risk in the general population, 0.1-0.2%.

Some studies suggest that SSRIs predispose to PPHN (Chambers et al, 2006; Kallen and Olausson, 2008);

others find no risk (Andrade et al, 2009; Wichman et al, 2009;

Wilson et al, 2011).


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SSRIs AND PPHN

FDA advisory (14/12/2011):

“It is premature to reach any conclusion about a

possible link between SSRI use in pregnancy and PPHN.”

Health care professionals advised “not to alter their current clinical practice of treating depression during

pregnancy”.

http://www.fda.gov/Drugs/DrugSafety/ucm283375.htm#data


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SSRIs AND ADHD

What applies to ASD conceptually applies to ADHD,

as well.


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OTHER ANTIDEPRESSANTS DURING PREGNANCY


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DULOXETINE IN PREGNANCY AND

LACTATION (Andrade, J Clin Psychiatry 2014)

Increased risk of spontaneous abortion

Limited data suggest no increase in overall

teratogenic risk (Einarson et al, J Clin Psychiatry 2012)

Case reports of poor neonatal adaptation syndrome

Infant exposure in breast milk <1% of the maternal

weight-adjusted dose (Lobo et al, Clin Pharmacokinet 2008;

Briggs et al, Ann Pharmacother 2009; Boyce et al, Arch Womens Ment Health 2011)

No data on risk of preterm birth, low birth weight, PPHN,

developmental delays and syndromes etc.


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RISKS WITH LAMOTRIGINE DURING PREGNANCY

Lamotrigine was formerly

considered to increase the risk of oral clefts.

Lamotrigine is now recognized to

be one of the safest

anticonvulsants in pregnancy.

Rasmussen et al, NEJM 2018


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LAMOTRIGINE DOSING DURING PREGNANCY

Lamotrigine is metabolized by glucuronidation.

Glucuronidation is induced during pregnancy.

Therefore, >50-100% increase in dose may be

required as pregnancy progresses.

The increased requirement peaks in the early

third trimester (week 32).

The requirement drops to baseline levels within 2

weeks postpartum, as the liver normalizes. (Tran et al, Neurology 2002; Pennell et al, Neurology 2004)


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LAMOTRIGINE DOSING AT THE END OF PREGNANCY

Lower the dose close to

term to reduce fetal

exposure. This is because

the glucuronidation pathway is immature in the neonate.

This will also lower the risk

of maternal adverse effects postpartum.


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RISKS WITH LITHIUM PREGNANCY (Patorno et al, NEJM 2017): 1

Cohort study Li exposed, n=663

Lamotrigine exposed, n=1945

Unexposed, n=1,322,955

Cardiac malformations, 2.41% vs 1.39% vs 1.15% RR for Li (vs unexposed): 1.65 (95% CI, 1.02-2.68)

RR significantly raised only at >900 mg/day Analyses may have been underpowered for lower

doses


87

RISKS WITH LITHIUM PREGNANCY (Patorno et al, NEJM 2017): 2

Right ventricular outflow tract obstruction defects, 0.60% vs 0.18% RR, 2.66 (95% CI, 1.00-7.06)

Results similar when lamotrigine was used as the reference group.


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ANTIDEPRESSANTS AND PREGNANCY-INDUCED HYPERTENSION

1216 women with PIH; 10 matched controls per case

Antidepressant use in cases vs controls, 3.7% vs 2.5% (OR, 1.53; 95% CI, 1.01-2.33)

Increased risks identified for SSRIs as a class; for

paroxetine; for ‘other antidepressants’. Other

analyses may have been underpowered. De Vera and Birard, Br J Clin Pharmacol 2012

Similar findings: Toh et al, Am J Psychiatry 2009; Reis and Kallen, Psychol Med 2010


89

TAKE-HOME MESSAGES ABOUT SSRIs IN PREGNANCY: 1

50-70% increased risk of 1st trimester fetal waste.

Small increase in the risk of preterm labour.

Small increase in the risk of low birth weight.

No increase in major or minor malformations.

Increased risk of septal heart defects and rare

malformations; but the absolute risk is low.

Definite risk of neonatal withdrawal syndrome.

Questionable risk of persistent pulmonary

hypertension of the newborn.


90

TAKE-HOME MESSAGES ABOUT SSRIs IN PREGNANCY: 2

Questionable risk of neurodevelopmental

syndromes such as ASD and ADHD.

Confounding by indication (severity of depression) probably explains most of the variance in the

adverse outcomes reported in literature.

If a woman requires an antidepressant before or

during pregnancy, it may be better to prescribe

the drug than not to do so.

Decision-making should be shared.


91

WEB RESOURCES

Australian Pregnancy Register

International Registry of Antiepileptic Drugs and

Pregnancy

United Kingdom Epilepsy and Pregnancy Register

North American Antiepileptic Pregnancy Registry

Lamotrigine Pregnancy Registry

Swedish Medical Birth Registry

LactMed

Motherisk


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MOTHERISK: www.motherisk.org

The Motherisk Program at The Hospital for Sick Children in Toronto, is a clinical, research, and

teaching program for antenatal drug, chemical, and

disease risk counseling.

It is affiliated with the University of Toronto.

Created in 1985, it provides evidence-based

information and guidance about the safety or risk to

the developing fetus or infant, of maternal exposure to drugs, chemicals, diseases, radiation,

and environmental agents.


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RECOMMENDED READING

Wisner et al, Am J Psychiatry 2000

Yonkers et al, Am J Psychiatry 2004

Gentile, J Clin Psychiatry 2008

Nguyen et al, Adv Ther 2009

Tuccori et al, Clin Ther 2009


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ENFIN…

THANK YOU!

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