Antidepressants in Pregnancy

Nicole Harrington Cirino MD Reproductive Psychiatrist

Assistant Professor, Dept. of Psychiatry and Ob/Gyn.
Chief, Women's Mental Health and Wellness
OHSU Center for Womens Health
 PMADs- Perinatal Mood and Anxiety Disorders

Antenatal Depression (AND)

Baby blues
Postpartum depression (PPD)
Postpartum psychosis
*Perinatal PTSD, *Panic Disorder
*Perinatal OCD (obsessive compulsive disorder)
Perinatal Bipolar Disorder mania, hypomania
*also treated with antidepressants during pregnancy 2
Antenatal Depression (AND)

Can be MDD Major Depressive Disorder or BPD Bipolar Disorder

Often undiagnosed or undertreated of 1837 pregnant women with
depression, 30% were receiving adequate treatment (Flynn 2006)
Incidence 3-10%, similar to non-pregnant controls.
Those who stop medication in the first trimester are
5 times increased risk for depression during pregnancy (65% risk)
57% of women went back on their antidepressant
Over 50% will develop postpartum depression.
Perinatal Suicide is the leading cause of MATERNAL MORTALITY
in the 1st year postpartum.
Antidepressant AD medications during pregnancy

SSRIs by far are the most studied medication in pregnancy than

any other class of medication >200,000 pregnancy outcomes
studied.
Antidepressants are the 2nd most prescribed class of drugs in the
world. *50% pregnancies in the U.S. are unplanned
Increased use of SSRI in pregnancy in US: 6.0% of pregnant
women 1999 to 10-13% in 2003
2016 Documented Risks of SSRI exposure in utero

Major malformations/cardiac malformations

Behavioral Functional Risks
Developmental delay
Psychiatric Illness in offspring
Autistic Spectrum Disorder (ASD)
Miscarriage
SGA/LBW/PTL
Neonatal Abstinence Syndrome
PPHN
Risk/Benefit ratio of AD use in Pregnancy

Autism
2012 Summary AJOG
Known: Teratogenic exposures produce a specific
pattern of malformation and do not increase incidence
of all defects.
Thalidomide

A sedative that was first marketed in the late 1950s.

Used widely in Germany prior to being pulled from US
market in 1962.
Associated with limb reduction defects, esophageal and
duodenal atresia, Tetralogy of Fallot, and renal agenesis.
20-25% of pregnancies exposed result in children with
anomalies.
Limb reduction was not observed in mice and rats and in
many cases no sign of teratogenicity.
 History of SSRIs and Teratogenesis

Prozac launched 1980s

Baseline rate of birth defects 3-4%. Cardiac Anomalies 1%
1980-2004 No increased risk for malformations
2005: GSK report to FDA Paxil leads to increased risk of VSD.
Retrospective database.
2005 2013: 30+ studies examining link between SSRIs and
malformations, mainly Heart Defects - conflicting results.
6/2014 Huybrechts NEJM Cohort 64,000 women exposed to AD No
substantial increase in the risk of cardiac malformations attributable to
antidepressant use during the first trimester of pregnancy.
4/2016 Judge dismisses 200 SSRIs related birth defect claims
Zoloft Lawsuits Dismissed: No Link to Birth Defects,
Says Judge- Medscape April 11th, 2016
Literature regarding Antidepressants in Pregnancy-
Strengths and Limitations

Studies are observational -retrospective, rely on prescription databases, teratology services, birth
registries or population records of birth defects
Thus little is known about medical, psychiatric, addiction condition of the mother or other exposures
Gold Standard-Prospective RCTs do not include pregnant women and may never.
Observational studies are designed to show association but not causation
Literature changes often
Animal studies tell us very little
Many positive reports never replicated.
Selection Bias: Positive studies over reported.
Law firms seized this information widely publicize.
Hot topic in the media
Physicians and patients use the media reports or advertisements from law firms to inform their
judgment.
Limitations of using registries to explain associations between
antenatal Antidepressant use and infant outcomes

