Perinatal Risks in Women with Depression and Bipolar Disease

Deborah Knudson González, MDForensic and Reproductive Psychiatrist

Disclosure Statement

With respect to the following presentation, there has been no relevant (direct or indirect) financial relationship between the party listed above (and/or spouse/partner) and any for-profit company which could be considered a conflict of interest

Objectives

§Overview of Perinatal Consult process:

§Review decisional conflict in pregnancy §Discuss the most common and challenging perinatal mental health illnesses§Discuss risks associated with psychotropic medication use in pregnancy and risks of untreated illness§Provide a case-based overview of basic principles to consider while weighing these risks

§ Lara is a 32 year old recently married F § PPHx: MDD, recurrent, severe (at least 3

episodes)multiple inpatient admissions in her early 20s, 2 suicide attempts in the remote past

§ maintenance tx: Escitalopram 20 mg, Bupropion XL 150 mg and Lorazepam 1 mg po bid

§ Prior attempts to d/c Escitalopram have resulted in a recurrence of symptoms and SI

§ Just learned that she is pregnant-unplanned

Lara’s Case

“Taking antidepressants during pregnancy might pose health risks for your baby — but stopping might pose risks for

you.”

“Like babies born to drug addicts, newborns may display S.S.R.I. withdrawal symptoms.”

Confusing and Contradictory Information

Invitations to join lawsuits for congenital malformations and antidepressant use in pregnancy

65% of the womenretrieved information from the Internet

Einarson (2012) (2009)

A Google search in 2009 using keywords “antidepressants, pregnancy” revealed 1,420,000 results

Common for women to experience decisional conflict concerning antenatal depression treatment

Battle (2013) Payne (2009) Einarson (2012)

Antidepressantsareoftenconsidered“luxury”medications

In a study, 1/3 hid from family and friends that they were taking antidepressants

Pharmacists sometimes refuse to fill a psychotropic medication if the patient is pregnant

Strong maternal feelings of shame, guilt, and confusion about prenatal use of antidepressant medications

Advised by family members and medical providers not to take medications

“Just deal with it”

Maternal Decisional Conflict

§“Good Mothers” protect their babies from harm and put their children’s needs before their own

§Contradictory advice given by family and friends

§Perceived risk is usually larger than evidenced-based risk

§“If I continue my medications, I will cause harm to my baby”

§ Initial risk perception appears to be a strong determinant of choice

Bonari (2005)wrught (2001)

Physician Decisional Conflict

lyerly(2011)Snellen(2014)

§Memories of the Thalidomide tragedy

§Tendency to notice the risks of intervening and not those risks of failing to intervene“Legally safer to not intervene”

§Lack of specialized training§ Conflicting and controversial data §“If I don’t prescribe, I will avoid

potential risks of the fetus”

This might lead to recommending that patients immediately discontinue their psychotropic medications

Take home point #1

üAcknowledgeuncertaintyandconflictwhilebeingmindfulofpersonalbias

Ms. Lara calls her psychiatrist

“I just found out that I am pregnant and have been reading all these awful things about my antidepressants, should I stop them?”

a. “I think that you should start to taper your medications, go down by half dose on both of your antidepressants”

b. “I don’t treat women who are pregnant, I suggest that we start looking for another psychiatrist that can take over your care.”

c. “This is a decision that requires careful thought, do not stop your medications now, come in to see me this week so that we can discuss next steps”

Take home point #2

üEncourageyourpatienttotaketimetothinkaboutherchoice-discouragetheurgetoimmediatelystopmedications*You might also need this time to think about alternatives to offer and how to frame the discussion

Weighing the Risksof Exposures

Untreated Illness

Suicide

MaritalStrain

Lossofemployment

Substance/AlcoholUse

PretermBirth

ObstetricComplications

RisksofPPDepressionandImpactonInfant

Medication Exposure

RiskofMalformations

Preterm Birth

PPHN

PNAS

Autism?

EffectsonNeurocognitivedevelopment

Lowbirthweight

Take home point #3

üNodecisionisrisk-free

*Decision is based on balancing risks associated to illness exposure versus risks associated with medication exposure and determining best course of action for each patient

How to weigh the risks?

