1. DEPRESSION DURING PREGNANCY TREATMENT WITH ANTIDEPRESSANTS
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Hello, and welcome Uwaterloo Pharmacy Students and McMaster Medical Students. My name’s Amanda Tavone, I’m a fourth year Uwaterloo Pharmacy Student. I’ll be giving a talk on depression during pregnancy.
Much less is known about effect of depression on pregnancy, the fetus, the neonate, and the mother, compared with the impact of antidepressants.
Amanda Tavone,
BSc. Pharm Candidate, BSc. Hon

2. Outline Prevalence of Depression in Pregnancy Risk Factors Etiology
Impact of Depression
Antidepressant Use During Trimesters
Impact of Antidepressant Use
Approach for Antidepressant Treatment During Pregnancy
Example

3. Aren’t Pregnant Women Usually Happy?
Pregnancy traditionally thought to be a time of emotional wellness
Current studies show that it is a high risk period for psychiatric illness in females, especially for those who have pre-existing psychiatric disorders
De las Cuevas, Carlos and Sanz2, Emilio J. Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy. Current Drug Safety, 2006, 1,

4. Prevalence of Depression During Pregnancy
Rates of mood disorders in women are approximately equal in pregnant and non-childbearing women
Prevalence of major depression in pregnant women is between 3.1% to 4.9%
Major/minor depressive episodes between 8.5% to 11%
In the literature, stated to be between 15-25%. Take home message: prevalent
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

5. Risk Factors for Depression during Pregnancy
Similar to those for postpartum depression:
History of depression
Lack of social support
Unintended pregnancies
Low socioeconomic status
Domestic violence
Marital status: Single
Anxiety
Stressful life events
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

6. Post-Partum Depression
Women with depression while pregnant have an increased risk of postpartum depression
Impact on the health of both mothers and infants
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

7. Etiology
Hypothesized role of changes in hormone concentrations during pregnancy and the postpartum period
Interactions and feedback systems occur between the hypothalamic-pituitary-ovarian (HPO) axis and the hypothalamic-pituitary-adrenal (HPA) axis
Evidence is starting to show a link between the HPA axis and psychological stress during pregnancy
Women’s cortisol levels higher when they have negative moods. We already know this for stress in regular people
Currently, minimal evidence to show a cause or symptomatology of depression that is different from pregnancy and other stages in life
Depressive symptoms are the same in pregnant women
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

8. Hypothesized Model: Maternal Depression
Maternal depression and low bw and prematurity is mediated by maternal cortisol and norepinephrine
Prenatal cortisol leves related to prematurity
Nore related to low BW
Certain studies showing depressed moms have lower dopamine levels during pregnancy, and infants had lower brazelton scale scores. “Infants of withdrawn moms, had highest cortisol levels, lowest dopamine and serotonin and asymmetrical EEG patterns.” Field et al.
Field, T., Diego, M., Hernandez-Reif, M. Prenatal depression effects on the fetus and newborn: a review
Infant behavior & development 29 (2006) 445–455

9. Depression During Pregnancy
Fetus may be directly affected by neurobiological substrates of depression, such as glucocorticoids, which cross the placenta
Fetus may be indirectly affected by neuroendocrine mechanisms in which depression modifies physiological maintenance of pregnancy
Indirect effect: hyperactivity of pituitary-adrenal axis, induces placental hypersecretion of corticotropin releasing factor, increases mymoetrial contractility, causing preterm delivery or abortion
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

10. Impact of Depression During Pregnancy

11. Impact of Depression During Pregnancy
Poor health behaviours of the mother:
Poor eating
Poor sleep
Subsequent OTC use
Alcohol
Tobacco
Caffeine
These may also have affects on the fetus
Continuing onward..

12. Impact of Depression on pregnancy, the fetus, and the neonate
Few studies have looked specifically on the impact of depression
Articles that show low birth weight, but current review article states inconclusive
Relationship to low birth weight is inconclusive, though previous articles have labelled low birth weight as one of the leading causes of fetal morbidity and mortality
Field et al., 2006
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

13. Impact of Depression
Studies that have focused on depression during pregnancy have shown a correlation with poor obstetrical outcomes including:
Preterm delivery (less than 37 weeks)
Postpartum depression
Neonatal symptoms (i.e. Behaviour)
Higher rates of placental abnormalities
Pre-eclampsia
Spontaneous abortion
Neonates requiring intensive care for postnatal complications
Low birth weight, fetal growth retardation, infants have growth retardation over first year of life. Other articles state that low birth weight is inconclusive. Some of the points above are also labelled as inconclusive in terms of evidence of outcome. See chart from Chaudron included on website.
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: Field T, Diego M, Hernandez-Reif. Prenatal depression eeffects on the fetus and newborn: a review. Infant Behavior and Development 29 (2006):

