Art of Psychotropics during Art of Psychotropics during Pregnancy & LactationPregnancy & Lactation

By:

Prof. Hani Hamed Dessoki, M.D. Psychiatry

Prof. Psychiatry

Head, Psychiatry Department

Beni Suef University

2014

Prevalence of Perinatal Depressive Prevalence of Perinatal Depressive and Anxiety Disorders and Anxiety Disorders

� DepressionDepression: approximately 14% within : approximately 14% within the first 2-3 months postpartum the first 2-3 months postpartum (similar rate during pregnancy). (similar rate during pregnancy).

� AnxietyAnxiety: At least 14 % in postpartum : At least 14 % in postpartum period combining panic disorder, OCD period combining panic disorder, OCD and generalized anxiety disorder.and generalized anxiety disorder.

� By far, the most common serious By far, the most common serious medical complications of the perinatal medical complications of the perinatal period. period.

IntroductionIntroduction

A substantial number of women of childbearing age A substantial number of women of childbearing age are prescribed psychotropic drugs, and because are prescribed psychotropic drugs, and because nearly nearly 50% of pregnancies are unplanned50% of pregnancies are unplanned, many , many women are still taking them upon becoming women are still taking them upon becoming pregnant.pregnant.

Psychotropic drugs are commonly used to treat Psychotropic drugs are commonly used to treat psychiatric disorders -- antidepressants, psychiatric disorders -- antidepressants, benzodiazepines, antipsychotics, antiepileptics, and benzodiazepines, antipsychotics, antiepileptics, and lithium.lithium.

FDA: “Use in Pregnancy”- Drug FDA: “Use in Pregnancy”- Drug categoriescategories Category A: Controlled studies show Category A: Controlled studies show no riskno risk Category B: Category B: NoNo evidence of evidence of risk in humansrisk in humans Category C: Category C: RiskRisk to humans to humans cannot be cannot be

ruled out ruled out Category D: positive evidence of Category D: positive evidence of riskrisk but it is but it is

possible in some situations the possible in some situations the benefitsbenefits may may outweigh the risks {outweigh the risks {benifit > risk}benifit > risk}

Category X: Toxic,Category X: Toxic, Contraindicated in Contraindicated in pregnancy. Risks outweigh the benefits in pregnancy. Risks outweigh the benefits in almost every situation almost every situation {risk > benif it}{risk > benif it}

Risk Periods for Foetal Risk Periods for Foetal Structural MalformationsStructural Malformations

2-4 weeks 2-4 weeks neuralneural tube closure tube closure 4-9 weeks 4-9 weeks heartheart is forming is forming 6-9 weeks is when the 6-9 weeks is when the oral cleftoral cleft closes closes by 12 weeks organogenesis is by 12 weeks organogenesis is

completedcompleted

TeratogenTeratogen

Word derived from "terato" meaning monster and Word derived from "terato" meaning monster and "gen," to give rise to, so teratogens give rise to "gen," to give rise to, so teratogens give rise to monsters (not really).monsters (not really).

Non-genetic factors that interfere with normal Non-genetic factors that interfere with normal embryonic, fetal differentiation and morphogenesis.embryonic, fetal differentiation and morphogenesis.

Children who have been exposed to teratogens Children who have been exposed to teratogens inutero will not pass their defect on to their inutero will not pass their defect on to their children.children.

Important factors in Important factors in TeratogenicityTeratogenicity

TimeTime . The gestational age of the fetus at the . The gestational age of the fetus at the t ime of the t ime of the exposure to the teratogen. Different exposure to the teratogen. Different organs of the body are forming at different times. organs of the body are forming at different times. There There is an "all or none" period in the first two weeks where is an "all or none" period in the first two weeks where the fetus is generally not susceptible to teratogens.the fetus is generally not susceptible to teratogens.

DosageDosage . To how much of the teratogen was . To how much of the teratogen was the fetus the fetus exposed.exposed.

The genotype of the fetusThe genotype of the fetus . The fetus may be . The fetus may be more or more or less less resistantresistant to the teratogen because of to the teratogen because of inactivationinactivation of the teratogen. of the teratogen.

