# Presentation: 003369

## Neonatal Antidepressant Effects 

- Katherine L. Wisner, M.D., M.S.
- Professor of Psychiatry, Obstetrics and Gynecology and Reproductive Sciences and Epidemiology
- Director, Women’s Behavioral HealthCARE
- Western Psychiatric Institute and Clinic/University of Pittsburgh Medical Center

## Goals 

- Risk-benefit decision making for treatment of depression during pregnancy
- Conceptualization of diagnosis and criteria for classifying neonatal effects after in-utero exposure to SSRI
- Assessment strategies; NIMH R01 60335: Antidepressant Use during Pregnancy

## Gender Differences in Prevalence of  Major Depression

- Women have 1.5-2.5 x the rate of depression relative to men between ages 15-54

- Kessler et al (1993) Journal of Affective Disorders

**Notes:**
Women are approximately 1.7 times as likely as men to report a lifetime history of MDE. Sex difference begins in early adolescence (age 10) and persists through the mid-50s. The sharp divergence in the 50’s is based upon a small sample size and not thought to be reliable.

Sex difference in depression is most pronounces among early adolescents, with the highest relative hazard of first onset (OR=2.3) in the age range 10-14.

This is a consistent finding throughout the world, regardless of how depression is diagnosed.

Since women are no more likely than men to be chronically depressed or to have ana acute recurrence in the past year – therefore higher prevalence is due to higher risk of 1st onset.
The NCS was a congressionally mandated survey with the specific goal of studying the comorbidity of psychiatric disorders. 8000 individuals, ages 15-54 interviewed. Used a supplemental nonresponse survey, with financial incentive, based on previous evidence that survey nonresponders tend to have higher rates of psychiatric d/o.

A structured psychiatric interview (DIS-diagnositc interiew schedule – can be administered by trained interviewers who are not clinicians) was administered to a representative US sample. Based on results that respondents underreport stem questions once they recognize that positive responses lead to more detailed questions, they used a life review section before probing any positive stem responses and to facilitate active memory search for lifetime episodes.

Anxiety d/o have an approximately 5% 1-yr prevalence form the same study

## Risk-Benefit Decision-Making for Depression during Pregnancy:  A Framework

- Wisner et al:  Risk-benefit decision-making for treatment of depression during pregnancy.  *Am J Psych 157: 1933, 2000*
- Healthy outcomes for mother and baby are the rule rather than the exception!

## Slide 5

## Prospective Data for Application to Model

- Wisner et al, *JAMA 1999;282:1264-1269*
- SSRI are not major morphological teratogens; therefore, they are commonly used and other reproductive outcomes have been observed
- Poor neonatal adaptation in 31.5% of infants in late-exposed group, 8.9% in early-exposure group for fluoxetine (*Chambers et al, NEJM)*

## Maternal Mental Health and Obstetric Complications

- Association of maternal depression OR 2.5 (1.1-5.4) & anxiety OR 3.2 (1.4-7.4) with preeclampsia (Kurki et al 2000; Obstetrics and Gynecology)
- Significant association between uterine artery resistance index and Spielberger state/trait anxiety scores (Teixeira et al 1999; British Medical Journal)
- Fetal growth restriction
- Preeclampsia

## Association of Maternal Stress, Anxiety, and Depression, with Altered Fetal Behavior

- Increased CRH during pregnancy was associated with decreased fetal responses to a novel stimulus (Sandman et al 1999; Ann NY Acad Sciences)
- Simulated and real stress was associated with altered fetal HR variability
- Suggestive of increased sympathetic activation
-  Delayed return of HR to baseline (Monk 2001; Psychiatric Quarterly)
- Infants of depressed mothers are irritable and difficult to console

## Depression and its Concomitants Affect Multiple Domains of Perinatal Health 

- Symptoms of Depression=physiological dysregulation
- Appetite changes/food choice
- Cognitive changes/educational needs
- Psychosocial relationships
- Prenatal care compliance
- Use of other drugs/smoking
- Choice of feeding methods

## Misra, Am J Prev Med  25:65, 2003

## Toon

## Do all SSRIs Increase Risk for  Neonatal Complications?

- Fluoxetine
- 4-fold increased rate
- Likely to develop by 4 hours of life [Long half-life (7 days; active metabolite with longer half-life)]
- Paroxetine
- Most commonly identified in the case reports
- High variability in time of onset (birth – 5 days postpartum)
- Anticholinergic – thus potentially associated with cholinergic overdrive
- Sertraline, citalopram, fluvoxamine
- Make inferences based on pharmacology