ü Think about risks of exposure to illness

What is Lara’s diagnosis?MDD, severe, recurrent in full remission

Establishriskifuntreated:§ LOW,MODERATE,HIGH

DSM V- criteria change

WithPeripartum Onset:appliesifonsetofmoodsymptomsoccursduringpregnancyorinthe4weeksfollowingdelivery

AppliestoDepression,BPADI&II(mixed,manic,hypomanicepisode),BriefPsychoticDisorderAmericanPsychiatricAssociation.(2013).Diagnosticandstatisticalmanualofmentaldisorders(5th

ed.).Arlington,VA:AmericanPsychiatricPublishing.

Depression During Pregnancy

§At least as prevalent as in non-pregnant patients

§Up to 50% of PPD begins in pregnancy

meta-analysis in 2004: §7.4% (first trimester)§12.8% (second trimester)§12.0% (third trimester)

Bennett(2004)Kessler(2001)

•Preterm birth1

•Low Birth Weight1

•Preeclampsia2

•Hypertension•Gestational diabetes•SA

Possible Obstetric Risks

1GroteNK(2010)2KurkiT(2000)Kozhimannil (2009)Dayan(2002)

*Important to note that there are limitations to this data

Stress Effect on Vasculature

Dysregulation of the HPA-axis

Release of stress hormones

Placental hypoperfusion

Restriction of oxygen and nutrients

Fetal Growth Restriction/Precipitation of

PTB

Stress Effect on Immune function

Increased Stress

Impaired Immune Function

Risks of urogenital and

amniotic infections

Premature rupture of

Membranes

§↑ Smoking (IUGR)

§↑ Substance/Alcohol abuse

§Poor nutrition and hygiene

§Lack of prenatal care or to follow

medical recommendations

§Increased c/section

§decreased pain tolerance

Effects on Modifiable Social Behaviors

Kozhimannil (2009)Andersson (2004)

Hormonal changes in Pregnancy

Risk Factors for Postpartum Depression

§Baby Blues§Child Care stressors§Personality Traits§Antepartum Depression§Poverty§Marital difficulties§Limited Supports

Cohen(2006)Burt(2005)O'Hara(1996)Beck(2001)Robertson(2004)

Risks-Postpartum Depression§ Early postpartum: highest risk of

depression period when compared with other periods in women’s lives

§ Women with only PPD episodes have a relatively higher risk for subsequent PPD episodes

§ Sibling history of PPD has been associated with increased risk of PPD in the early PP

§ Early PPD might indicate later BPAD diagnosis

BlochM(2003)CooperPJ(1995)Fortyetal.(2006)Munk-Olsen(2012)

Early Postpartum Symptoms§Postpartum Blues: 15-84%1

prevalence§Mild and transient§dysphoric mood, mood lability, crying, anxiety, insomnia, loss of appetite, and irritability

1Henshaw C.(2003)2O'HaraMW(1991)3HarrisB.etal.(1994)

§Poorer language and IQ in children into adolescence

§Unresponsive, inconsistent, unavailable, or rejecting care by the mother toward the child

§Intrusive/harsh with their infants§Lower rates of infant safety practices §Decreased behaviors such as reading, singing, and playing games with their child

§Risks of behavioral problems from childhood to adolescence

Postpartum Exposure to Illness

Cambell,SB(2004),NECCR(1999),Akman,I(2006),Flynn,HA(2004),Paulson,JF(2006),Brand&Brennan(2009),Nulman (2015)

• Suicide accounts for about 20% of postpartum deaths- the second most common cause of mortality in postpartum women

*Some studies suggest pregnancy and postpartum as protective against suicide attempts1/3rd to1/20th expectedrateofsuicide

B.Pitt(1968),HendrickV(2000)

Perinatal Depression and Suicide

Why does pregnancy seem protective?

§ There might be increased support during pregnancy

§ Protective effect of motherhood

§ Biological explanation? Increased serotonin during pregnancy?

Answers from a general inpatient unit:

§ Suicide would harm the children

§ It would not be fair to leave the

children to the care of someone else

§ A desire to watch the children grow

Linehan (1983)

Suicide Risks§ Inpatient psychiatric admission in the postpartum

§ Long term suicide risk is 17x higher than gen female population

§ Teenage pregnancy

§ Stillbirth/infant loss

§ Likely, infertility

§ IPV

§ Unmarried

§ Abortion

§ Psychiatric diagnosis/substance abuse

Highrateofdramaticmethods:jumpinginfrontofatrain,self-incineration,jumpingfromaheight

Back to Lara’s case§ Consider severity of her illness so far…ü Illness severe§What has been her response to medication taper or d/c?üSx Recurrence when d/c antidepressant§ Have there been any high risk behaviors?üYes, multiple suicide attempts, inpatient admissions§ How has she been doing on current

regimen? Is she stable? ü Yes

How to weigh the risks?

