WALID SARHAN F.R.C.Psych

A -Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities to the fetus in any trimester of pregnancy.

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US FDA pregnancy drug labeling categories

B Animal studies have revealed no evidence of harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women.OrAnimal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester

C Animal studies have shown an adverse

effect and there are no adequate and well-controlled studies in pregnant women.OrNo animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.

D Adequate well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective.

X Adequate well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risks. The use of the product is contraindicated in women who are or may become pregnant.

Antidepressant medications SSRIs

Fluoxetine (Prozac)Sertraline (Zoloft)-solotikParoxetine (seroxat)Fluvoxamine (faverin)Citalopram (Cipram)Escitalopram (cipralex)-purlex

SNRIsVenlafaxine (Effexor)Duloxetine (Cymbalta)Desvenlafaxine (Pristiq)

Antidepressant medications Other

Wellbutrin (Bupropion)○ Norepinephrine and dopamine

TrazodoneMirtazapine (Remeron)

Tricyclic AntidepressantsAmitriptyline (tryptizol)Nortriptyline (nortrilene)Imipramine (Tofranil)Clomipramine (Anafranil)

MAOIsPhenylzine (Nardil)Tranylcypromine (Parnate)

Medication Choice

An individual decision that’s made on a case

by case basis!

Medication choices Pre-conception taper Stop medications entirely Stop and restart if symptoms Stop and restart after 1st trimester Continue through pregnancy Decrease dose Reduce or discontinue in late

pregnancy Transition to psychotherapy

General guidelines

Treat a woman as if she could become pregnant at any time…Up to 80% of pregnancies are unanticipatedDocument use of birth controlEncourage use of folic acid and multivitamin

FDA labels

Patients read them They will change They will be changing

Standard information on background ratesFetal risk dataClinical considerationsRegistry information

FDA Classifications Most psychotropics are C None are A No antidepressants are FDA approved for

pregnancyNo drug is “safe”No good randomized, placebo-

controlled studiesMost studies are retrospective, case

reports, and registry data

FDA categories of Antidepressants in Pregnancy as of 9/24/10

Medication Pregnancy Category Lactation Risk

Fluoxetine C Safety Unknown

Paroxetine D Safe

Sertraline C Safe

Citalopram C Safety Unknown

Escitalopram C Safety Unknown

Bupropion C Possibly Unsafe

Venlafaxine C Safety Unknown

Nortriptyline D Probably Safe

Amitriptyline C Probably Safe

Mirtazapine C Safety Unknown

Trazodone C Probably Safe

Pregnancy factors that may increase medication concentrations Reduced gastrointestinal motility

Absorption changes for some medicationsReduced fecal elimination

Serum proteins lowerMay result in higher ‘free’ drug concentrations

Pregnancy factors that may decrease medication concentration

Total blood volume increases 30 – 40%2nd and 3rd trimesters extravascular volume

increases○ Results in lower plasma levels of meds

Increased kidney plasma flow 30%GFR increased by 50%

○ Renal excreted drugs have faster elimination

Pregnancy factors that may decrease medication concentration

Nausea and vomitingReduced absorption

Increased liver metabolismMay result in increased elimination of certain

medications

Antidepressant Blood Levels and Pregnancy

Prepregnancy Conception 20 weeks Delivery Postpartum

Adapted from Sit et al 2008

What should we be concerned about?

1. Organ malformation (teratogenicity)○ Miscarriage is worst outcome of this

2. Neonatal Adaptation○ Physical and behavioral symptoms noted

shortly after birth Related to drug use near time of birth Limited duration

3. Long term behavioral abnormalities

Medication Background

Incidence of major birth defects in US is 2 to 4%65 – 70% of unknown cause2 – 4% medication related

Period of maximum vulnerability for birth defects of the nervous system is 14 – 35 days post conception

Medication Background

Women usually find out when already 5-7 weeks gestation

Therefore, may want to keep same medication if it’s working

Antidepressants During Pregnancy

SSRI complicationsCongenital anomaliesPersistent Pulmonary Hypertension of

the NewbornNeonatal adaptation syndrome

SSRIs DURING PREGNANCY AND RISK OF PERSISTENT PULMONARY HYPERTENSION IN THE NEWBORN: population based cohort study from the five Norodic countries

The risk of persistent pulmonary hypertension of the newborn is low, but use of SSRIs in late pregnancy increases that risk more than twofold .

The increase risk seems to be a class effect

BMJ .2011JAN 12,:d8012.doi:10.1136/bmj

Paroxetine Has FDA warning against using in first

trimester due to increased risk of cardiac defects

Neonatal Adaptation Syndrome

Cohort study (n = 120), included venlafaxineNeonatal abstinence syndrome

occurs in 30% of neonates exposed to SRIs in utero

Monitor for 48 hours after birth

Levinson-Castiel R (2006) Arch Pediatr Adolesc Med 160: 173-176.

Neonatal Adaptation Syndrome

Tremors Increased muscle tone Feeding difficulties Irritability Respiratory problems Increased reflexes Increased crying Sleep changes Seizures

Moses-Kolko EL et al (2005) JAMA 293: 2372-2382Moses-Kolko EL et al (2005) JAMA 293: 2372-2382

SSRIs and Persistent Pulmonary Hypertension N = 377 women with PPHN infants N = 836 matched controls

Blinded nurses interviews N = 14 PPHN infants exposed to SSRI

after 20 weeks gestation (n = 6 for controls)OR = 6.1 (95% CI: 2.2-16.8)

Use of SSRI before 20 weeks or use of non-SSRI at any time during pregnancynot associated with PPHN

Risk increases from 2/1000 to 6/1000

Chambers CD et al (2006). NEJM 354;6: 579-587.

