SAFETY OF ANTIDEPRESSANT USE DURING PREGNANCY

Daniel HuismanPharmD CandidateUIC College of PharmacyApril 26, 2012

Objectives

Describe the epidemiology, risk factors, symptoms, and consequences of maternal depression

Identify the role of SSRIs in the treatment of depression

Describe the potential link between PPHN and SSRI use

Evaluate clinical trials analyzing the risks of SSRI exposure in newborns regarding the development of PPHN

Apply evaluation to a patient case

Introduction

In July 2006, the U.S. Food and Drug Administration issued a warning regarding a potential link between selective serotonin-reuptake inhibitors (SSRIs) and persistent pulmonary hypertension of the newborn (PPHN) based on a study published in the New England Journal of Medicine that showed a 6-fold increased risk.

Introduction

In December 2011, after review of additional studies, the FDA revised its initial warnings, recommending physicians continue antidepressant therapy in pregnant women due to a variety of health issues caused by untreated maternal depression.

Introduction

In January 2012, the British Medical Journal published a study warning pregnant women that they can significantly increase the risk of their infants developing PPHN if they take certain SSRIs.

Patient Case

BV is a 27 y/o AAF presenting to clinic with plans of becoming

pregnant in the near future. BV has concerns of continuing her

antidepressant therapy and wants to discuss her options for treatment

during pregnancy.

HPI:

BV has had 7-8 episodes of depression in the past several years. The

most recent episode was less than a year ago, and she failed therapy

with fluoxetine. During these episodes, BV experienced loss of

appetite, disconnect from family, panic attacks, and drug/alcohol abuse.

Patient Case

PMH:

Major depressive disorder (2003)

History of panic attacks

Patient Case

SH:(-) tobacco – quit smoking 3 months ago(+) EtOH – occasionally(+) illicits – marijuana sociallynot married; lives with boyfriend of 2 years

Allergies/ADRs: NKDA

Medications:Sertraline 50mg – 1 tab PO qdailyMultivitamin Centrum – 1 tab PO qdailyOxycodone 10mg – 1 tab PO q4h prn back pain

Maternal Depression

Affects approximately 10-20% mothers-to-be

and new mothers (up to 12 monthspostpartum)

- about 18 million Americans annually

Prenatal depression Postpartum depression Postpartum psychosis

Maternal Depression – Risk Factors History of mood disorders Substance abuse problems Maternal depression from previous pregnancy Family history Life stress Poor marital status Low socioeconomic status Lack of social support/community network Unplanned or unwanted pregnancy Race/ethnicity

Prenatal Depression

Both major and minor episodes beginning during and lasting up to 6 months after pregnancy

Period prevalence – 18.4% Incidence – 14.5% Low screening rate (23-45%)

Lack of time (72%) Lack of reimbursement (48%) Stigma (45%)

Only about 50% of women follow up with depression medication

Prenatal Depression - Symptoms Crying, weepiness Sleep problems Fatigue Appetite disturbance Anhedonia Anxiety Poor fetal attachment irritability

Prenatal Depression - Consequences

Affects both the newborn and mother Untreated

Potential poor compliance, nutrition, sleep habits, exercise habits More likely to abuse tobacco, alcohol, illicits More likely to engage in risky behavior (suicidal behavior) 3.4x more likely to deliver pre-term 4x more likely to deliver low birth weight baby Obstetrical complications (pre-eclampsia, excessive bleeding, placental rupture,

premature rupturing of water) Increased risk for developing postpartum depression Increased use of health care services including emergency room visits

Treated w/ SSRIs Potential increased risk for newborn developing PPHN Black Box Warning – increased risk for suicidal thinking and behavior

Economic issues $83.1 billion spent on depression in 2000 26.2 billion spent on premature births in 2005

Selective Serotonin Reuptake Inhibitors (SSRIs)

citalopram (Celexa) escitalopram (Lexapro) fluoxetine (Prozac) fluvoxamine (Luvox) paroxetine (Paxil, Paxil CR) sertraline (Zoloft)

SSRIs - Indications

Major depressive disorder Others

Obsessive-compulsive disorder Panic disorder Post traumatic stress disorder Social anxiety disorder

Off-label Alcoholism Insomnia IBS

SSRIs – Mechanism of Action Inhibition of CNS neuronal reuptake of

serotonin Weak affect on norepinephrine and

dopamine reuptake Varying affinity for muscarinic, GABA,

benzodiazepine, alpha1, alpha2, beta-adrenergic, dopaminergic, histaminergic receptors

SSRIs – Safety in PregnancyCategory C:CitalopramEscitalopramFluoxetineSertralineFluvoxamine

Category D:Paroxetine Cardiac malformations (primarily ventricular and atrial

septal defects

Persistent Pulmonary Hypertension of the Newborn (PPHN)

Overview Occurs when pulmonary vascular resistance remains elevated

after birth Results in right-to-left extrapulmonary shunting of blood through

fetal circulatory pathways Leads to inadequte pulmonary perfusion severe hypoxemia,

respiratory distress, and acidosis that may not respond to conventional respiratory support

Epidemiology Incidence – 1-2 per 1000 births Prevalence of resulting neurologic disability – 15-60% Mortality – nearly 40%

SSRIs and PPHN

Hypothesized that SSRIs accumulate in the lungs where they increase

pulmonary vascular resistance due to their vasoconstrictive properties.