The genotype of the mother.The genotype of the mother. Mothers also Mothers also dif fer in their dif fer in their ability to ability to detoxifydetoxify the teratogen. the teratogen.

Two Basic AssumptionsTwo Basic Assumptions

1. All medications cross the placenta and 1. All medications cross the placenta and also enter breast milk. also enter breast milk.

2. We do not yet know all the potential 2. We do not yet know all the potential risks from medication exposure. risks from medication exposure.

We talk about the “Risk/Benefit ratio”.We talk about the “Risk/Benefit ratio”. Risks of treatment vs the benefits of Risks of treatment vs the benefits of

treatment or treatment or risks of treatmentrisks of treatment vs vs risks of risks of non-treatmentnon-treatment..

= ?

Consider non-pharmacological measuresConsider non-pharmacological measures Normal incidence: 2-4% major, 15% minorNormal incidence: 2-4% major, 15% minor Discuss & document Pros/Cons: balance risks Discuss & document Pros/Cons: balance risks

and benefits & provide written informationand benefits & provide written information Obtain & document informed consentObtain & document informed consent Post-prescription follow upPost-prescription follow up Delivery: should the dose be changed around Delivery: should the dose be changed around

delivery timedelivery time

Psychotropics in Pregnancy: General Psychotropics in Pregnancy: General ConsiderationsConsiderations

Psychotropics in Pregnancy: General Psychotropics in Pregnancy: General Considerations Considerations cont’dcont’d

� Explain risks and benefits of medication and Explain risks and benefits of medication and non-medication treatment approaches, non-medication treatment approaches, respect the mother’s wishes, document respect the mother’s wishes, document decision-making. decision-making.

� Don’t use medication unless truly necessary, Don’t use medication unless truly necessary, especially during the first trimester. especially during the first trimester.

� Dose medications to adequately treat Dose medications to adequately treat disorders (i.e., disorders (i.e., don’t under-medicate to don’t under-medicate to decrease drug exposuredecrease drug exposure). ).

Measuring the Risk of Psychiatric Measuring the Risk of Psychiatric Medicines During PregnancyMedicines During Pregnancy

When testing a psychiatr ic medication's When testing a psychiatr ic medication's effects on pregnancy, doctor's look for effects on pregnancy, doctor's look for three things: three things:

Occurrence of birth defects (structural Occurrence of birth defects (structural teratogenesis) teratogenesis)

Occurrence of behavioral problems (behavioral Occurrence of behavioral problems (behavioral teratogenesis) teratogenesis)

Occurrence of unusual symptoms directly after Occurrence of unusual symptoms directly after birth (perinatal syndromes) birth (perinatal syndromes)

MDD in pregnancyMDD in pregnancy

10-16% of women have major depression during 10-16% of women have major depression during pregnancypregnancy

Associated with problems for both mother and fetusAssociated with problems for both mother and fetus When emerges in pregnancy, is frequently overlookedWhen emerges in pregnancy, is frequently overlooked Pregnancy is neither protective, nor exacerbating for Pregnancy is neither protective, nor exacerbating for

depressive disordersdepressive disorders Under-recognized and under-treated in primary care Under-recognized and under-treated in primary care

settingssettings

Cohen L, Nonacs R (editors): Mood and Anxiety Disorders During Pregnancy and Postpartum (Review of Psychiatry Series, Vol 24, Number 4). Washington, DC, APPI, 2005

Risk of Untreated Risk of Untreated Depression in PregnancyDepression in Pregnancy Maternal Depression may cause:Maternal Depression may cause:

Preterm birth, low birth-weight, smaller head circumference, and lower Apgar scores

Contribute to poor self-care, inattention to prenatal Contribute to poor self-care, inattention to prenatal carecare

Women are more likely to smoke, use alcohol or Women are more likely to smoke, use alcohol or illicit drugsillicit drugs

Children of depressed mothers are more likely to Children of depressed mothers are more likely to have behavioral problems, delays in cognitive, have behavioral problems, delays in cognitive, motor and emotional developmentmotor and emotional development

Risk for suicideRisk for suicide

Nonacs R, Viguera A, Cohen L. Psychiatric Aspects of Pregnancy. Womens Mental Health, a Comprehensive Textbook. Ed. Susan Kornstein and Anita Clayton. New York, NY, 2002.

