Maternal Depression and Prematurity Sharon Hammer MD

1. Maternal Depression and Prematurity Sharon Hammer MD Assistant Professor Psychiatry UNMC

4. Develop a more comprehensive view of perinatal depression. • Understand the risk/benefit decision-making needed for use of ADs during pregnancy. • Review the literature to appreciate the controversies regarding risk of preterm birth in SRI-treated pregnant women.

5. Perinatal Depression • Usually represents recurrent depressive illness. • Average age onset MDD is early 20’s or teen years in high risk women (FH depression plus adverse early environment.) • Anxiety and depressive disorders are the most common chronic medical disorders of childbearing years.

6. Rates of Depression in OB Practices • 10% pregnant women in suburban clinics. • 20% in urban medical center clinics. Half of the depressed women had discontinued ADs when becoming pregnant. Only 14 % were receiving any form of treatment for their depression. Marcus, Journal of Women’s Health, May 2003; 12(4)

7. Exposure to Maternal Depression Exposure to Antidepressant Medication

8. Risk of Recurrence of MDD During Pregnancy Relapse of Major Depression During Pregnancy in Women Who Maintain or Discontinue Antidepressant Treatment • Cohen JAMA 2006 Vol. 295, No.5

9. First prospective study evaluating risk of relapse. Women recruited from perinatal psychiatry clinics in 3 U.S. sites. During pregnancy: 26% of women who maintained medication relapsed. 68% of women who discontinued medication relapsed.

10. When relapse occurs, it occurs early: 50% relapsed during first trimester. 90% relapsed by end of second trimester Predictors of relapse: History of recurrent MDD for > 5 years. History of 4 or more depressive episodes.

11. Why Perinatal Depression Matters Ripple Effects of Perinatal Depression Epigenetic effect Pregnancy outcomes Neonatal effects Postpartum Depression Childhood exposure to depressed mom

12. Impact of Depressed Mothers Infant attachment Cognitive Development in children Emotional Regulation in children

13. Major Depression is a physiologic illness that presents with psychological symptoms • Alterations in Hypothalamic-Pituitary-Adrenal Axis • Alterations in Cortisol Rhythm • Measurable Sleep and EEG Changes • Alterations in Neurotransmitter Levels • Changes in Neuroimaging and EEG Studies

14. Epigenetics in Psychiatric Illness The in-utero environment affects promotor region of genes to either inhibit or accelerate their expression. • MDD and anxiety creates a state of chronic physiologic stress and alters HPA-axis function that affects the in-utero environment. • These changes in the in-utero environment result in “fetal programming” that affects the offspring’s risk of medical and psychiatric illness throughout the lifespan.

15. Overkalix Study Effect of availability and prices of food on future offspring in isolated Swedish village. An individual’s risk of cardiovascular disease and diabetes and overall mortality rate was affected by whether or not their grandmother had been exposed to “feast” or “famine” while in-utero. KaatiEur J Human Genetics 10(11)

16. Epigenetics and the Brain • 20,000 genes in human DNA • 50% of genes are expressed only in the brain. • The brain is the most plastic and metabolically active organ in the body. • Brain is highly sensitized to the in-utero environment resulting in fetal programming that changes gene expression.

17. Serotonin Transport Gene5-HHTLPR • Variants of 5-HHTLPR are associated with expression of anxiety, depression and anger. • Dutch Study: 1500 women and their infants genotyped. • Maternal anxiety assessed at 20-weeks and infant temperament at 6-months of age. PluessBiol Psychiatry 2011;69

18. Babies with short-variant of the gene exhibited significantly higher rates of temperament abnormalities if they were exposed to maternal anxiety in-utero compared with babies with the same genetic variant who were not exposed to maternal anxiety in-utero.

19. Effects of MDD on Pregnancy Increased physiological “stress load” in depressed pregnant women. • HPA-axis hyperactivity and higher levels of cortisol and ACTH have been linked to increased risk of preeclampsia. • Finnish study showed 2.5 to 3-fold increased risk of developing preeclampsia during pregnancy. • Depressed women require more analgesia during labor and delivery and have more forcep and C-section deliveries.

