Download Antidepressants in Pregnancy and Breastfeeding

Psychotropic Medications in
Pregnancy and Breastfeeding.
INTRODUCTION
The Perinatal Period.
• A uniquely stressful time.
• Pre-existing psychological conditions can be
exacerbated by the stresses of the period.
• Many psychological illnesses have an increased
risk of onset at this time.
• Whether some psychological illnesses occur
uniquely in this period is controversial.
Some Trends in the treatment of
Maternal Psychological Illness (1).
•
maternal age means greater chance of prior
treatment of a psychological illness.
• treatment of depression generally in women
of childbearing years.
• detection of depression via screening
programs (antenatally and postnatally).
• recognition of “PND” beginning antenatally
(ie antenatal depression).
More Trends in the treatment of
Maternal Psychological Illness (2).
•
concern about the effects of maternal
depression/anxiety on an infant’s psychological
development.
• use of a wider range of new medications, eg,
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–
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atypical antipsychotics
anticonvulsants
new antidepressants
use of medications in combination
Trends in treating Psychotic Illness.
•
successful therapies = social functioning =
rate of psychotic patients becoming pregnant.
• New antipsychotics = no prolactin effect =
reduced incidence of medication-induced birth
control. proportion of patients with psychotic
illness becoming pregnant.
Epidemiology of Psychiatric Illness
in Pregnancy.
• Pregnancy does not protect against mental
illness as was previously thought.
• 5-10% of women have clinically significant
psychological symptoms.
• 70% of women with a history of recurrent major
depression will relapse during pregnancy.
• 50% of women with untreated Bipolar Disorder
will develop an episode in Pregnancy.
Epidemiology of Postnatal
Psychiatric Illness.
• 2-3 x increased risk of onset of psychiatric
illness in the first weeks postpartum.
• Time of greatest risk of psych. hospitalisation
for a woman cf any other time in her life.
– The risk is as high as 20x
• 10 - 20% of women will develop PND.
• Risk higher if any previous history of illness.
Clinical Situations Involving
Pregnancy and Psychotropics.
• previous episode/s of Major Depression, Bipolar
Disorder or psychotic illness and considering
pregnancy
• currently taking a psychotropic medication and
considering pregnancy
• currently taking a psychotropic medication and
has become pregnant
• first onset of depression or anxiety disorder
during current pregnancy
Clinical Situations Involving
Breastfeeding and Psychotropics.
• previous history of postnatal depression or
psychosis requiring prevention (prophylaxis)
while breastfeeding
• previous history of depressive illness where
postnatal prophylaxis may be advisable
• new onset of postnatal psychiatric illness
requiring medication whilst breastfeeding
Potential Treatments for Maternal
Psychiatric Illness.
• No treatment
• Psychotherapy
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–
–
–
Supportive
Cognitive behavioural
Interpersonal
Psychodynamic
• Medications
• ECT
Supportive Psychotherapy.
• has many helpful components.
• information (education), and advice, which is
especially relevant to new mothers
• the ventilation of difficult thoughts and feelings,
• support, praise, encouragement and reassurance
• positive focussing,
• all presented in the context of the therapist’s
reliability, consistency and continuity of care.
Psychotherapeutic Management (1).
• Some women will only consider psychotherapy.
• Some mild to moderate depression can be
contained by this approach.
• It is important to reassure the woman who is
“phobic” about medication that you respect
their position.
• Ongoing intermittent psychotherapy allows for
monitoring and re-evaluation.
Psychotherapeutic Management (2).
• Supportive psychotherapy builds good will with
the woman who is for the time being opposed to
medication.
• Helps to create a therapeutic alliance that will
be needed if the depression worsens.
• Avoid the dichotomy, “Well if you don’t want
my medication I can’t help you”.
– or “…. I don’t want to see you.”
• Always keep the “door open”.
General Issues to Consider.
• Mothers and babies elicit strong emotions.
• We each bring our own attitudes and values into
the situation - what are they? Be aware of them.
• How many patients? One or two or more?