14. Impact of Depression Birth outcomes Neonatal outcomes
Maternal outcomes

15. Impact of Depression Birth Outcomes- Effects on Growth
Study of pregnant women compared the effects of untreated depressive symptoms, use of SSRIs, and no depressive symptoms or use of SSRIs
Prospective population based study from fetal life onward
N=7696 pregnant women included pregnant mothers (91.3%) had no or low depressive symptoms, 507 pregnant mothers (7.4%) had clinically relevant depressive symptoms and did not take SSRIs, and 99 pregnant mothers (1.3%) took SSRIs
SSRI use was assessed by questionnaires in each trimester and verified by pharmacy record
Measures: fetal ultrasonography at each trimester. Fetal body and head growth measured repeatedly
Pregnant women who were untreated for depressive symptoms had lower total fetal body growth (-4.4g/wk, 95% CI: -6.3 to -2.4; p<.001) and head growth (-.08mm/wk; 95% CI: to -0.03; p=.003) re
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:
Marroun EH et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry 2012; 69:

16. Impact of Depression : Neonatal Outcomes - Behavioural
More than one study showed that depression during pregnancy was correlated with greater developmental delays in infants
Both of these studies were self-reports of depression
Another study that used more objective assessments for depression did not have the same relationship
Ref 26, 27, 28
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

17. Impact of Depression on: Neonatal Outcomes- Behavioural
Increased risk for irritability
Decreased activity and attentiveness
Fewer facial expressions
Their negative effects continues into later infancy and their cortisol responses to mild stress can cause negative effect when toddlers.
Infants have been shown to have inferior mental, motor and emotional development, and later social and emotional problems during childhood.
Include a number of small sample populations that use scoring
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: Field T, Diego M, Hernandez-Reif M: Prenatal depression effects on the fetus and newborn: a review. Infant Behav Dev 2006; 29:

18. Impact of Depression During Pregnancy on the Mother
Vegetative symptoms
Self-harm
Suicide
Psychosis
Depression and anxiety in early pregnancy linked to pre-eclampsia?
We can’t forget the mom
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:
Kurki et al. Depression and anxiety in early pregnancy and risk for pre-eclampsia. Obstet Gynecol 2000; 95:

19. Antidepressant Treatment During Pregnancy

20. Treatment with Antidepressants
Majority of women with depression do not obtain treatment during pregnancy
So you can look at this and say well let’s treat then.... Especially after seeing the last few slides
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

21. Antidepressant Use in Pregnancy
Concern: all psychotropic medications pass through the placenta
Use of antidepressants during pregnancy has increased. This is also due to the overall increase in SSRI use.
In pregnant women SSRIs are most frequently prescribed, then SNRIs, TCAs, and rarely, monoamine oxidase inhibitors (similar to general population)
33) cohort
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

22. Antidepressant Use During Pregnancy
Rates of use during pregnancy are highest during the first trimester
Antidepressant use decreases from the first to the second to the third trimester
Rates of use during pregnancy are somewhat lower than those who take them before or after pregnancy.
Ironically though, depression has been stated to get worse throughout pregnancy from first to second. Field et al. 2006
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

23. Antidepressant Use During Pregnancy
Declining trend of antidepressant use throughout pregnancy terms may be due to third-trimester exposure and poor neo-natal adaptation syndrome
Treatment is usually inadequate during pregnancy; lower doses are taken.
May be due to concern from patient and provider about a dose-dependent correlation between exposure and obstetrical and neonatal outcomes (not supported by evidence)
Describe neonatal adaptation syndrome
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

24. Antidepressant Use During Pregnancy
Stopping antidepressants during pregnancy, puts women at a higher risk for recurrence of depression.
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

25. Antidepressant Use During Pregnancy
Cohen LS et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006; 295:
Prospective study analysis determined time to relapse of depression during pregnancy. n= 201
Result: Women who discontinued medication relapsed significantly more frequently over the course of their pregnancy compared to women who continued taking their medication. HR, 5.0; 95% CI, p<.001
Used DSM-IV criteria