Variables not controlled for or unable to be assessed without clinical interviews

antidepressant dose and actual use
comorbid general medical disorders (including obesity)
comorbid psychiatric disorders
exposure to tobacco, alcohol, and illicit drugs
exposure to other prescription and nonprescription medications
nutritional status
inadequate prenatal care
delivery complications
Pharmacologic Risks during Pregnancy

1st Trimester - Morphologic risk

<2 weeks No maternal/ fetal exposure
1-5 weeks Neural Tube Development
3-8 weeks Cardiac
6-9 weeks Lip and Palate

2nd-3rd Trimester (> 14 weeks)

Neonatal Behavioral/Cognitive/Affective Risks
Neonatal effects (toxicity/withdrawal)
Maternal side effects
Maternal Outcomes (preeclampsia, PTL)
 Risk of Untreated Antenatal Depression

(Fields 2006, 2011)

Decreased prenatal care, poor nutrition
Increased maternal use of tobacco, alcohol or cocaine
Maternal suicidal/homicidal behavior increased
Premature delivery, Lower birth weight and smaller head circumference
Increased risk of preeclampsia. Diabetes, cesarean delivery
Developmental delays in the infant
Poor maternal infant bond and infant attachment
Decreased rates of breastfeeding
Increase in affective disorders in children and adolescents (Buss 2012)
Alterations in the right amygdala of the neonate (Graboi 2013)
Maternal Treatment of antenatal depression appears to help normalize cortisol levels (OHara 2013)
Risk of Untreated Postpartum Depression

Subjective Report of Sleep Difficulties

Colic
Child development
Ineffective emotional regulation /Behavior Disturbance
Greater anxiety
Attachment difficulties (secure versus avoidant or disorganized attachments)
Higher cortisol levels in infants through adolescents
Poor social interactions
Delays in both cognitive and language development
Bayley Mental Development Index 18 mo (Boys>girls)
General Cognitive Index 4 y/o
McCarthy Scales of Childrens Abilities 4 y/o
 Risk = ?
Benefit
2016 Documented Risks of SSRI exposure in utero

Major malformations/cardiac malformations

Behavioral Functional Risks
Developmental delay
Psychiatric Illness
Autism
Miscarriage
SGA/LBW/PTL
Neonatal Abstinence Syndrome
PPHN
Behavioral Functional Risks in Offspring SSRI exposed infant

TCAs, SSRIs, SNRIs: 72 month follow-up cognitive function (IQ),

temperament and behavior No effect. (Nulman 1997, Nulman
2002, 2012)
No differences in cognitive function, verbal comprehension,
expressive language, mood, arousability, distractibility, behavior
problems (TCA, FLX) (Byatt 2013)
In utero SSRIs have not been linked to long term
neurobehavioral deficits but untreated depression has.
MMR and Autism
Serotonin Hypothesis: Autism and SSRIs

Serotonin modulates brain development

SSRIs block reuptake and increase serotonin in the
intracellular space
Reports that ASD patients have higher platelet serotonin
levels termed hyperserotoninemia
ASD associated with
Decreased capacity to synthesize serotonin
Altered serotonin 2A binding
Autism effects 1 in 68 in 2016
GMOs and autism?
Graphic Diagnosis of Autism
ASD Pathogenesis: Largely genetic

ASD has a genetic etiology, which leads to altered brain development,

resulting in the neurobehavioral phenotype.
Epidemiologic studies indicate that environmental factors account for few
cases.
Genetics: ASD linked to tuberous sclerosis complex, fragile X syndrome, 15q
duplication/triplication or deletion, Smith-Lemli-Opitz syndrome, and
untreated phenylketonuria.
Multiple studies that found higher rates of depression and other psychiatric
illnesses in mothers of autistic children than mothers of controls (Daniels
2008, Piven 1999)
Prenatal SSRIs and risk of ASD (Autistic Spectrum Disorders)

