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Chittaranjan Andrade
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ANTIDEPRESSANT DRUGS AND PREGNANCY
2-hour clinically-oriented
workshop.
Chittaranjan Andrade, MD
Professor in Psychopharmacology
National Institute of Mental
Health and Neurosciences Bangalore, India
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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.
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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.
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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the course of preexisting depressive disorder [especially if medication was withdrawn].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)
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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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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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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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SSRIs AND RISK OF ASD: 2 (Andrade, J Clin Psychiatry 2017 a & b)
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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SSRIs AND RISK OF ASD: 3 (Andrade, J Clin Psychiatry 2017 a & b)
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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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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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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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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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 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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OBERLANDER ET AL: 2 (Arch Gen Psychiatry 2006)
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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OBERLANDER ET AL: 3 (Arch Gen Psychiatry 2006)
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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OBERLANDER ET AL: 4 (Arch Gen Psychiatry 2006)
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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Lund et al (Arch Pediatr Adolesc Med 2009)
(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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Lund et al (Arch Pediatr Adolesc Med 2009)
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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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
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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
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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.
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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.
Chittaranjan Andrade
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.
Chittaranjan Andrade
93
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