26. Impact of Antidepressants During Pregnancy

27. Impact of Antidepressant Use During Pregnancy
Pregnancy loss
Growth reduction (reduced head growth, low birth weight, small for gestational age)
Preterm birth
Malformations
Neonatal adaption
Slower neonatal and infant motor development
Persistent pulmonary hypertension
Infant and child behavioural effects
Mother’s health
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:

28. Impact of Antidepressant Use During Pregnancy
Not all studies have shown associations between antidepressant use and outcomes
Difficult to determine cause and effect, since there are confounding factors, such as substance use, co-morbid conditions (i.e. anxiety) , socioeconomic status, ethnicity, prenatal anger, combined optimism and pessimism
In the literature it’s hard to determine cause and effect, because of confounding factors: withdrawn vs intrusive dperession, prenatal anxiet, prenatal anger, combined optimism and pessimsm. Ethnicity: african – american women tend to deliver premature babies.
High opimism but low pessimism- better less likely to deliver preterm infaants than those with high optimism and pessimism.
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170:
Field et al. Prenatal Depression effects on the fetus and newborn: a review. Infant Behavior and Development 29 (2006):

29. Birth Outcomes Taking a look at: Miscarriage Effects on growth
Malformations
Birth weight
Gestational Age
Preterm delivery

30. Miscarriage
Increased risk with use in early pregnancy 12.4% (10.8%-14.1%, n=1534) vs 8.7% (7.5% to 9.9%; n = 2033)
Objective of study: determine baseline rates of spontaneous abortions and whether antidepressants increased those rates
6 cohort studies of 3567 women (1534 exposed, 2033 unexposed). Matched on important confounders
Authors concluded that depression itself cannot be ruled out
Hemels ME, Einarson A, Koren G, Lanctot KL, Einarson TR. Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis. Ann Pharmacother May;39(5):803-9.

31. Effects on Growth
Prospective population-based study from fetal life onward
7696 pregnant women included in study: 570 pregnant mothers (7.4%) had clinically relevant depressive symptoms and used no SSRIs, and 99 pregnant mothers (1.3%) used SSRIs
SSRI use assessed by questionnaires in each trimester and verified by pharmacy records
Fetal ultrasonography done at each trimester
Reduced fetal head growth in mothers who used SSRIs (-0.18mm/wk, 95% CI: to -0.07, p= .003)
Higher risk for preterm birth (not statistically significant)
Marroun EH,  et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry. 2012 Jul;69(7): .

32. Malformations Structural Malformations No association between SNRI use
Conflicting data for TCA use
Conflicting data for SSRI use (specifically paroxetine)
Cardiac Malformations
No increase in rate with SSRI use (4 studies)
Increase risk in first trimester exposure to paroxetine (three studies). Not found in three other studies
Combination of SSRI and benzodiazepine may increase congenital heart defects
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

33. Low Birth Weight Increased risk with SSRI or TCA use
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

34. Small for Gestational Age
Small increased risk with SSRI use compared with depressed mothers who did not take SSRIs
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

35. Preterm Delivery Inconclusive relation
Some studies found an increased risk, others did not
More exposure, more likely to decrease gestational age
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

36. Neonatal Outcomes Behavioural Persistent Pulmonary Hypertension
Long term growth, IQ, Behavioural

37. Neonatal Outcomes Behavioural Persistent pulmonary hypertension
Increase in risk for irritability, jitteriness, seizures in mothers who took TCAs
Increase in risk for irritability, tachypnea, hypoglycemia, weak/absent cry and seizures in mothers who took SSRIs in late pregnancy
Persistent pulmonary hypertension
Conflicting data
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

38. Neonatal Outcomes Continued
Long term growth, IQ, behavioural
Limited Information
Most studies how no relationship with use of SSRIs or TCAs
Slower in reaching developmental milestones but “catch up” by 19 months
Possibility of increased risk to autism spectrum disorder?
IQ, language, development- no difference
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

39. Maternal Outcomes
Pregnancy-induced hypertension, pre-eclampsia, and eclampsia
Increased risk by approximately 50%
Limitations in studies: linked databases, control for depression and confounding risk factors, mother’s report of antidepressant use
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

40. Approach and Strategies
TREATING DEPRESSED PREGNANT WOMEN

41. General Approach to Treating Depression During Pregnancy
Obtain thorough history
Meet with patient to review risk and benefits at trimesters of pregnancy
Inter-professional collaboration with obstetrician, pediatrician, and psychiatrist
Identify triggers: have a plan if dose change needed
Encourage healthy lifestyle
Know limitations of studies
“Big Picture” Approach
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