ü Think about risks of exposure to Medications

What are Lara’s medications?Sertraline and Bupropion-provide counseling on both of these separately

Where can I get information about these agents?

üMicromedex- ReprotoxüLactmedüMGH Center for WMH websiteüMotherisk websiteüMother to baby websiteüConsult with a colleagueüConsider using MCPAP for moms

FDA pregnancy categories are currently not as helpful

1-855-Mom-MCPAP

TelephoneConsultation

Consider Pregnancy Stage

First Trimester Exposure

üOrganogenesis- Early toxic exposure (day 1-17) results in miscarriageüCNS – neural tube closes 4 weeks after fertilization (6 w GA)üCardiac formation complete at day 56üOrganogenesis complete day 60

SSRIs- Structural and/or Behavioral Teratogens?

§Some studies have implicated an increase risk of cardiovascular defects(Paroxetine, Sertraline)ü Recent large cohort study reassuring

§Recent association between SSRI use and Autismü Conflicting data, likely an effect of the underlying illness

Payne(2015),Huybrechts (2014),Kaplan(2016),

Benzodiazepines in Pregnancy§Commonly prescribed despite limited data§Do not appear to be major teratogens- early studies associated with multiple defects, no syndromeüOral cleft association questionable- not supported by cohort studies but association found on case-control studies (2x)üMeta-analysis reassuring

Enato(2011)

Second Trimester Exposure

üContinued brain development

üPreterm BirthüEffects on Growth

of Fetus and Labor

Third Trimester Exposure

ü Persistent Pulmonary Hypertension of the Newborn

ü Exposures can affect neonatal adaptation

ü Physiologic Dependence in Newborn

ü Effects on Growth of Fetus and Labor

ü Postpartum Hemorrhage-SNRI (?)

Hanley(2016)

PPHN

§Baseline risk- 1-2/1000§10% mortality§Associated with SSRI exposure in 3rd

trimester§Recent studies suggest a very low absolute risk 2-4/1000

Huybrechts(2015)

Neurodevelopment after SSRI Exposure

§ Effect on Psychomotor Development§ Emotional/Adaptive Function§ Anxiety§ ADHD

ü Does not appear to impact Intelligence- strong data

Kaplan(2016)

Preterm Birth

§Duration of treatment appears to be a risk factor§Does not appear to be associated with very preterm birth§Cannot rule out effect of underlying illness

Huybrechts(2014)

Neonatal Adaptation Syndrome

ü Fussiness, irritability, crying, changes in muscle tone, hypothermia, difficulty feeding, respiratory difficulties

ü Self-limiting, longer and more complicated when SSRI combined with BZD

üNo evidence that discontinuing antidepressants several weeks prior to delivery will change infant outcome

Salisbury(2016)

Benzodiazepine Risks with later Exposure

§Neonatal Withdrawal§Floppy baby syndrome§PTB §LBW

Possible influences on Neonatal Outcomes

§Timing of Exposure§Length of Exposure§Medication Dose

∆indrugconc

↑plasmavolume

↑cardiacoutput

Bloodflow∆s

Respiratory∆s

↓albumin

↑GFR

Consider Pharmacokinetics changes during pregnancy

Take Home Point #4

üPsychotropic medication dosages might need to be increased as pregnancy progresses in order to achieve prior therapeutic response

∆indrugconc

Take Home Point #5

üTreat with Lowest Effective Dose§Some studies suggest an increased risk of malformations (antiepileptics) which are dose dependent§SSRI dose has been implicated with PTB risks in some studies§Unclear relationship with PNAS

Exposure through Breast Milk

§ Variable degree of exposure through breast milk§ When looking at the data consider negative outcome to

the infant over pharmacological data§ No long term data but experts agree that continuing to

breastfeed is reasonable

ü Lactmed

49

Infant monitoring is needed during lactation for certain medications

Drug InfantMonitoring

Carbamazepine CBZlevel,CBC,liverenzymes

Valproic acid VPAlevel(freeandtotal),liverenzymes,platelets

Lamotrigine Rash,liverenzymes,lamictal level

Lithium BUN,CRE,TSH,CBC

Typicalantipsychotics Stiffness,CPK

Atypicalantipsychotics

Weight,bloodsugar

Take home point

üMostpsychotropicagentsarereasonabletocontinueduringbreastfeeding.üDonotautomaticallychangeamedicationthatisworkingforoneofunknownbenefitbasedonbreastfeedingdesire

