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, – 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 – 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?

• • • • 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

ill effects 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

Pathways of Exposure in Pregnancy.

MATERNAL MEDICATIONS Umbilical Cord DIRECT EXPOSURE Amniotic Fluid 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.

• • • • • • • 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.

• • • • • • • Miscarriage possible slight increase Malformations Intra-uterine deaths no increase Low birth weight no increase slight increase Prematurity slight increase Withdrawal syndromes can occur Behavioural sequelae as yet unknown

FDA: “Use in Pregnancy”- Drug categories.

• • • • 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.

• • • • 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 Amniotic Fluid Prenatal Care 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 MATERNAL MENTAL ILLNESS BREAST MILK DIRECT EXPOSURE ENVIRONMENT MATERNAL CARE 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: – 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 Agitation/Jitteriness Poor Feeding Hypotonia 7 Sleepiness/Lethargy 0 Gastrointestinal symptoms Total Reports 3 26 Withdrawal Syndrome 15 Breast milk Transfer 4 7 4 1 3 3 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 – 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: – 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.