## Placental Passage of SSRIs

- Placental passage = _[SSRI] umbilical vein_
-                         [SSRI] maternal serum
- 					                     Potency of serotonin
-                                 Placental Passage	            inhibition (IC50)
- Sertraline, paroxetine	0.29 (lowest)		0.19; 0.29
- Citalopram, fluoxetine	0.89			1.8; 6.8

- Hendrick et al 2003; AJP

## Neonatal SSRI Pharmacology

- High interindividual variability
- Preterm/full term status
- Exposures to additional drugs (CYP inducers/inhibitors)
- Overall health of newborn
- Genetic polymorphisms
- 8% of Caucasians and 2% African Americans are poor metabolizers due to CYP 2D6 genotype
- Activity of serotonin catabolic and synthetic enzymes
- Availability of serotonin nutritional precursors

## “Poor Perinatal adaptation”

- Jitteriness
- Hypo-thermia

- “Poor Perinatal adaptation”
-              (Chambers et al 1996)

- “Serotonin overstimulation”
-    (Laine et al 2003)

- Tachypnea/ respiratory distress/ desaturation on feeding
- Hypoglycemia
- Poor tone
- Weak/absent cry

- Myoclonus
- Restlessness
- Tremor
- Shivering
- Hyperreflexia
- Nausea
- Involuntary movements
- Rigidity

## Symptom Domains in Neonates Exposed to SSRI

- Feeding/Digestive disturbance
- Sleep disturbance
- Temperature regulation disturbance
- Respiratory disturbance
- Tone disturbance
- Metabolic disturbance
- Nonspecific symptoms

## Current Questions

- What symptoms characterize this syndrome(s)?
- What is the incidence of this syndrome(s)?
- Is the neonatal behavioral syndrome consistent with drug withdrawal or intoxication (and when does neurobehavioral teratology begin)?
- Are all SSRIs equally likely to cause a neonatal behavioral syndrome?
- Because the risks of not treating depression often outweigh the risks of treatment, what strategies can prevent, minimize, or treat these symptoms in order to improve maternal and infant health outcomes?

## Finnegan Scale Modification for Gestational SSRI Exposure

- Addition of items described in SSRI literature review
- Removal of items specific for narcotic withdrawal
- Research is needed to establish time course-symptom set relationships, and clinical severity thresholds which dictate specific interventions

## NIMH R01 60335Antidepressant Use During Pregnancy

- Naturalistic Study-Pregnancy and 24 months post-birth; multiple outcomes assessed
- 1- pregnant women with depression, not medicated (+dep/-drug)
- 2- not depressed, taking antidepressants (-dep/+drug)
- 3- normal controls (-dep/-drug)
- 4- [+dep/+drug]

## Substudy Design

- At week 36:  risk benefit discussion, mothers choose:  1) to taper drug 2 weeks before EDC (or d/c fluoxetine) and re-start immediately after birth, or 2) continue drug through the remainder of pregnancy.
- Weekly SIGH-ADS monitoring from weeks 36-birth for depression assessment in mothers.
- Outcomes in mothers and infants (Birth, 2 wk; 3,6,12,18 and 24 mo) will be compared across the groups.

## Current Questions 

- Does taper regimen (or d/c Fluox) affect the near-term fetus _in utero_?
- Does the behavior of infants born to mothers who taper compare to unexposed infants?
- Do mothers become symptomatic during the taper phase?
- Does re-starting medication at birth prevent recurrence of the depressive episode?
- Does breastfeeding provide any protection by exposure through breastmilk?

## Assessment Strategies

- Rater is blind to exposure status/hypotheses
- Maternal serum/Cord blood antidepressant level; mother breastfeeding baby level wk 3
- Cry analysis (B, 2 week)
- Pediatric neuro exam/neurobehavioral assessment (B, 2 week)
- Modified Finnegan Scale (B, 2 week)

## b

## b

## Potential Strategies to Manage Toxicity

- Parental education/cognitive strategies
- Taper/stop maternal drug prior to due date if risk of maternal illness doesn’t outweigh risk of complications
- Conservative management strategies
- Frequent small feedings /high calorie
- Swaddling
- Severe symptoms (Hypothetical only, dose ranging safety and efficacy study and clinical trial needed)
- Cyproheptadine?
- Add back low doses of fluoxetine if withdrawal symptoms emerge

## Potential Strategies to Manage Withdrawal

- Lactation may provide minimal additional dose to reduce rapid drug concentration drop
- Conservative management strategies 		Frequent small feedings/high calorie
- Swaddling
- Pharmacologic treatment with same drug, lower concentrations; hypothetical, requires dose ranging safety/efficacy study and clinical trial

## Mental Healthis Fundamental to Health

*David Satcher, M.D.*