Multiple Medication Exposure

§Common in pregnancy§Limited studies§Implicated in worse neonatal outcomes

Take Home Point

üAvoid Polypharmacy if Possible

Back to Lara’s case§ You have both determined that staying on an antidepressant given her

history is a reasonable choice§ Is Lamotrigine indicated?üShe reports that lamotrigine significantly improved her mood and

impulse control, no SHB since she has been treated with this agent§ Does she need both antidepressants to remain stable? üYou learn that wellbutrin was added due to SSRI induced sexual SE§ Is her current SSRI dose the lowest EFFECTIVE dose?üSymptoms improved only on 20 mg of Escitalopram§ Can you consider a benzodiazepine Taper?üPatient is motivated to do so

Take Home Point

üGo with history of response

üIf no history of prior response, choose agents best studied with best outcomes

Exposure to Bipolar illness associated risks

§preterm birth§risks of c-section§Small head circumference §Neonatal hypoglycemia§ Increased rates of

substance abuse§Nicotine use§Overweight§Behavioral risks

BPAD Course of Illness in Pregnancy

§pregnancy similar to non-pregnant state

§25-30% mood recurrence rate during pregnancy

§Usually depressed or mixed episode

§higher during the 1st trimester

§decreased risk of psychiatric admission during pregnancy

ü RAPID DISCONTINUATION OF TREATMENT and ANTIDEPRESSANT USE-high risk

Sharma(2012)Diflorio(2010),Viguera(2000)

BPAD Course of Illness during Pregnancy

Discontinued mood stabilizer§37%moodepisoderecurrence

Continuedmoodstabilizer§85.5%moodepisoderecurrence

§Shortertimetorecurrence§Longerdepressiveepisodeduration

§Greaterriskifmedicationisdiscontinuedrapidly

Viguera (2007)

BPAD- Postpartum Course

During the postpartum risks are HIGH: Increased risks of developing psychotic episodes

Possible etiology includes:§ hormonal change§ Sleep deprivation and interference with

circadian rhythms during late pregnancy§ frequent newborn feeding

(Heronetal.2005;JonesandCraddock2005)Kendell(1987)Yonkers(2004)

BPAD- Postpartum Course

§ 100x more like to experience PP

psychosis when compared to the general

population

ü260/1000 women when compared to 1-

2/1000

§ Risk of inpatient admission first 30 days

PP:

ü20% BPAD vs 3% Schizophrenia

Munk-Olsen(2006)

> 23 times more likely to be admitted with an episode of bipolar disorder in the first postpartum month

§Primiparity as a risk factor for postpartum psychoses§Potentially life-threatening to both the woman and her newborn child§Consider BPAD or Schizoaffective Illness

Developing Postpartum Psychosis

Kendell(1978)Benvenutietal(1991)VanHartesvelt(1986)

§ 0.05-0.4% incidence

§ Differs from other psychotic presentations

§ Usually occurs within the first 3 days after delivery

§ Mood fluctuations

§ Confusion

§ marked cognitive impairment suggestive of delirium

§ Bizarre behavior

§ Insomnia

§ Visual and auditory hallucinations, and unusual (i.e. tactile and olfactory) hallucinations

Postpartum Psychosis

K.L.Wisneretal.SymptomatologyofaffectiveandpsychoticillnessesrelatedtochildbearingJ AffectDisord,30(1994),pp.77–87

PP Psychosis- Experience

FeltinavacuumFearsofleavingthehospitaltogohomeInabilitytosleepFromwantedbabytounwanted- anxiety,guiltandshameWonderingifthebabyistheirsCalloustx ofthebabyWorldseemedunrealBrainismissingsomething

ü Thereisaneedforthepsychiatristtodiscussthisdisorderandriskswnextofkin

Engqvist (2013)

Take Home Point

üPatients with Bipolar Disorder at are at high risk of mood episodes during pregnancy and in the PPüStrongly consider continuing a mood stabilizer during pregnancy

