Rachel Shmuts, D.O.Assistant Clinical Professor

Rowan School of Osteopathic MedicineDepartment of Psychiatry

Should I stay on my medication?

Is it safe to be on medication while I’m pregnant?

Am I a “bad” mom for wanting to stay on my medication?

Can I breastfeed on medication?

RISK vs. RISK and RISK vs. BENEFIT◦ Risk of untreated illness vs. risk of treatment

FDA safety categories & labeling

Pharmacodynamics/kinetics in pregnancy

Provider uncertainty avoidance of appropriate discussions

What is the incidence of major birth defects in the general population in the U.S.?A. 0.5-1%

B. 1-3%

C. 5-10%

D. 15-20%

What is the incidence of major birth defects in the general population in the U.S.?A. 0.5-1%

B. 1-3%

C. 5-10%

D. 15-20%

1975 FDA developed categorical guidelines for safety and prescribing medication during pregnancy

Limited amount of animal data Extremely small amount of human data New data not applied to update category

assignment Discounts risk of untreated illness &

recurrence and/or severity of illness Progression of categories misinterpreted as

increasing potential for harm Misinterpretation that drugs within same

category confer same amount of risk Most psychotropics are “C” or “D”

December 2014 – Pregnancy and Lactation Labeling Rule (PLLR)

Went into effect June 30, 2015

https://s3.amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf

Pregnancy◦ Info for pregnancy exposure registry

◦ Risk summary, clinical considerations, data

◦ Includes labor and delivery

Lactation◦ Info on amount of drug and potential effects on

infant

Females and males of reproductive potential◦ New subsection

◦ Need for pregnancy testing, contraception, infertility

Prescription drugs and biologics on/after 6/30/2001 – phased in gradually

OTC products not affected

Compliance by drug manufacturers

Poor prenatal care, self-neglect, reduced compliance

Substance abuse & smoking Low birth weight & growth retardation Pre-term delivery Late pregnancy◦ Pre-eclampsia◦ Operative delivery◦ NICU admission◦ SUICIDE & self-harm

Psychosis infanticide

Cohen naturalistic study◦ MDD can be relapsing and remitting

Risk of relapse of MDD discontinued SAME in pregnant vs. nonpregnant patients◦ 70% off meds

◦ 30% on meds

Changes in maternal metabolism affect drug levels symptoms risk of illness vs. risk of med revisited

Activated HPA axis◦ ACTH & βendorphin

Changes in metabolism of 5HT◦ Lower serum tryptophan

Increased catabolism of trytophan due to immune activation in early pregnancy

Increased cortisol decreased uterine blood flow

All medications cross placenta

No psychotropic drug approved by FDA for use in pregnancy◦ All off-label

3 main types of fetal/congenital risks1. Teratogenesis/teratogenicity

2. Neonatal syndromes/symptoms

3. Long-term (a.k.a. neurobehavioral) effects

Teratogen: agent that interferes w/in utero development process of organ malformation/dysfunction

Teratogenic: exposure associated with significant ↑ deformities OVER baseline risk

Baseline congenital malformations 1-3%◦ 65-70% unknown etiology

Risks may be conceptualized and evaluated by timing of exposure◦ < 2 wks: nonviability (“blighted ovum”)◦ 1st trimester (3-8wks): morphological problems◦ 2nd & 3rd trimesters: growth & functional development

Formation of major organ systems by 12 weeks◦ Each system has its own “critical period”◦ Highest vulnerability to teratogenic effects

Neural tube folding and closure brain and SC –4 weeks◦ Range 14-35 days post-conception◦ Central nervous system damage often occurs prior to

patient knowing she is pregnant

Heart and great vessels – 4-9 weeks◦ However, entire 1st trimester considered

Types of “intrauterine toxicity”◦ Intrauterine death

◦ Physical malformations

◦ Growth impairment

Obstetrical complications◦ Operative birth

◦ C-section

“Neonatal withdrawal”

“Perinatal abstinence syndrome”

Spectrum of physical and behavioral sxsobserved in acute neonatal period attributed to med exposure at or near time of delivery

Anecdotal reports, larger samples needed

Examples◦ SSRIs neonatal adaptation syndrome◦ Methadone opioid withdrawal syndrome◦ Benzodiazepines floppy baby syndrome◦ High potency antipsychotics EPS

◦ Confounding by indication

“Behavioral teratogensis”

Neuronal migration & differentiation occur prenatally but also early in life

CNS is plastic and dynamic even after NT closure

Risk of long-term effects conferred throughout pregnancy

May be subtle and delayed

Very little data◦ ONLY animal studies show abnormalities in brain

receptor number and function

Nature vs. nurture

Cognitive◦ Learning problems or disabilities

◦ Impaired problem solving

Behavioral◦ Abnormal activity levels

◦ Fetal alcohol syndrome

Emotional◦ Impaired bonding and attachment

Most studies are small samples

Prospective samples smaller than retrospective case-controls

500-600 exposures needed to demonstrate 2-fold increase in risk for a malformation

Relative risk vs. ABSOLUTE RISK

Medication exposure inferred from pharmacy records

Risk of psychotropic medication effects on fetus often overestimated

◦ Media influence

◦ “Intuitive dread”

◦ Relative value of each outcome

◦ Availability heuristic

Maternal self-esteem tied with sense of not causing harm to fetus at expense of not caring for self

Influence of significant others

Strongest predictor of treatment decisions are recommendations directly given by physician

Risk of litigation minimized by DOCUMENTING INFORMED CONSENT (evidence that full conversation took place)

Decision to use psychotropic medications during pregnancy/lactation must be collaborative & individualized

Preconception counseling is ideal!