In addition, higher circulating levels of serotonin in the fetal lung may

result in proliferation of pulmonary smooth-muscle characteristic of

PPHN due to the neurotransmitter’s mitogenic and comitogenic

properties. SSRIs also inhibit the synthesis of nitric oxide, a vasodilator

important to regulating vascular tone in utero and postnatal life.

Selective Serotonin Reuptake Inhibitors and Risk of Persistent Pulmonary

Hypertension of the Newborn

Chambers et al.

N Engl J Med 2006; 354:579-587

Chambers et al.

Objective To assess whether PPHN is associated with exposure to SSRIs during late

pregnancy

Study Design Retrospective, case-control study

Methods Subjects from 97 institutions in four major metropolitan areas were identified

between 1998 and 2003 Admission/discharge records and NICU logbooks reviewed for PPHN patients Weekly telephone calls made to community hospitals with PPHN patients that

might not have been referred to major centers

Chambers et al.

Selection of patients and controls Diagnostic criteria for PPHN

Gestational age > 34 weeks Severe respiratory failure after birth

Need for intubation and mechanical ventilation

Evidence of pulmonary hypertension 5% or greater gradient between preductal and postductal oxygen saturation Echocardiographic evidence

Exclusion Criteria Evidence of any cardiac anomaly except for patent ductus arteriosus, patent foramen

ovale, atrial septal defect, or a single muscular ventricular septal defect

Control group Infants born after 34 weeks No malformations Matched based on hospital and date of birth (+/- 30 days)

Chambers et al.Assessment of exposure Nurses conducted interviews with mothers of patients and

controls within six months of delivery Demographic characteristics Medical/obstetrical history Habits and occupations Use of all medications (including OTC) from the period of two

months before conception to the end of pregnancy Specifically asked about medication for depression (name, indication, dose, start/stop

dates, frequency and amount taken) Recall was enhanced by calendar that highlighted individual menstruation history

Antidepressants classified as “SSRIs” or “other” SSRIs evaluated – citalopram, fluoxetine, paroxetine, sertraline Others – amitriptyline, imipramine, nortriptyline, bupropion, venlafaxine,

trazodone Late pregnancy defined as 20 weeks after the first day of the

last menstrual period until delivery

Chambers et al.Results637 enrolled – 377 diagnoses matched w/ 836 controlsFrequency of death up to interview

- 3% in PPHN group vs. 0% in control groupCrude Any antidepressant / any time (OR 1.3) SSRIs only / any time (OR 1.5) SSRIs only / before 20th week (OR 0.3) Any antidepressant / after 20th week (OR 2.9) SSRIs only / after 20th week (OR 5.1)Adjusted Maternal diabetes, race/ethnicity, BMI, NSAIDs, alcohol, tobacco Any antidepressant / after 20th week (AOR 3.2); p=0.008 SSRIs only / after 20th week (AOR 6.1); p=0.001 SSRIs only / after 26th week (AOR 6.1)

Chambers et al.Conclusions Findings may be consistent with transient

complications in 20-30% of newborns with late exposure found in other studies tachypnea, failure to cry, cyanosis, etc.

Exposure to non-SSRI antidepressants not associated with PPHN

Exposure to SSRI in first half of pregnancy not associated with PPHN

BMI, smoking, diabetes, NSAID use in late pregnancy did not attenuate association

6-fold increased risk in developing PPHN with late exposure to SSRIs

Chambers et al.

Limitations Retrospective design

Inaccurate recall Other medications?

Small amount of PPHN diagnoses in infants with late exposure to SSRIs Difficult to analyze specific dosing/drug

Selective serotonin reuptake inhibitors during pregnancy and risk of persistent

pulmonary hypertension in the newborn: population based cohort study from the

five Nordic countries

Kieler et al.

BMJ 2012;344:d8012

Kieler et al.

ObjectiveAssess whether the use of SSRIs duringpregnancy increases the risk of PPHN, andwhether such an effect might differ betweenspecific SSRIs

Study DesignMultinational, population based cohort study

Kieler et al.MethodsObtained data from: medical birth registers

Maternal characteristics, pregnancy, delivery, neonatal period, ICD-10 codes

prescription registers Dispensed substances, formulations, dates

cause of death registers Date and cause

Patient registers Admissions to hospital, discharge, primary/secondary diagnoses

Danish Psychiatric Central Register Psychiatric diseases

Kieler et al.

ExposuresSSRIs

Fluoxetine, citalopram, paroxetine, sertraline, escitalopram

Other antidepressants (subanalysis) Clomipramine, venlafaxine, imipramine, amitriptyline, duloxetine,

dosulepine, milnacipran, trazodone, nefazodone, moklobemide

Ever use Three months before start of pregnancy until delivery

Late pregnancy 140 days after start of pregnancy until delivery

Early pregnancy Three months before start of pregnancy until pregnancy length of 55

days

Kieler et al.