Mood Stabilizers in Pregnancy

§Lithium§Lamotrigine§Carbamazepine§Valproic Acid§Atypical antipsychotics

Lithium- Risks

§Ebstein – initially thought to be much higher risk than it is

now thought (10-20x increased risk – 0.05 to 1%)

§Nephrogenic DI – maternal or fetal

§Transient hypothyroidism of neonate

§Neonatal hypotonicity, lethargy, prematurity

§No developmental/cognitive effects

Hogan,Freeman(2016)

Lithium- monitoring§Fetal echo or level 2 ultrasound

§Transmitted into breast milk (infants with

30-50% maternal dose), infant drug levels

§20th weekGAon- monthlyserumlithium

levelsandroutinethyroid/renalfunction

laboratorytestsbedrawnandweekly

beginning4 weeksbeforeexpecteddelivery

§Near delivery must dose carefully

Hogan,Freeman(2016)

Lamotrigine in Pregnancy

§ Relatively Safe when compared to other AEDs

§MM risk comparable to general population

§ Risk of oral clefts not found in consistently

§No developmental abnormalities up to 6 yrs of age

§Consider importance of dosing given estrogen induced metabolism

Hogan,Freeman(2016)

Reimers (2005)

Estrogens(COC,HRT,pregnancy)

IncreasedUGT1A4

IncreasedclearanceofLamotrigine

SusceptibilitytoIllness

Lamotrigine Metabolism in Pregnancy

Lamotrigine Monitoring§Consider a baseline lamotrigine dose prior to

conception or immediately upon learning of

pregnancy

§Continue to monitor lamotrigine levels

throughout pregnancy, might be guided by

clinical status vs consider monthly

§ If there was a need to adjust dose during

pregnancy, consider risks of intoxication in the

postpartum

Clark(2013)

§ CONSIDER ALTERNATE TREATMENT in reproductively aged women § If none available, recommend folate supplementation§ General recommendations are to avoid valproate and carbamazepine in child

bearing women and pregnancy§ Level 2 ultrasound 11 – 13 weeks to detect NTD & up to 20 weeks to detect

cardiac & facial malformations

Adedinsewo (2013)

• Teratogen: NTDs, oral clefts, skeletal abnormalities• Lower cognitive function• Higher risk of ASD

Meador(2009)Baxter(2014)

Antipsychotics• FDA warning in 2011: neonatal EPS or withdrawal with all

antipsychotic drugs (restlessness, tremor, feeding difficulties, increased tone, dystonias, and parkinsonism)• First generation•Data from Haldol available since 1966•High potency first generation have not been found to

have elevated teratogenicity• Low potency considered less safe• Some associations with LBW and PTB

Hogan,Freeman(2016)

Second generation-Antipsychotics§>200% increase in the prescription of these medications between 2000 and 2011

§Limited Data but reassuring as not being major teratogens, questionable association with cardiac defects

§Large for gestational age babies§Low birth weight§Maternal weight gain§Risk of gestational diabetes§Quetiapine lowest placental passage, lowest passage into breast milk

Hogan,Freeman(2016)

Electroconvulsive Therapy (ECT)

§Electrical current applied during induced paralysis and sedation and brief seizure induced§Usually 6-12 sessions administered every other day§Extremely effectiveüMood disordersüPsychotic disorders

Lara’s case- Conclusion§ Lara remained on Escitalopram throughout pregnancy- infant

experienced mild respiratory distress which resolved within seconds, no other health concerns

§Wellbutrin was discontinued without recurrence of mood sx§ Lara remained on lamotrigine and there was no need for a dose

increase during pregnancy§Attempts to taper lorazepam were initially challenging, tapered

very slowly as she would experience significant anxiety with taper.use was prn by the end of her pregnancy§ Lara decided to breastfeed and infant continues to bemonitored by pediatrician

In Summary…• Confirm diagnosis• No decision is risk-free• Think chronologically in terms of risks to the fetus and the mother• Non pharmacologic treatments first, particularly for mild symptoms• Go with past history of response• If no history of prior response, choose agents best studied with best

outcomes• Aim for monotherapy• Aim for remission• Prescribe lowest effective dose • Few choices are absolutely safe or unsafe (Depakote=exception)• FDA categories are less than helpful- consider other resources and

consultation with colleagues• Work with patient’s treatment team

Thanks for your attention!