–
–
–
–
The mother,
the mother and foetus/baby
the parental couple,
the family
The Clinical Problem: Defining
Exposure (1).
• We focus on the issue of exposure.
• There are 2 exposures:
1. What will the foetus/baby be exposed to in
terms of medication? (in utero & breastfeeding)
2. What will the foetus/baby be exposed to in
terms of maternal psychiatric illness? (in utero
& breastfeeding)
The Clinical Problem: Defining
Exposure (2).
• The foetus/baby will be exposed to something.
“There is no such thing as non-exposure.” Z.
Stowe.
• The foetus/baby will be exposed to medication
or psychiatric illness or both.
• Our role is to help the mother and her partner
decide which path of exposure is best for them.
Two Basic Assumptions.
1. All medications cross the placenta and also
enter breast milk.
2. We do not yet know all the potential risks
from medication exposure.
• We talk about the “Risk/Benefit ratio”.
• Risks of treatment vs the benefits of treatment.
• or risks of treatment vs risks of non-treatment.
The Risk/Benefit Ratio.
• The risks associated with medication are fairly
fixed even if some of them are as yet unknown.
• The risks associated with maternal psychiatric
illness varies enormously for each individual.
• Hence we ask, “What is the risk-benefit ratio
for this woman, given her current symptom
pattern or what has happened in her previous
episodes of illness?”
Maternal Psychiatric Illness. What
are the risks Prenatally? (1)
•
•
•
•
•
Effects on Mother and foetus and/or baby.
poor compliance with obstetric/medical care
poor maternal health/nutrition
abuse of alcohol and cigarettes
abuse of other substances including over the
counter remedies
suicidality, self-harm, recklessness
Maternal Psychiatric Illness.What
are the risks - Postnatally?
•
•
•
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deficits in mother-infant attachment
neurobehavioural sequelae
increased failure to breastfeed
separations at home, possible psychiatric
hospitalisation
• abuse, neglect, self harm, recklessness
• rarely, suicidality/infanticide
Maternal Psychiatric Illness.
Further risks.
•
•
•
•
•
•
Effects on Family and Environment
reduced care of other children
emotional neglect of other children
marital disturbance
occupational deterioration
reduced social network
etc.
What about the direct effects of mat.
psych. illness on the foetus?
• These are potential effects on the foetus via
changes in maternal blood chemistry, hormones,
catecholamines, immune function etc,
• What happens to the foetus in untreated maternal
psychiatric illness?
• What are the long term consequences of untreated
maternal psychiatric illness (eg depression) for
offspring into childhood, adolescence, etc.
Potential direct effects of Maternal
Depression/Stress.
• Effects on foetus
– changes in the HPA axis
– lower birth weight
– prematurity
– behavioural teratogenicity
What has been shown?
• Deleterious effect on obstetric outcome and
later infant development.
• Severe Stress and Depression may:
– impede foetal growth
– smaller head circumference
– increased rate of preterm delivery and other
complications
– long term behavioural problems in offspring
The Placenta as a Filter.
• In an Ideal World:
• the placenta would
screen out any direct illeffects from maternal
psychiatric illness.
• the placenta would block
the medication from
reaching the baby (or the
medication would have
no effect on the baby)
Does the placenta filter out direct
effects of maternal psych. illness?
• Research to date suggests No.
• Cortisol (stress hormone) levels in the umbilical
chord are typically higher than in the maternal
serum.
• There are also possible abnormalities in
immune function across the placenta.
• Research is difficult because of the obvious
confounding effects of the postnatal period.
Does the placenta filter out effects
of medication?
• Yes, to some extent.
• the concentrations of antidepressant
medications in the umbilical chord leading to
the baby are less than in the maternal circulation
• there is incomplete placental passage of
antidepressants
• “As a class of drug, antidepressants cross the
placenta less that just about any other drug”.
– Z Stowe.
The Placenta as a Filter. What Gets
to the Baby?
• Chord Samples: ratios 0.29 to 0.89
– sertraline<paroxetine<fluoxetine<citalopram
– Hendrick 2003
• Blood samples:
– maternal vs infant (breastfeeding) 1/50 to 1/200
• Milk Samples:
– concentrations in mother’s blood/in milk/ in babies
blood
Pathways of Exposure in Pregnancy.