Participants Identified those born after 33 weeks

between 1997 and 2006 in Denmark, Finland, Iceland, Norway, and Sweden

Exclusions meconium aspiration

most common cause of PPHN

Kieler et al.

Results1,618,255 births 11,014 with late SSRI exposure

33 (0.29%) PPHN diagnoses (AOR 2.1) 17,053 with early SSRI exposure

32 (0.19%) PPHN diagnoses (AOR 1.4) 1,588,140 with no exposure

1,935 (0.12%) PPHN diagnoses 3,130 with other antidepressant exposure

3 (0.09%) PPHN diagnoses (early AOR 0.6; late AOR 2.9) Previous hosptial stay for psychiatric disorder(not using antidepressants)

AOR 1.3 Previous psychiatric hospital stay (using antidepressants in late pregnancy

AOR 3.1

Absolute risk for PPHN = 3 per 1000 births

Kieler et al.

Conclusions Use of SSRI after 20 weeks gestation is

associated with a risk for developing PPHN of 3 per 1000 liveborn infants

Specific SSRIs have similar increased risks of PPHN suggests class effect

Incidence of PPHN most likely not associated with disease state alone

Kieler et al.Strengths Large study Used information from health registers (avoid inaccurate recall) Multinational, population based

Limitations Exposure measured as dispensed drugs, not ingestion No assessment of exposures to more than one antidepressant PPHN and symptomatic patent ductus arteriosus share ICD code Analysis only before 8 weeks and after 20 weeks gestation

Cardiac development occurs between 5-22 weeks gestation

Additional StudiesMaternal use of selective serotonin re-uptake inhibitors and persistent pulmonary

hypertension

of the newborn.

Kallen B, Olausson PO

Pharmacoepidemiol Drug Saf. 2008 Aug;17(8):801-6 SSRI use in early pregnancy (OR 2.4) SSRI use in late pregnancy (OR 3.6)

Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not

with maternal use of selective serotonin reuptake inhibitors.

Wilson KL et al.

Am J Perinatol. 2011 Jan;28(1):19-24. Epub 2010 Jul 6.

11,923 births – 20 PPHN cases Cesarean delivery (OR 4.9) SSRIs used in second half of pregnancy (OR 0.0)

PPHN found in 5% of controls and none of case groups

Antidepressant use and risk of persistent pulmonary hypertension of the newborn.

Andrade S et al.

Pharmacoepidemiol Drug Saf. 2009 Mar;18(3):246-52. Five total PPHN cases SSRI use in 3rd trimester – PPHN prevalence of 2.14 per 1000 No SSRI use in 3rd trimester – PPHN prevalence of 2.72 per 1000

Conclusions

Study results are inconsistent Sample sizes are small Larger, more detailed studies are warranted Absolute risk for PPHN remains low Several health issues resulting from untreated maternal

depression Benefit of treatment with SSRI seems to outweigh the

risk Choice of specific SSRI is of minor importance Health professionals and patients should continue to

discuss treatment options until further research is conducted

Back to the patient case…

Is it appropriate to use an SSRI in thispatient if she becomes pregnant?

Yes. There is inadequate evidence available tosupport avoiding SSRI use in pregnancy due to

anassociation with PPHN. Risks vs. benefits oftreatment should be discussed in detail with thepatient.

Back to the patient case…

Plan Continue sertraline 50mg PO qdaily

Have pateitn follow up regularly with psychiatrist

Discuss with family/loved ones about supportive care and monitoring for suicidal and risk-taking behaviors

Counseling If patient desires to discontinue SSRI, strongly

suggest discussion with doctor first about risks vs. benefits and tapering

References Persistent newborn pulmonary hypertension. Medscape Reference.

http://emedicine.medscape.com/article/898437-overview. Accessed April 21, 2012.  

Drug safety and availability. U.S. Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm283375.htm. Accessed April 21, 2012. 

Santoro K, Peabody H, Schoenman J, et al. Identifying and treating maternal depression: strategies & considerations for health care plans. National Institute for Health Care Management Foundation . http://nihcm.org/pdf/FINAL_MaternalDepression6-7.pdf. Published June 2010. Accessed April 21, 2012 

Wickersham RM, ed. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwerhealth; 2012. http://online.factsandcomparisons.com . Accessed April 21, 2012. 

Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacology & Therapeutics. 1999;85(2000):11-28. 

Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354(6):579-587. 

Andrade AE, McPhillips H, Loren D, et al. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiology and Drug Safety. 2009;18:246-252. 

Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ. 2011;344:d8012.

Kallen B, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension

of the newborn. Pharmacoepidemiol Drug Saf. 2008 Aug;17(8):801-6.

Wilson KL, Zelig CM, Harvey JP et al. Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol. 2011 Jan;28(1):19-24. Epub 2010 Jul 6.