42. When Should We Be Giving Antidepressants to a Pregnant Patient?
After thorough evaluation
Major Depression
Mild-Moderate depression: psychosocial supports, modify stressors
Treating depression during pregnancy can be difficult; no safe answer
Not treating depression can have serious consequences
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

43. Strategies for Using Antidepressants in Pregnancy
Monotherapy, if possible
Avoid first trimester exposure
Avoid first trimester antidepressant and benzodiazepine combinations
Continue using antidepressants if depression is severe
Taper dose, do not stop suddenly
Treat to remission
Use lowest effective dose
Tapering and d/c before delivery- not needed due to risk of recurrence of postpartum depression-
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

44. Non-Pharmacological Measures
Psychotherapy alone or in combination with antidepressants
Individual/group therapies
Bright light therapy
ECT (reserved for severe depression)
No reports of impact on fetal, neonatal, or birth outcomes
ECT- little evidence to show harm to fetus or mom, carefully monitor. Obstet Gynecol. 2009 September; 114(3): 703–713. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists,
Kimberly A. Yonkers, M et al.
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

45. Topics to be Discussed at Each Trimester

46. First Trimester Exposure
Known and unknown risks for:
Specific malformations
Pregnancy loss or miscarriage
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

47. Second Trimester Exposure
Effects on:
Fetal growth
Birth weight
Size for gestational age
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

48. Third Trimester Exposure
Effects on:
Birth weight
Size for gestational age
Risks for:
Persistent pulmonary hypertension
Neonatal adaptation syndrome
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

49. For The Clinician
Check out my website: depressionduringpregnancy.weebly.com

50. Read More Website for the clinician contains:
Pamphlet/Resource for your patients
Summary/review
Critical appraisal of literature
This presentation
Cited three review articles on depression and antidepressant use during pregnancy
Critical appraisal
Case reports- higher for paroxetine
Fluoxetine looks the best
These were in cuevas review

51. Summary
More is known about the effects of antidepressants on birth, neonatal, and maternal outcomes than depression itself
Keep in mind: many limitations in studies
For women with mild-moderate depression without a history of recurrent or severe depression, psychotherapy may be enough
If the patient’s history points to a need for an antidepressant-symptom severity, recurrence- consider treatment
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

52. Clinical Example

53. In Practice
A 25 year old woman comes into your family health team; 6 weeks pregnant.
History of recurrent major depression;
Medications for the past 5 years:
Fluoxetine 40mg/day,
Clonazepam 0.25 mg daily as needed
Had 1 suicide attempt; at 16 years old
Has been under the care of a psychiatrist since 13 years old. Has taken sertraline, citalopram, venlafaxine, lithium, olanzapine in the past.
Has psychosocial support from a therapist
Adapted from Chaudron 2013
Adapted from Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

54. In Practice
Mother has history of eating disorder, father and brother suffer from alcoholism
Miscarried 2 years ago at 7 weeks
Advice of the obstetrician: discontinue medication. Patient is worried that if she stops, she will relapse. She decreased her fluoxetine to 20mg 6 weeks ago and stopped clonazepam
Patient is worried about miscarriage, depressive relapse.
She is currently experiencing general anxiety and loss of appetite with some nausea.
Adapted from Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20

55. What do you think?

56. Monitor for anxiety and depression;
Avoid use of clonazepam: Combination of SSRI and benzodiazepine may increase congenital heart defects
Decreasing the dose of fluoxetine to 20mg may or may not be enough for our patient
Monitor for anxiety and depression;
If acute anxiety, clonazepam as needed?
If persistent anxiety or depressive symptoms that are not adequately met, may have to increase fluoxetine

57. Thank you
QUESTIONS?

58. References
Chaudron LH. Complex Challenges in Treating Depression During Pregnancy. Am J Psychiatry 2013; 170: 12-20
De las Cuevas, Carlos and Sanz2, Emilio J. Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy. Current Drug Safety, 2006, 1,
Field, T., Diego, M., Hernandez-Reif, M. Prenatal depression effects on the fetus and newborn: a review. Infant behavior & development 29 (2006) 445–455
Marroun EH et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry 2012; 69:
Kurki et al. Depression and anxiety in early pregnancy and risk for pre-eclampsia. Obstet Gynecol 2000; 95:
Hemels ME, Einarson A, Koren G, Lanctot KL, Einarson TR. Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis. Ann Pharmacother May;39(5):803-9