MATERNAL MEDICATIONS
Umbilical
Cord
Amniotic
Fluid
DIRECT
EXPOSURE
BABY
Pathways of Exposure in Pregnancy
MATERNAL MEDICATIONS
Prenatal Care
Obstetrical
Outcome
INDIRECT EXPOSURE
BABY
Potential effects of exposure to illness
and medications for the foetus/baby.
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Miscarriage
Structural Malformations/Teratogenicity
Intra-uterine death
Growth Impairment (low birth wgt).
Prematurity
Neonatal toxicity and withdrawal
Behavioural teratogenicity
– cognitive, emotional, social, behavioural.
Effects of Antidepressants on Foetus.
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Miscarriage
Malformations
Intra-uterine deaths
Low birth weight
Prematurity
Withdrawal syndromes
Behavioural sequelae
possible slight increase
no increase
no increase
slight increase
slight increase
can occur
as yet unknown
FDA: “Use in Pregnancy”- Drug
categories.
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Category A: Controlled studies show no risk
Category B: No evidence of risk in humans
Category C: Risk to humans cannot be ruled out
Category D: positive evidence of risk but it is
possible in some situations the benefits may
outweigh the risks
• Category X: Contraindicated in pregnancy.
Risks outweigh the benefits in almost every
situation.
Risk Periods for Foetal Structural
Malformations.
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2-4 weeks neural tube closure
4-9 weeks heart is forming
6-9 weeks is when the oral cleft closes
by 12 weeks organogenesis is completed
Pathways of Exposure in Pregnancy
MATERNAL MEDICATIONS
Umbilical Cord
Prenatal Care
Amniotic Fluid
Obstetrica
lOutcome
INDIRECT EXPOSURE
DIRECT EXPOSURE
BABY
Psychotropics and Breastfeeding.
• It is widely accepted that
there are many benefits
in breastfeeding both
biologically and in terms
of mother-baby
attachment.
• Do these benefits
outweigh the potential
risks of psychotropic
ingestion?
Pathways of Exposures in
Breastfeeding.
NEWBORN
MATERNAL MEDICATIONS
BREAST MILK
DIRECT EXPOSURE
INFANT
Pathways of Exposures in
Breastfeeding.
NEWBORN
MATERNAL MEDICATIONS
BREAST MILK
MATERNAL MENTAL ILLNESS
ENVIRONMENT
MATERNAL CARE
DIRECT EXPOSURE
INDIRECT EXPOSURE
INFANT
Adverse Effects of Psychotropics on
Breastfeeding. (1)
• As with pregnancy, this depends on the class of
medication.
• All psychotropic drugs pass into the breast milk.
• Antidepressants as an example:
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various adverse effects reported
mostly non-specific
many studies show no ill effects
contraindicated in premature, low birth wgt, or
medically ill babies.
Maternal SSRI use and Adverse
reactions. (ADRAC, August 2003)
Symptoms
Withdrawal BreastSyndrome milk
Transfer
Agitation/Jitteriness 15
4
Poor Feeding
7
4
Hypotonia
7
1
Sleepiness/Lethargy 0
3
Gastrointestinal
3
3
symptoms
Total Reports
26
13
Adverse Effects of Psychotropics on
Breastfeeding. (2)
• Anti-anxiety (Anxiolytics)
– various adverse effects reported mostly sedation,
lethargy, sleep disturbance and in some instances
respiratory depression.
– The risk seems to diminish as the infant matures due
to better metabolism gets older.
– Long acting benzodiazepines (eg diazepam Valium)
are more likely to build up in the infant.
– Diazepam, lorazepam are secreted at higher levels in
breast milk cf. oxazepam.
Adverse Effects of Psychotropics on
Breastfeeding. (3)
• Antipsychotics
– generally OK to breastfeed
– some adverse effects noted.
