This document provides information on FDA pregnancy drug labeling categories and discusses various antidepressant and other psychotropic medications. It describes the FDA categories A through X for evaluating risks of medications during pregnancy and lists common antidepressants along with their FDA categories. For each medication class, it summarizes potential risks to the fetus or newborn based on available studies. The document emphasizes making individualized treatment decisions and monitoring for potential neonatal side effects.

1. WALID SARHAN F.R.C.Psych

2. US FDA pregnancy drug
labeling categories
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.
.

3. B Animal studies have revealed no evidence of
harm to the fetus; however, there are no adequate
and well-controlled studies in pregnant women.
Or
Animal 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

4. C Animal studies have shown an adverse
effect and
there are no adequate and well-controlled
studies in pregnant women.
Or
No animal studies have been conducted and
there are no adequate and well-controlled
studies in pregnant women.

5. 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.

6. 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.

7. Antidepressant medications
 SSRIs
 Fluoxetine (Prozac)
 Sertraline (Zoloft)-solotik
 Paroxetine (seroxat)
 Fluvoxamine (faverin)
 Citalopram (Cipram)
 Escitalopram (cipralex)-purlex
 SNRIs
 Venlafaxine (Effexor)
 Duloxetine (Cymbalta)
 Desvenlafaxine (Pristiq)

8. Antidepressant medications
 Other
 Wellbutrin (Bupropion)
○ Norepinephrine and dopamine
 Trazodone
 Mirtazapine (Remeron)
 Tricyclic Antidepressants
 Amitriptyline (tryptizol)
 Nortriptyline (nortrilene)
 Imipramine (Tofranil)
 Clomipramine (Anafranil)
 MAOIs
 Phenylzine (Nardil)
 Tranylcypromine (Parnate)

9. Medication Choice
An individual decision
that’s made on a case
by case basis!

10. 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

11. General guidelines
 Treat a woman as if she could become
pregnant at any time…
 Up to 80% of pregnancies are unanticipated
 Document use of birth control
 Encourage use of folic acid and multivitamin

12. FDA labels
 Patients read them
 They will change
 They will be changing
 Standard information on background rates
 Fetal risk data
 Clinical considerations
 Registry information

13. FDA Classifications
 Most psychotropics are C
 None are A
 No antidepressants are FDA approved for
pregnancy
 No drug is “safe”
 No good randomized, placebo-
controlled studies
 Most studies are retrospective, case
reports, and registry data

14. 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

15. Pregnancy factors that may increase
medication concentrations
 Reduced gastrointestinal motility
 Absorption changes for some medications
 Reduced fecal elimination
 Serum proteins lower
 May result in higher ‘free’ drug concentrations

16. 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

17. Pregnancy factors that may decrease
medication concentration
 Nausea and vomiting
 Reduced absorption
 Increased liver metabolism
 May result in increased elimination of certain
medications

18. Antidepressant Blood Levels and
Pregnancy
Prepregnancy Conception 20 weeks Delivery Postpartum
Adapted from Sit et al 2008

19. 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
A Long term behavioral abnormalities

20. Medication Background
 Incidence of major birth defects in US is
2 to 4%
 65 – 70% of unknown cause
 2 – 4% medication related
 Period of maximum vulnerability for birth
defects of the nervous system is 14 – 35
days post conception

21. Medication Background
 Women usually find out when already
5-7 weeks gestation
 Therefore, may want to keep same
medication if it’s working

22. Antidepressants During Pregnancy
 SSRI complications
 Congenital anomalies
 Persistent Pulmonary Hypertension of
the Newborn
 Neonatal adaptation syndrome

23. 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

24. Paroxetine
 Has FDA warning against using in first
trimester due to increased risk of cardiac
defects

25. Neonatal Adaptation
Syndrome
 Cohort study (n = 120), included
venlafaxine
 Neonatal 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.

26. 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: 2372-2382

27. 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 pregnancy
 not associated with PPHN
 Risk increases from 2/1000 to 6/1000
Chambers CD et al (2006). NEJM 354;6: 579-587.

28. SSRI Long Term Effects
 Prospective cohort study
 TCA (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 groups
 IQ negatively associated with duration of
depression
 Language negative associated with # MDD
episodes after delivery
Nulman et al (2002) AJP 159: 1889-1895.

29. Tricyclics in pregnancy
 The studies are conflicting
 Fetal tachycardia?
 One case report
 Neonatal symptoms
 Tachypnea
 Tachycardia
 Cyanosis
 Irritability
 Hypertonia
 Clonus
 Spasm
ACOG 2007

30. 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
features
 Effective for manic episode
 Effective for acute schizophrenia episode?