Recommendations for Recommendations for Antidepressant Treatment in Antidepressant Treatment in Pregnant WomenPregnant Women

Psychotherapy is first line for mild-moderate depressionPsychotherapy is first line for mild-moderate depression Psychotherapy + antidepressant recommended for Psychotherapy + antidepressant recommended for

moderate to severe depressionmoderate to severe depression Individualized risk-benefit analysisIndividualized risk-benefit analysis SSRI antidepressant SSRI antidepressant considered first-lineconsidered first-line Successful historySuccessful history of antidepressant treatment: data of antidepressant treatment: data

should be reviewed with mom, and considered first lineshould be reviewed with mom, and considered first line

Altshuler L, Cohen, L, Moline M et al. Treatment of Depression in Women: A Summary of the Expert Consensus Guidelines. Journal of Psychiatric Press: 185-208, May, 2001.

Recommendations continuedRecommendations continued

ECT for psychotic depressionECT for psychotic depression Review all risks and benefits of treatmentReview all risks and benefits of treatment Mom’s should be monitored carefully for increased Mom’s should be monitored carefully for increased

depression, mania or psychosisdepression, mania or psychosis Dosages may need to be adjusted Dosages may need to be adjusted GoalGoal is monotherapy and minimal effective dosage is monotherapy and minimal effective dosage

Altshuler L, Cohen, L, Moline M et al. Treatment of Depression in Women: A Summary of the Expert Consensus Guidelines. Journal of Psychiatric Press: 185-208, May, 2001

Antidepressants in Antidepressants in Pregnancy and LactationPregnancy and Lactation

� SSRIs relatively safe even during 1st trimester except paroxetine (increases birth defect rates). Worrisome recent reports that exposure during late pregnancy more than doubles prevalence of pulmonary hypertension in newborns.

� SSRIs (especially sertraline, citalopram, paroxetine) and TCAs (especially nortriptyline) relatively safe in breast-feeding. Fluoxetine accumulation, TCA-induced seizures. Venlafaxine accumulates in milk. Insufficient information about newer antidepressants, trazodone.

� Bupropion: FDA risk category B.

� MAOIs associated with growth retardation, congenital malformations.

FDA WarningFDA Warning

Neonates exposed to SSRIs and Neonates exposed to SSRIs and SNRIs during the late 3rd trimester SNRIs during the late 3rd trimester have demonstrated increased have demonstrated increased complications complications Prolonged hospitalizationJitteriness, tremor, apneathese symptoms are consistent with either

toxicity or withdrawalCaution - Neonatal work up

Depression, anxiety & Depression, anxiety & insomniainsomnia

BenzodiazepenesBenzodiazepenes

Third TM use CLEARLY associated with “floppy baby Third TM use CLEARLY associated with “floppy baby syndrome” – prolonged severe withdrawalsyndrome” – prolonged severe withdrawal

No long term studies of infant neurobehaviorNo long term studies of infant neurobehavior Question of oral cleft with early exposureQuestion of oral cleft with early exposure Should be tapered, not stopped abruptlyShould be tapered, not stopped abruptly

Mood StabilizersMood Stabilizers

LamictalLamictal has a growing safety profile has a growing safety profile Anti-psychotics not well studied – maybe safe?Anti-psychotics not well studied – maybe safe? Lithium Lithium

1st TM risk of cardiac malformations – fetal echo Need to monitor levels closelyNeonatal abstinence syndrome

Valproate (Depakote) and Carbamazepine (Tegretol) Valproate (Depakote) and Carbamazepine (Tegretol) should be avoidedshould be avoided