Adverse Effects of Psychotropics on
Breastfeeding. (4)
• Lithium:
– contraindicated in most cases
– if mother strongly desires can be done with very
close monitoring
• Anticonvulsants
– Some adverse effects reported, some quite serious
– again can be done if mother strongly desires this and
is made aware of the risks.
Approach to Management
•General Principles
–Plan Ahead
Planning Ahead
Try to Pre-empt Difficulties.
• Try to discuss the issues prior to pregnancy
along with discussion of contraception.
• Planning ahead is the key. This allows time for
informed decisions. Have a plan in place based
on the “risk-benefit ratio”.
• Try to involve partners and families where
appropriate.
• The woman and her partner must ultimately
decide what is best for them.
If Planning a Pregnancy.
• Stop medications, if possible, while attempting
conception.
– This depends on the persons previous psychiatric
history.
• Stop medications on becoming pregnant
– by testing each cycle.
– again this depends on the history and should not be
as a matter of routine.
Approach to Management: Early
Pregnancy. (1)
• Discuss the strengths and weaknesses of each
treatment modality.
• Discuss the risks and benefits of the various
options - “Risk-Benefit ratio”.
• No decision is risk free.
• Try to minimise exposures.
• Avoiding all drugs in the first trimester is the
ideal, but this is not always possible.
Approach to Management: Early
Pregnancy. (2)
• Treat the mental illness as expertly as possible.
• Avoid changing medications (this will add a
new exposure).
• Stick with medications with good body of
information.
• Avoid poly-pharmacy.
• Avoid anticonvulsants unless absolutely
necessary and monitor with ultrasound.
Approach to Management: Later in
Pregnancy
• Pharmacokinetics can change in pregnancy and
doses may need to be changed.
• Use lowest dose but be ready to increase dose
or reintroduce a previous medication.
• Discontinuation effects.(Neonatal Withdrawal).
Consider gradual reduction of medication and
ceasing prior to delivery (controversial).
How Are Decisions Made? A
Question of Balance.
• Decisions are rarely clear cut.
• Usually there are two or more very reasonable
options between which the mother and the
physician have to chose.
• Some factors lead to one decision, other factors
lead to a different decision.
• Weighing the risks is a colaborative process
between parents and physician.
Who Decides and How?
• Ultimately it must be a mother’s and partner’s
decision.
• This relies on the information we provide but
also on her assessment based on:
– her values and her choices
– her desires for the future and how she gives weight
and meaning to different risks and the different
information presented
• There is rarely a “right answer”.
External Considerations.
• Family pressures
• Partner pressures
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–
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doesn’t believe in depression as a diagnosis
doesn’t believe in medications
hasn’t seen an episode of depression yet
doesn’t want her to be like his mother/aunt etc
Individual Psychotropics.
Classes of psychotropics.
• Antidepressants
– SSRI’s
– Tricyclics
– MAOI’s
• Mood Stabilisers
– anticonvulsants
– lithium
• Antipsychotics
Antidepressant medications.
• Tricyclics
• SSRI’s (fluoxetine sertraline paroxetine
citalopram fluvoxamine)
• SNRI’s venlafaxine (Efexor-XR)
• reboxetine (Edronax)
• mirtazapine (Avanza)
• MAOI’s
Tricyclic Antidepressants.
• Extensive data that there are no structural
abnormalities in the foetus
• nortriptyline and desipramine have less
anticholinergic side effects
• low incidence of perinatal syndromes
• Nulman (2002). No negative behavioural
sequelae up to 6 years.
• The data is reassuring
Fluoxetine (Prozac, Lovan)
• Increased risk of:
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miscarriage, 14% cf 7%
low birth weight
premature birth
decreased ARGAR Scores
minor anomalies
admission to NICU
poor neonatal adaptation
Fluoxetine (Prozac, Lovan)
• No increased malformations
• some perinatal syndromes
• Chambers study...