31. Non pharmacological
treatments
 Decrease caffeine, nicotine, alcohol
 Improve sleep
 Increase relaxation
 Psychotherapy
 Interpersonal
 Cognitive Behavioral
 Support groups
 Education
 Marital counseling
 Decrease psychosocial stressors
 Communicate with obstetrical team

32. 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

33. 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

34. Half Lives of
Antidepressants
Fluoxetine 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)

35. 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)

36. Anticonvulsants – Summary
Drug FDA Fetal Risk Summary
Lithium D Ebstein’s anomaly, “floppy baby” syndrome
reported
CBZ D FHS, NTD, neurodevelopment effects?
VPA D Major and minor congenital abnormalities,
intrauterine growth retardation, hyperbilirubinemia,
hepatotoxicity, transient hyperglycemia, neural tube
defects (day 17 – 30)
Topiramate C
Lamotrigine C Unsafe with breastfeeding
Gabapentin C 4 reports of normal pregnancy, 1 report of
respiratory distress

37. Lithium and
Breastfeeding
 Breast Feeding
 Breast milk [Li] = 30-100% mother serum [Li]
 Cyanosis, ⇓ muscle tone, T-wave changes
 Not a good idea

38. Anticonvulsants
 All studies done in women receiving
anticonvulsants for epilepsy
 None in women with primary psychiatric
disorder
 Women with epilepsy bear more children
with malformations
○ 3.5 %
Morrow J et al (2006) J Neurol Neurosurg Psychiatry 77: 193-198.

39. Valproic Acid
 Intrauterine growth retardation
 Developmental delay
 Neonatal toxicity
 HR decelerations
 Withdrawal symptoms
○ Irritability, feeding problems, abnormal tone
 Liver toxicity
 Hypoglycemia
Yonkers 2004

40. Valproic Acid
 Increased glucoronidation in pregnancy
 Lower VPA levels
 In lactation
 Breast milk / infants
○ < 1% - 10% concentration
○ Thrombocytopenic purpura
○ Anemia
○ Generally felt to be reasonable
Yonkers 2004, Gentile 2006

41. Carbamazepine in
Breastfeeding
 “Probably safe”
 Possible effects
 Transient cholestatic hepatitis
 hyperbilirubinemia

42. Lamotrigine in
Pregnancy
 N = 14 pregnant women
 LTG monotherapy
 LTG metabolism increases during
pregnancy
○ % in relative clearance (dose in mg/weight in
kg/serum conc in mg/L)
 1st trimester = 118% higher
 2nd trimester = 171% higher
 3rd trimester = 208% higher
 Postpartum = 4% higher
Pennell et al. Neurology; 62: 292-295, 2004

43. Antipsychotics in Pregnancy
Drug FDA Fetal risk summary
Haldol C
Chlorpromazine C
Aripiprazole C
Olanzapine C
Seroquel C
Risperidone C
Clozapine B
ZELDOX C

44. Benzodiazepines
 Behavioral effects
 Impaired learning and memory, absence of
startle reflexes, other sustained/subtle
behavior
 Data is conflicting

45. BZD and Pregnancy
Drug FDA Fetal risk summary
Alprazolam D Reports are conflicting. Cleft plate risk increased to
7/1000. Withdrawal after in utero exposure reported
(crying/restlessness)
Clonazepam D Little data on teratogenicity. Newborn toxicity noted
(apnea, cyanosis, lethargy, and hypotonia).
Diazepam D Accumulates in fetus 1-3x mother. T1/2 prolonged.
Increased risk of cleft palate. Floppy infant
syndrome and withdrawal possibility.
Triazolam X Little data available, but similar to other BDZ.

46. Benzodiazepines and
Pregnancy
Generally, if must use BZs in pregnancy,
stick with ones that are short acting and
don’t have metabolites, e.g. lorazepam

47. 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.

48. 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
pregnancy
 But sertraline is generally agreed to be “safest”
 Must weigh risks and benefits with the
mother (and partner) on an individual basis

49. Take Home Points
 SSRIs may be associated with septal
defects, PPHN, and a neonatal
syndrome.
 SSRIs are “safe” in breastfeeding
 Sertraline and paroxetine probably safest
 ECT is safe with pregnancy and
breastfeeding

50. 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

51. 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

52. THANK YOU
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