SSRI Long Term Effects

Prospective cohort studyTCA (n = 46), FLX (n = 40), No MDD (n =

36) Children’s IQ, language, development,

temperament assessed and compared○ Ages 15 -71 months

No differences between groupsIQ negatively associated with duration of

depressionLanguage negative associated with # MDD

episodes after delivery

Nulman et al (2002) AJP 159: 1889-1895.

Tricyclics in pregnancy

The studies are conflicting Fetal tachycardia?

One case report Neonatal symptoms

TachypneaTachycardiaCyanosisIrritabilityHypertoniaClonusSpasm

ACOG 2007

Electroconvulsive Therapy Safe and effective treatment

70% of patients who have not responded to medications respond well to ECT

Effective for major depressive episode○ Especially with psychosis or melancholic

featuresEffective for manic episodeEffective for acute schizophrenia episode?

Non pharmacological treatments

Decrease caffeine, nicotine, alcohol Improve sleep Increase relaxation Psychotherapy

InterpersonalCognitive Behavioral

Support groups Education Marital counseling Decrease psychosocial stressors Communicate with obstetrical team

Breastfeeding Most medications excreted into breast milk

Amount infant receives is based on mother milk:plasma ratio and amount of breast milk received

Most important determinant of drug penetration is mother’s plasma levels

Drug levels in breastmilk are less than what crosses the placenta

Medications in breastfeeding Avoid long half life or sustained release

medications Schedule medication dosing

immediately after feeding or right before long rest period

Advise mother to monitor for oversedation, especially with cosleeping

Half Lives of AntidepressantsFluoxetine 2-3 days

Citalopram 34 hours

Escitalopram 30 hours

Sertraline 29 hours

Paroxetine 24 hours

Bupropion 12 hours

Duloxetine 12 hours

Venlafaxine 5 hours (metabolite = 11 hours)

Mood Stabilizer Medications Lithium (Lithobid) Valproic Acid (Valproate, Depakote,

Depakene) Carbamazepine (Tegretol, Equitro) Lamotrigine (Lamictal) Topiramate (Topamax) Atypical antipsychotics

Risperidone (Risperdal)Olanzapine (Zyprexa)Quetiapine (Seroquel)Ziprasidone (Geodon)Aripiprazole (Abilify)

Lithium and Breastfeeding Breast Feeding

Breast milk [Li] = 30-100% mother serum [Li]Cyanosis, muscle tone, T-wave changes

Not a good idea

Anticonvulsants

All studies done in women receiving anticonvulsants for epilepsyNone in women with primary psychiatric

disorderWomen with epilepsy bear more children

with malformations○ 3.5 %

Morrow J et al (2006) J Neurol Neurosurg Psychiatry 77: 193-198.

Valproic Acid

Intrauterine growth retardation Developmental delay Neonatal toxicity

HR decelerationsWithdrawal symptoms

○ Irritability, feeding problems, abnormal toneLiver toxicityHypoglycemia

Yonkers 2004

Valproic Acid

Increased glucoronidation in pregnancyLower VPA levels

In lactationBreast milk / infants

○ < 1% - 10% concentration○ Thrombocytopenic purpura○ Anemia○ Generally felt to be reasonable

Yonkers 2004, Gentile 2006

Carbamazepine in Breastfeeding “Probably safe” Possible effects

Transient cholestatic hepatitishyperbilirubinemia

Lamotrigine in Pregnancy N = 14 pregnant women

LTG monotherapyLTG metabolism increases during

pregnancy○ % in relative clearance (dose in mg/weight in

kg/serum conc in mg/L)1st trimester = 118% higher2nd trimester = 171% higher3rd trimester = 208% higherPostpartum = 4% higher

Pennell et al. Neurology; 62: 292-295, 2004

Benzodiazepines

Behavioral effectsImpaired learning and memory, absence of

startle reflexes, other sustained/subtle behavior

Data is conflicting

Benzodiazepines and PregnancyGenerally, if must use BZs in pregnancy,

stick with ones that are short acting and don’t have metabolites, e.g. lorazepam

NEROLEPTICS

Typical neuroleptics: Haldol ,clopixol atypical neuroleptics: Risperidone,

Olanzapine ,Seroquel Careful in choice in pregnancy and

lactation for the side effects. Sedation with Seroquel. Weight gain with olanzapine. Risperidone could be a good choice in

pregnancy and lactation.

Take Home Points Depression in pregnancy is common Untreated depression in pregnancy carries

risks for both the mother and the child No antidepressants are FDA approved in

pregnancyBut sertraline is generally agreed to be “safest”

Must weigh risks and benefits with the mother (and partner) on an individual basis

Take Home Points

SSRIs may be associated with septal defects, PPHN, and a neonatal syndrome.

SSRIs are “safe” in breastfeedingSertraline and paroxetine probably safest

ECT is safe with pregnancy and breastfeeding

Take Home Points

Lithium is moderately safe in pregnancy?? but not with breastfeeding

Carbamazapine and Valproic Acid are not safe in pregnancy but moderately safe with breastfeeding

Lamotrigine and the atypical antipsychotics seem to be relatively safe in pregnancy but need more data

Benzodiazepines are associated with clefting

Resources

www. Motherisk.org http://www.womensmentalhealth.org http://www.emorywomensprogram.org www.postpartumprogress.typepad.com Yonkers et al, 2009 APA and ACOG

Consensus Statement, General Hospital Psychiatry and Obstetrics and Gynecology

THANK YOU

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