– increased risk of minor malformations
– increased risk of preterm labour
– increased admission to special care
• Extensive data which is mostly reassuring
Other SSRI’s (1)
• These have tended to be looked at as a group
• No increase in
– congenital malformations
– miscarriage / stillbirth
• increased preterm labour,
• decreased APGAR scores
• problems in “neonatal adaptation” (previously
reported as withdrawal syndromes) especially
paroxetine
Other SSRI’s (2)
• problems in “neonatal adaptation” (previously
reported as withdrawal syndromes) especially
paroxetine
• Casper J Pediatrics 2003
– 31 mother - baby pairs, various SSRI’s
– found a negative effect on motor development and
motor control
Venlafaxine
• Einarson Am J Psych. 2001
• 150 women all used venlafaxine during
pregnancy and 34 used it throughout.
• No increased risk of malformations but numbers
small.
Other antidepressants
• Bupropion/Mirtazapine/Reboxetine
• No evidence yet that they are harmful but this
could easily change
• Not much data
• We just don’t know
MAOI’s
•
•
•
•
Not much data/studies
Not used very often in pregnancy
What we know is concerning
We don’t know if they are dangerous though
Anxiety Disorders.
• High cortisol levels are problematic for the
foetus
• benzodiazepines are problematic
• Try CBT
• try SSRI’s as first line
• use short acting drug
• try to wean before delivery
Benzodiazepines (1).
• Neonatal sedation or withdrawal
• Floppy baby syndrome (baby is not responsive
and listless)
• Oral Cleft Palate?
– This is controversial 0.6% cf 0.06%
– some studies dispute this
– risk period is 6 - 9 weeks hence avoid during
Benzodiazepines (2).
•
•
•
•
animal data ...?behavioural teratogens
the data is confusing and not reassuring
Long acting agents can build up in the infant
SSRI’s are preferable
Bipolar Disorder - 3 problems.
1. Very high relapse rate.
2. When untreated it is a very dangerous
condition for mother and baby.
3. The main treatments (except ECT) are all
known teratogens.
• Consider ECT. This is not always readily
available and patients may not prefer it.
Anticonvulsants - Valproate.
• The most dangerous psychotropic medication.
• Discuss with any woman of reproductive age.
• 5 times higher rate of malformations or
pregnancy complications.
• Neural tube defects incr. from 0.3% to 1-5%
– may be reduced by folate supplementation.
• Increases defects in heart/limbs/genitals/CNS
and face.
Using Valproate.
• Discuss ahead of time, before pregnancy.
• Supplement with folate 4 mg per day from 4
weeks pre conception to 12 weeks gestation.
• Check foetal alpha-fetoprotein.
• Do high resolution ultrasound at 16 -18 weeks.
• Give vitamin K in final month of pregnancy.
• Keep serum level below 70 if possible.
• Give in divided doses rather than once daily.
Valproate and Breastfeeding.
• Valproate compatible with breastfeeding
Lithium.
• increases Ebstein’s abnormality by 10 - 20 times
(1 in 1000 cf 1 in 20,000)
– used to be thought to be 400 times
•
•
•
•
foetal diabetes insipidus can occur
floppy baby syndrome
has been around a long time
a lot of data, but the data is concerning.
Using Lithium in pregnancy.
• High resolution foetal ultrasound at 16 - 18
weeks to check for Ebstein’s abnormality.
• Give in small divided doses if possible.
• Monitor maternal serum levels which can
change dramatically.
• Taper dose by a half dose 2 weeks before
delivery.
• Hydrate the woman in labour.
Lithium in Breastfeeding.
• Discourage breastfeeding.
• Very high infant serum levels up to 50% of the
maternal level.
• High risk of toxicity in the infant, especially if
dehydration in the infant. eg GIT virus with
diarrhoea etc.
• Many reports of infant toxicity.
Carbamazepine (Tegretol).
• The data is quite concerning.
• Associated with many different adverse
outcomes in pregnancy.
• It is however, like valproate, compatible with
breastfeeding (levels 6% to 65% of maternal
level).
• Some case reports of adverse outcomes in
breastfeeding.
Lamotrigine.
• A prospective trail did not show increased risk
for major malformations but small sample size.
• Supplement with folate through pregnancy.
• Breastfeeding: infant serum levels 25% to 30%
of maternal serum.