VALPROIC ACID VALPROIC ACID RECOMMENDATIONSRECOMMENDATIONS Reduce daily dose, 3-4 divided dosesReduce daily dose, 3-4 divided doses 4-5 mg folic acid before conception 4-5 mg folic acid before conception

and throughout pregnancyand throughout pregnancy Vitamin K (20/mg/day) first trimester Vitamin K (20/mg/day) first trimester

and lastand last Vitamin K (IM) 1mg at birthVitamin K (IM) 1mg at birth High resolution ultrasound 16-18 High resolution ultrasound 16-18

weeksweeks

Lithium in Pregnancy –Lithium in Pregnancy –Treatment of Bipolar DisorderTreatment of Bipolar Disorder

Morphologic risksMorphologic risks : Epsteins’ anomaly : Epsteins’ anomaly Incidence 1 per 1000 (.05-.1%) associated Incidence 1 per 1000 (.05-.1%) associated

with Lithiumwith Lithium4 fold increase in risk4 fold increase in riskDiagnosed at 16 weeks. Often surgically Diagnosed at 16 weeks. Often surgically

correctable.correctable. Neonatal ToxicityNeonatal Toxicity

Floppy baby syndrome, Nephrogenic Floppy baby syndrome, Nephrogenic Diabetes Insipidus in the fetus-(reversible), Diabetes Insipidus in the fetus-(reversible), Neonatal hypothyroidismNeonatal hypothyroidism

Recommendations for Recommendations for Antidepressant Treatment in Antidepressant Treatment in Lactating WomenLactating Women

Individualized risk-benefit analysisIndividualized risk-benefit analysis PsychotherapyPsychotherapy

Mild to moderate depression Psychotherapy Psychotherapy ++ antidepressant antidepressant

Moderate to severe depression NoNo prior antidepressant: prior antidepressant:

Paroxetine or Sertraline Prior successful successful antidepressant treatmentantidepressant treatment

Discuss data with mom; consider as first line

Academy of Breastfeeding Medicine Protocol Committee Clinical Protocol #18: Use of Antidepressants in Nursing Mothers. Breastfeeding Medicine. VOl 3. (1), 2008.

Antipsychotic Meds-NeurolepticsAntipsychotic Meds-Neuroleptics

First-generationFirst-generation : : Phenothiazines=Phenothiazines=

Thorazine, Thorazine, Mellaril, Mellaril, Stelazine, Stelazine,

Non Phenothiazines= Non Phenothiazines= Haldol Haldol (butyrophenones)(butyrophenones)(high potency)(high potency)

Atypical Antipsychotics Atypical Antipsychotics (2(2ndnd and 3 and 3rdrd gen)= gen)=

Clozaril, Clozaril, Zyprexa, Zyprexa, Risperdal, Risperdal,

Seroquel,Seroquel,ZeldoxZeldox

SerdolectSerdolectInvega,Invega,

AbilifyAbilify

Cat B: Clozapine (clozapex(Cat C: •Trifluoperazine, Thioridazine(mellaril), Droperidol , Pimozide, Fluphenazine (modecate), •Flupenthixol, Zuclopenthixol (Some cases of birth defects and gestational metabolic complications were recorded).

Neuroleptics

HaloperidolHaloperidol Haloperidol is rated Haloperidol is rated FDAFDA PregnancyPregnancy

Category C.Category C.

It has been on the market for more than 40It has been on the market for more than 40 years, and there is years, and there is no evidenceno evidence that, that,

when used during pregnancy, they increase when used during pregnancy, they increase the rates of major malformations.the rates of major malformations.

It is associated with It is associated with no increased riskno increased risk to to fetus or baby, and are recommended for fetus or baby, and are recommended for use during pregnancy in high-risk patients.use during pregnancy in high-risk patients.

Chlorpromazine (Thorazine) Chlorpromazine (Thorazine) Chlorpromazine is rated Chlorpromazine is rated FDAFDA PregnancyPregnancy Category C. Category C. In animals, increasedIn animals, increased risk of congenital malformations risk of congenital malformations

((involving skeletal and centralinvolving skeletal and central nervous systems, eye, cleft nervous systems, eye, cleft palate, fetal death, and reducedpalate, fetal death, and reduced fetal weight gainfetal weight gain). ).