8 studies thus far: 5 show an association(not causation) (OR 2.54, 2.2, 1.85), 3 do
not.
Confounding factors that were difficult to/not controlled for
underlying burden of maternal psychiatric illness including Major
Depressive Disorder (Daniels 2008)
underlying indication for antidepressant use
genetic history of ASD
maternal illness/stress during perinatal period
ASD also linked to SSRI use before but not during pregnancy (OR 1.46)
Summary - The rise in ASD disorders have been consistently linked to
maternal obesity, advanced maternal and paternal age, gender, family history
of ASD and maternal and perinatal stress. Risk with SSRIs likely either no
increased risk or minor increased risk after confounding factors
controlled for.
Proposed 87% increased risk w/
SSRI exposure
JAMA study specifics: 87% increased risk of ASD
Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Ped

Observation design from Canadian registry: Prospective Cohort. AD exposed (n >4700) or

not exposed (n >140,000).
N=31 exposed infants with ASD
3.2% use of antidepressants measured using prescription drug registry (single prescription)
Potential confounding factors adjusted for: maternal age, maternal psychiatric and general
medical illnesses, and gender of the child
Potential confounding factors not adjusted for: illicit drugs, ethanol, or tobacco; maternal
body mass index; use of assisted reproduction; maternal autoimmune illness; paternal
psychiatric illness; paternal age, autistic siblings; severity of depression; maternal ASD
Results: Exposure to any antidepressant during the second and/or third trimester (but not 1st
trimester_ was associated with an increased risk of autism spectrum disorder. (hazard ratio
1.87, 95% CI 1.2-3.0). In addition, exposure to SSRIs during the second and/or third
trimester was associated with an increased risk (hazard ratio 2.2, 95% CI 1.2-3.9).
After adjusting for maternal depression (hazard ratio 1.75 95% CI 1.03-2.97)
Absolute risk: Control ASD 0.72% ASD with AD Exposure: 1.26%
 Results
Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117.
Study Population
Evaluation of sample

>
AD-exposed mothers are

Older
Less educated
More disadvantaged

More psychiatric morbidity

(affective disorders and
others)

More medical morbidity

Used with permission Eric Fombonne MD OHSU

 Detection bias
Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117

Children with AD expsosure are

diagnosed earlier than in the unexposed
group

322.69/82= 3.93 years

145.64/40= 3.64 years
11.30/31= 3.59 years

In Table 3, mothers exposed to

Combined use:
11.73/5= 2.34 years

Used with permission by Eric Fombonne M.D. OHSU

Results
Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117

Association Between Antenatal AD Exposure and the Risk of ASD

Other issues
Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117

Used with permission by Eric Fombonne M.D.

Take Home messages: SSRIs and ASD

1. Eight large studies thus far have shown inconsistent results.

2. Risk with SSRIs likely either no increased risk or minor
increased risk after confounding factors controlled for.
3. Likely there is an association, but we can not prove causation.
4. Absolute risk: Control ASD 0.72% ASD with AD
Exposure: 1.26%
5. Relative Risk/ OR/ HR: 1.87 or 87% increased risk
6. (Bourkhris et al JAMA) has not changed my treatment.
7. (Bourkhris et al JAMA) has changed my informed consent
discussion and documentation.
Poor Neonatal Adaptation, Poor neonatal adjustment syndrome
(or neonatal behavioral syndrome)

Agitation and restlessness

Irritability and continuous crying
Insomnia or somnolence
Poor feeding, vomiting, and diarrhea
Hypoglycemia
Hypothermia
Respiratory distress
Altered muscle tone, hyperreflexia, jitteriness, shivering, and
tremors
Seizures
Neonatal Adaptation Syndrome (NAS) Inconsistent findings
and methodological errors

Failure to blind investigators, non standardized measures and failure to

control for maternal depression have led to inconsistent findings
Incidence varies from 5 to 85 percent.
Approx. 25% of infants with late SRI exposure vs 10% no exposure
Premature infants higher risk
Concomitant medications (eg, benzodiazepines) increase risk
Defined as immediate (first 48 hours) early (first 14 days) or late (first 30
days).
Unclear if withdrawal or toxicity
Symptoms largely resolved with minimal interventions.
(Warburton 2010 and Salisbury 2016 ) Stopping AD at 38 weeks did not
improve neonatal outcome.
 Salisbury Am J Psychiatry 2016