• No reports of adverse outcomes thus far.
• Theoretical risk for life threatening rash.
Olanzapine.
• An atypical antipsychotic used increasingly in
Bipolar Disorder.
• One prospective study showed no increased risk
in pregnancy but small sample size.
• breastfeeding: Limited information.
• Some case reports of adverse effects, but ?if
related to the medication.
General guidelines for managing
Bipolar Disorder in Pregnancy.
• Plan ahead and discuss risks.
• Abrupt discontinuation greatly increases relapse
in Bipolar Disorder.
• Reduce medications if possible.
• Consider ECT (good safety data in pregnancy)
• Monitor pregnancy closely with ultrasound.
• Consider options for post partum prophylaxis.
Mild - Moderate Bipolar Disorder
• Avoid medications in first trimester if possible.
• Gradually taper medication before pregnancy or
immediately on discovery of pregnancy.
• Reintroduce mood stabiliser immediately if any
deterioration in mood.
• Strongly advise for post partum prophylaxis.
Severe Bipolar Disorder.
• Maintain prophylaxis throughout the pregnancy
despite dangerousness of medication.
• Consider switching from an anticonvulsant to
lithium prior to pregnancy or switching to
olanzapine.
If Pregnancy occurs while on an
anticonvulsant.
• Foetus has possibly already been exposed at the
high risk period for neural tube defects.
• Switching to a different agent increases the
number of drugs foetus is exposed to.
• No good options.
• Need full discussion with the woman about
what she thinks is best for her. A balancing act
depending on the woman’s history of illness.
Post Partum Management of
Bipolar Disorder.
• Prophylaxis is very important in this period.
• Postpartum psychosis has a 4% risk of
infanticide and 5% risk of suicide.
• 30 - 40 % of women with untreated Bipolar
Disorder will have an episode of post partum
psychosis.
Breastfeeding in Bipolar Disorder.
• Breastfeeding is relatively contraindicated
while taking lithium.
• Consider using an anticonvulsant while
breastfeeding. The woman would then need to
weigh benefits of breastfeeding vs the unclear
risks of breastfeeding with an anticonvulsant.
• In this context being on a prophylactic
medication should take precedence to
breastfeeding.
Antipsychotic drugs.
• High potency drugs: eg haloperidol
• Neonatal extra pyramidal signs, are self limiting
and resolve.
• No known teratogenicity based on surveillance
data.
• Low potency drugs: eg chlorpromazine
• Neonatal anticholinergic symptoms
• ?some teratogenicity not supported by
surveillance data.
Approach To Management
- Postnatal
Approach to Reducing exposures in
Postnatal illness. (1) Newport
(2002).
• Document all psychiatric illness exposures
(impaired maternal care, alcohol cigarettes
drugs etc,)
• If evidence of severe maternal impairment, err
towards medication exposure.
• Consider non-medication modalities according
to their availability.
Approach to Reducing exposures in
Postnatal illness. (2)
• Exposure in breastfeeding is much less than the
exposure in utero.
• Hence stick to same medication that the infant
has already been exposed to.
• If infant has not yet been exposed, use a
medication of previous response for the mother.
i.e. Don’t experiment with new medications.
• Use a medication with data.
Approach to Reducing exposures in
Postnatal illness. (3)
• Avoid poly-pharmacy. Monotherapy at any dose
is preferable to 2 or more medications.
• Reduce infant exposure with pump and dump at
8 - 9 hours.
• Monitor the infant for side-effects.
– discontinue breastfeeding or discontinue the
medication depending on the circumstances.
Partners and others in family
• Support partners as well, they are neither
expendable or always durable.
• Are they for or against management
suggestions?
• If against, find out why.
– doesn’t believe in depression
– has never experienced her depression
– doesn’t want her “addicted” to medication
Summary.
• Goal is to balance the reduction of exposures
from both illness and medication
• The severity of the illness tends to determine
the options.
• Use a medication of prior response and,
• Use a medication of prior infant exposure.
• Use a medication with data.
• Try to use monotherapy.