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.
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
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.
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.
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
(and eventually you may need to up the dose) Can alternative allow us to avoid med or use lower dose?
Why should you know this…your patients will read it..the good news? The FDA is going to change its labelling to include registry information, standard information on background rates
Paxil- OR 2.08 for congenital malformations – VSD – retrospective 3581 Swedish registry study – 4 % paxil major congenital anom vs 2 % with other AD 6.1 OR for PPH
Women get constipated, morning sickness
To appreciate some of the data that I’ll share on anti D in pg, some background info…
A couple of those helpful hints… It will be around for a while…though metabolism does change during pregnancy…