NEONATAL SIDE EFFECTS: There are reported instances of NEONATAL SIDE EFFECTS: There are reported instances of prolonged jaundice, extrapyramidal signs, hyperreflexia or prolonged jaundice, extrapyramidal signs, hyperreflexia or hyporeflexiahyporeflexia in newborn infants whose mothers received in newborn infants whose mothers received phenothiazines prenatally.phenothiazines prenatally.

Atypical AntipsychoticsAtypical Antipsychotics

Atypical Antipsychotics are rated Atypical Antipsychotics are rated FDAFDA PregnancyPregnancy Category C. Category C.

These risks have been reported rarelyThese risks have been reported rarely with with FGAs. FGAs.

Hence, the choice of the less harmful option Hence, the choice of the less harmful option in pregnancyin pregnancy should be limited toshould be limited to FGAs FGAs in in drug-naive patients. drug-naive patients.

When pregnancyWhen pregnancy occurs during occurs during antipsychotic treatment, the choice to antipsychotic treatment, the choice to continuecontinue the previous therapy should be the previous therapy should be preferredpreferred..

Gentile S., Schizophrenia Bulletin (2008)

Evidence Based StudyEvidence Based Study

EPS Treatments during EPS Treatments during PregnancyPregnancy

DiphenhydramineDiphenhydramine is probably safest although is probably safest although birth defects rate somewhat higher with 1st birth defects rate somewhat higher with 1st trimester exposure; increased malformation trimester exposure; increased malformation rate with benztropine, trihexyphenidyl, and rate with benztropine, trihexyphenidyl, and especially amantadine. especially amantadine.

Propranolol is reasonably safe. Propranolol is reasonably safe.

Psychotropics and BreastfeedingPsychotropics and Breastfeeding

It is widely accepted that It is widely accepted that there are many benefits in there are many benefits in breastfeeding both breastfeeding both biologically and in terms of biologically and in terms of mother-baby attachment.mother-baby attachment.

Do these benefits Do these benefits outweigh the potential risks outweigh the potential risks of psychotropic ingestion?of psychotropic ingestion?

Typical antipsychotics Typical antipsychotics As Haloperidol (Haldol); especially at high As Haloperidol (Haldol); especially at high

dose, have occasionally been associated dose, have occasionally been associated with adverse reactions in breastfed infants with adverse reactions in breastfed infants (eg urinary retention, dystonic reactions). (eg urinary retention, dystonic reactions).

Chlorpromazine as a drug "for which the Chlorpromazine as a drug "for which the effect on nursing infants is unknown but effect on nursing infants is unknown but may be of concern". may be of concern".

Psychotropics and BreastfeedingPsychotropics and Breastfeeding

Atypical antipsychotics Atypical antipsychotics Preliminary data suggest that olanzapine (Zyprexa) and Preliminary data suggest that olanzapine (Zyprexa) and

risperidone (Risperdal) have low infant doses relative to risperidone (Risperdal) have low infant doses relative to the maternal weight-adjusted dose and, given the lower the maternal weight-adjusted dose and, given the lower adverse effects in the mother, these medications are adverse effects in the mother, these medications are being increasingly used during lactation (safest).being increasingly used during lactation (safest).

Prolactin-sparing antipsychotic may be useful, e.g., Prolactin-sparing antipsychotic may be useful, e.g., quetiapine.quetiapine.

Clozapine (Clozaril) contraindicated in breastfeeding (due Clozapine (Clozaril) contraindicated in breastfeeding (due to high concentrations in breast milk) unless strongly to high concentrations in breast milk) unless strongly indicated for maternal well-being. indicated for maternal well-being.

Please, give only good fertilizer…

Guidelines for Treatment of Mania Guidelines for Treatment of Mania During Pregnancy/LactationDuring Pregnancy/Lactation

� First trimester: Haloperidol for psychosis, clonazepam for agitation; if mood stabilizer is necessary, lithium may be first choice. ECT.

� Second/Third trimester/Postpartum: Lithium or anticonvulsants, haloperidol and/or clonazepam if truly needed. Continue treatment postpartum if no obstetric complications. Follow breast-fed infants closely.