RCT compared
neurobehavioral outcomes in
243 infants in the first 30 days
of life using Neonatal Intensive
Care Unit Network
Neurobehavioral Scale.
No Exposure _____________
Depression ______________
SSRI __________________
SSRI+ BDZ _____________
 Salisbury Am J Psychiatry 2016

No Exposure _____________
Depression ______________
SSRI __________________
SSRI+ BDZ _____________

Conclusion:
No evidence of NAD first 48
hours or 7 days.
SSRI exposed infants had
higher CNS stress signs,
poorer self regulation and
higher arousal at day 14.
Quality of movement is poorer
throughout the first 30 days.

Depression exposed infants

has overall lower arousal
scores.
Kieviet N, Hoppenbrouwers C, Dolman KM, et al.
Risk factors for poor neonatal adaptation
after exposure to antidepressants in utero.
Acta Paediatr 2015; 104:384.

Prospective observational study that examined infants (n

= 247) exposed to antidepressants (largely SSRIs) during
the third trimester, the incidence of poor neonatal
adaptation was lower among infants who were breastfed
or fed both breast milk and formula, compared with infants
exclusively fed formula (odds ratio 0.3, 95% 0.1-0.7)
SSRIs and PPHN Persistent Pulmonary HTN Newborn
2006 FDA issues a public health advisory
Risk of PPHN general population 1.2-2/1000
(Chambers 2006): SSRIs taken >20 weeks gestation may be associated with 1% absolute risk
of PPHN (OR 6.1) N=377 infants. Case controlled, retrospective.
(Kallen 2008) showed a much lower risk marginally clinically significant than the 1% originally reported. (Odds Ratio
2.01) SSRI was associated with a 0.15% Absolute risk (1.5 per 1000)
(Andrade 2009, Wichman 2007): 2 larger studies have found no association between antidepressant use during
pregnancy and PPHN,
(Kieler et al 2012) prospective , national registry with 1.6 million controlled for OR 2.1. Absolute risk increased from 1.2
to 3.0/1000. Not controlled for depression.
(Stephansson 2013) No increased rate of neonatal mortality associated with SSRI
(Huybrechts 2015) Controlled for depression severity No increased risk. OR 1.1
Absolute risk increased to 2.1/1000 from 3.1/1000 (OR 1.5)
C-section and BMI had greater risk than SSRI exposure.
SSRI exposure may lead to small increased risk for PPHN, Absolute risk from 2/1000 to
3/1000
(OR 1.5) but not as high as Chambers original report.
SSRI and Preterm labor/ Miscarriage/ Birth Weight/APGAR

Miscarriage -Although controversial, several studies link increase risk of

miscarriage with SSRI use from 8 vs. 12 %. Poorly controlled studies.
Anderson et al (2014) compared miscarriage rate of women who
continue SSRI use versus those that discontinue SSRIs prior to
pregnancy. No increased rate of miscarriages. (N=1,279,840)
Decreased gestational age (3-5 days) linked to SSRI use
LBW risk appears clear but incidence small Seen in illness state and
with SSRI exposure. 75g lower birth weight.
APGAR Decrease of 0.5 points on 1 and 5 minute Apgar
Psychotropics in Pregnancy-Basic Principles

Nothing is Safe
Avoid first trimester exposure if possible for known
teratogens.
If you are going to treat TREAT. Dont expose women to AD
and illness state.
Preconception counseling-Gold Standard
Reconfirm diagnosis
Maximize non-psychopharm approach
Avoid polypharmacy if possible
Do not wean at 38 weeks
Define and discuss R/B ratio
Basic Prescribing Guidelines based on data limitations