Focus on risks of medication use vs. risks of untreated mental illness

Considerations◦ Severity of illness◦ History of illness course on previous tapers◦ Stage of pregnancy◦ Plans to breastfeed◦ Level of functioning

Antidepressants◦ SSRIs

◦ TCAs

Mood stabilizers & AEDs

Typical and atypical antipsychotics◦ Anticholinergics for EPS

Anxiolytics◦ BZDs

◦ β-blockers

Maternal influences◦ Delayed gastric emptying

◦ Decreased albumin levels (protein-binding)

Fetal influences◦ Low levels of drug protein

bound◦ Immature hepatic

metabolism◦ Permeable blood-brain

barrier

Fetal effects◦ Impaired drug

transportation back to maternal circulation + reduced drug metabolism

◦ Fetal levels > maternal levels

Higher than average relative risk, but small absolute risks of teratogenesis

Older agents w/more data > newer agents w/less data

Monotherapy when effective

Minimal effective dose for shortest duration

Maximize nonpharmacologic strategies

Pre-conception planning is ideal

RISK VS. BENEFIT

Many medications thought not to be safe in pregnancy may be used in lactation

Evaluation by percentage of maternal serum level = relative infant dose (or maternal-infant ratio)◦ Generally accepted <10% as

low risk

Infant levels◦ Age & prematurity

◦ Hepatic enzymatic capacity

Breast-feeding◦ Infant benefits

Bonding & attachment

Lower infection

Lower mortality

Cognitive development & intellectual function

◦ Maternal benefits

Involution of uterus

Suppression of ovulation

◦ Portable and cheap

Passage into breast milk effected by◦ Volume of distribution

◦ Molecular weight

Low > high

◦ Lipid/water solubility

Lipid passes more easily

◦ Affinity for plasma & milk proteins

Unbound crosses alveolar membranes

◦ pH of blood & milk (ionization)

◦ Blood flow to breast

Absolute infant dosage◦ Milk yield

◦ Milk composition – major factor in drug concentration

Hind milk – fat rich – lipid soluble

Colostrum – protein-rich –protein-bound

◦ Breast emptying

◦ pH differential

Limited neonatal physiology◦ Immature hepatic & renal

function (lower GFR)

◦ Higher gastric pH, slower bowel motility -unpredictable absorption

◦ Rapid increase in ability to metabolize meds in 3rd month of life

◦ Premature – psychotropic drugs not recommended

Drug levels too high toxicity

Drug levels too low withdrawal◦ More harm than drug itself

Drug levels normal/acceptable side effects

Antidepressants◦ Lower exposure in breast

milk than during pregnancy

◦ Low risk

Sertraline

Paroxetine

Nortriptyline

◦ Higher risk

Citalopram

◦ Contraindicated

Doxepin

Bupropion

Toxicity◦ Poor feeding

◦ Irritability

◦ Sedation/sleeping problems

Overall, considered compatible

Medication dependent

Monitor mother

Monitor child – involve pediatrician

Psychoeducation on signs & sxs of toxicity

Collaboration w/psychiatrist, OB, & peds

Timing of feeding◦ Prior to taking medication

◦ Short-acting monotherapy

◦ Stored milk from non-peak pumps

Physicians not always aware of current recommendations on short and long-term risks of medication

Rapidly growing published studies, often w/different recommendations

Significant variation in methodology varied interpretations

Studies that do not report increased risk often get ignored by physicians and media

Lawsuits and legal involvement

No medication/drug is absolutely safe

Current safety categorization may be inadequate in guiding treatment

Developmental, short-term, and long-term effects of medication possible

Every treatment decision relies on assessment of RISK vs. BENEFIT of medication exposure

Do not overlook significant risks of untreated/inadequately treated psychiatric illness

Single, smallest effective dose for shortest duration

Cott AD, Wisner KL. Psychiatric disorders during pregnancy. International Review of Psychiatry. August 2003: 15, 217-30.

Massachusetts General Hospital Women’s Mental Health program - http://womensmentalhealth.org

Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. Pharmacologic management of psychiatric illness during pregnancy: Dilemmas and guidelines. The American Journal of Psychiatry. May 1996: 153(5), 592-606.

Pearlstein T. Use of psychotropic medication during pregnancy and the postpartum period. Women’s Health. 2013: 9(6), 605-15.

Menon SJ. Psychotropic medication during pregnancy and lactation. Arch Gynecol Obstet. 2008: 277, 1-13.

Pregnancy and Lactation Labeling (Drugs) Final Rule. Available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm. Accessed August 15, 2016.