Guidelines for Treatment of Anxiety Guidelines for Treatment of Anxiety Disorders During Pregnancy/LactationDisorders During Pregnancy/Lactation

� Panic Disorder: SSRIs or secondary amine TCAs. Clonazepam if a benzodiazepine is necessary.

� Obsessive-Compulsive Disorder: SSRIs or clomipramine if SSRIs are ineffective (risk of hypotension during pregnancy, infant seizures).

Managing Pregnancy in Women Managing Pregnancy in Women Who Require Chronic Psychotropic Who Require Chronic Psychotropic MedicationMedication

� Emphasize the importance of birth control and Emphasize the importance of birth control and planning pregnancies. planning pregnancies.

� Stop meds during 1Stop meds during 1stst trimester, if feasible. trimester, if feasible.� Plan A: If possible, taper and stop medication prior Plan A: If possible, taper and stop medication prior

to attempts to conceive, e.g. at the beginning of a to attempts to conceive, e.g. at the beginning of a menstrual cycle. menstrual cycle.

� Plan B: Detect pregnancy as early as possible (2 Plan B: Detect pregnancy as early as possible (2 wks with OTC pregnancy tests), then taper/stop wks with OTC pregnancy tests), then taper/stop medication. medication.

ConclusionsConclusions Minimize medications and poly-pharmacyMinimize medications and poly-pharmacy

Document, document, document!Document, document, document!

In all cases, optimizing the mother’s health and ability to In all cases, optimizing the mother’s health and ability to parent should be considered crucial for the developing parent should be considered crucial for the developing childchild

Consider non-pharmacologic strategiesConsider non-pharmacologic strategies

MCQMCQ

When testing a psychiatr ic medication's When testing a psychiatr ic medication's effects on pregnancy, doctor's look for the effects on pregnancy, doctor's look for the following: following:

A. Occurrence of birth defects. A. Occurrence of birth defects. B. Occurrence of behavioral problems. B. Occurrence of behavioral problems. C. Occurrence of unusual symptoms directly. C. Occurrence of unusual symptoms directly.

D. All of the above.D. All of the above.

MCQMCQ

The following mood stabilizer can be The following mood stabilizer can be used safely in bipolar depression used safely in bipolar depression during pregnancy:during pregnancy:

A. LamictalA. LamictalB. Lithium B. Lithium C. Valproate (Depakote) C. Valproate (Depakote) D. Carbamazepine (Tegretol)D. Carbamazepine (Tegretol)

  HEALTHY CONSUMERHEALTHY CONSUMERAre Antidepressants Safe During Pregnancy?Are Antidepressants Safe During Pregnancy?By RONI CARYN RABINBy RONI CARYN RABIN  SEPTEMBER 1, 2014  SEPTEMBER 1, 2014 6:17 PM6:17 PM Up to 14 percent of pregnant women take Up to 14 percent of pregnant women take

antidepressants, and the Food and Drug antidepressants, and the Food and Drug Administration has issued strong warnings that one Administration has issued strong warnings that one of them, paroxetine of them, paroxetine ((PaxilPaxil), may cause birth ), may cause birth defects.defects.

But the prevailing attitude among doctors has been But the prevailing attitude among doctors has been that that depression depression during during pregnancypregnancy is more  is more dangerous to mother and child than any drug could dangerous to mother and child than any drug could be. Now a growing number of critics are challenging be. Now a growing number of critics are challenging that assumption.that assumption.

Three new studies have heightened concerns about Three new studies have heightened concerns about longlong--term developmental effectsterm developmental effects. . Researchers at Researchers at Johns Hopkins UniversityJohns Hopkins Universityreported in Aprilreported in April that boys  that boys with autism were nearly three times more likely to with autism were nearly three times more likely to have been exposed to S.S.R.I.s before birth than have been exposed to S.S.R.I.s before birth than typically developing boys. typically developing boys.

Hani Hamed Dessoki, MD Psychiatry Prof. of Psychiatry

Head, Psychiatry DepartmentFaculty of Medicine - Beni Suif University

 Email: hanipsych@yahoo.comWebsite: www.hanipsych.com