Use older medications over newer medications

~800 cases can detect a two fold increase in malformation risk
~10 year window to obtain this data
Unknown does not mean safe
Human data over animal data
Know how to quickly access resources
www.womensmentalhealth.org
reprotox.org through Micromedex
Managing antidepressants in pregnancy

Dose increase needed in the late 2nd/3rd trimester-

Pharmacokinetics
Using the EPDS to monitor medication response.
3 weeks should see partial remission, if no response
consider changing agents.
If partial response 3-6 increase dose.
Goal is to achieve full remission, not just response.
Do not wean 38 weeks or change at delivery
Common medications for antenatal depression

Others
SSRIs Venlafaxine (Effexor)
Duloxetine (Cymbalta)
Fluoxetine (Prozac)
Mirtazapine (Remeron)
Paroxetine (Paxil)
Bupropion (Wellbutrin)
Sertraline (Zoloft)
TCAs Tricyclic
Citalopram (Celexa) Antidepressants
Escitalopram (Lexapro) Nortriptyline (Norpramin)
Amitriptyline (Elavil)
Trazodone
Non SSRI antidepressants in pregnancy-
What do we know?

TCAs; 10 retrospective studies show no risk of malformation.

Nortriptyline and Desipramine believed to be no increased
risk.
Buproprion GSK pregnancy registry and Cole et al 2007 no
increased risk.
Venlafaxine: Included in many SSRI studies, same risk as
SSRIs.
Mirtazepine with single prospective study, a few retrospective
reports (n<200 cases).
Duloxetine 2004, generic 2013 three prospective studies to
date n=650 women, shows no increase rate major
malformations. Long term data not available.
Whats not on the list

Vilazodone (Viibryd) -SNRI

Asenaprine (Saphris) - AP
Vortioxetine (Brintellix )- SSRI
Lithium (Lithobid, Eskalith)
Lamotrigine (Lamictal)
Aripiprazole (Abilify)
Non Pharm Treatment for PPD

IPT/CBT therapy
Group and couples therapy
Other psychotherapy/social interventions
Light therapy (20 minutes qam)
Exercise (40 minutes 3-4 days a week)
Acupuncture
ECT
Depression and Sleep

Sleep preservation is a common strategy for treatment of

perinatal mood disorders
Depression and sleep inexplicably linked in pregnancy
and postpartum
Consider adjunctive sleep medication third trimester
(Khazaie et al 2013) RCT Trazodone and
Diphenhydramine vs placebo protective against PPD
L-methylfolate for depression in pregnancy:
Deplin 15 or 30mg (15,000 or 30,000 mcgs) in dietary supplement

Used for partial- or non-response to selective serotonin reuptake inhibitors

(SSRIs) in MTHFR enzyme gene mutations
Folates are converted to the active form of l-methylfolate by 5,10-
methylenetetrahydrofolate reductase (MTHFR).
50% Caucasians have a mutation on MTHFR gene, Individuals with these
less efficient forms of the MTHFR gene may be more prone to folate
deficiency
L-methylfolate is the naturally occurring, biologically active form of folic acid,
Recommended Dietary Allowance (RDA) 1000 mcg for pregnant and
lactating women. No published studies have assessed the safety of high
doses of l-methylfolate in pregnancy. Certain cases where high doses
(usually 4 to 5 mg) under medical supervision used.
Patient is
contemplating
pregnancy and
currently on
antidepressants

Yonkers et al 2009
Patient with MDD
who is pregnant and
on antidepressants

Yonkers, et al 2009
Resources for Medications in
Pregnancy and Breastfeeding

Reprotox: www.reprotox.org
Motherisk.org: www.motherisk.org 1-877-439-2744
www.infantrisk.com ; (806) 352-2519; phone app also available
Organization of Teratology Information Services:
www.mothertobaby.org; good handouts
MGH Womens Mental Health Program:
www.womensmentalhealth.org
LactMed: www.lactmed.nlm.nih.gov
E-Lactania: http://www.e-lactancia.org/ingles/inicio.asp
Tox Net www.toxnet.nlm.nih.gov

(c) PSI 2014 ~ PostpartumSupportInternational 60