20. Women obtain less prenatal care. • Take fewer prenatal vitamins. • Higher rates of alcohol and illicit drug use during pregnancy. • Poorer quality sleep. • Gain less weight during pregnancy. • Smoke cigarettes more often.

21. Neonatal Outcomes Infants born to depressed mothers show a variety of physiologic abnormalities. • Display elevated baseline cortisol levels and disrupted circadian rhythm patterns that persist for the first 2 years of life. • Exhibit exaggerated behavioral and cortisol stress responses.

22. The cortisol changes in neonates have been correlated to motor and sleep changes. • Babies are less active in-utero to acoustic stimulation and have poorer quality movements and decreased muscle tone at birth.

23. More disrupted sleep patterns that persist over the first several months of life. • Display the same pattern of reduced brain electrical activity over the left frontal lobe on EEG as seen in depressed adults.

24. Antenatal depression and risk of depression in offspring Prospectively followed 4500 pregnant women and their offspring in Avon region of England. Assessed mothers and fathers for antenatal and postnatal depression using EPDS. Maternal and paternal PND associated with higher rates of depression in their adolescents offspring at age 18 but only for parents with lower education levels.

25. Paternal AND had no effect on offspring. Maternal AND was associated with higher rates of depression in adolescents and was not mitigated by any risk factors. Risk pathways to offspring from AND and PND are different. AND risk pathway may be more biologically determined since not mediated by environment factors. Pearson, JAMA Psychiatry Supplement October 9, 2013

26. Offspring of Depressed Parents: 20 Years Later • Cohort of offspring of moderately to severely depressed parent for 20 years. • 3-times rate of depression than the gen. pop. • Earlier age of onset, between 15 and 20 years, especially in girls. • 3-times rate of anxiety disorders. • 3-times rate of substance abuse. Weissman, Am J Psychiatry 163:6, June 2006

27. As the population ages, offspring are showing a higher rate of medical illness and mortality. • Significantly higher rate of cardiovascular illness. • Hypothesis: Chronic HPA-axis dysfunction results in altered immune and platelet function.

28. “Antenatal major depression represents a child’s earliest adverse life event” and “contributes to a child’s subsequent vulnerability to adulthood illness.” Misri Can J Psych 2004 49(10) Henry Clin Obstetrics and Gynecology 2004

29. Studying Antidepressant-Use in Pregnancy What is exposure? Exposure to SRI + illness (no remission or partial remission) + psychosocial risks (abuse, poverty, lack of access to healthcare) + environmental exposures (diet, pollution) + stress (cortisol HPA-axis dysregulation) result in outcome.

30. Antidepressants in Pregnancy SRIs are the most studied group of drugs used during pregnancy. >30,000 studies published looking at pregnancy outcomes. About 7% of U.S. women use an SRI at some point during their pregnancies.

31. Limitations in SRI-exposure studies Best study design is controlled, prospective studies but expensive, time-consuming therefore number of study subjects is generally low. Retrospect or chart review studies use much larger number of subjects but are limited by: Recall bias on part of patients. Use of pharmacy records to define “exposure.” (15% have no measurable drug levels.) Differing assessments for and definitions of depression. Failure to assess for depression in SRI-exposed patients. Failure to account for confounders (use of tob, Etoh, SES and depression severity)

32. There is no true control group for women who take SRIs during pregnancy. • Only depressed or anxious women take SRIs during pregnancy so are outcomes measuring the SRI, the effects of residual mental illness, a persistent biologic risk factor in depressed women or a combination? • Women with more severe psychiatric illness are the ones most likely to continue medication during pregnancy. • It is not possible to study the effects of SRI-use during pregnancy in the absence of maternal mental illness. • There will never be a perfect data set.

33. What does the literature show? Some studies show that both SRI-exposure during pregnancy and antenatal major depression are associated with increased risk for preterm delivery while some studies do not show increased risk with either type of exposure.

34. Neonatal Outcomes After Prenatal Exposure to SRIs and Maternal Depression Population data health and prescription records were evaluated for 119,547 women who delivered babies over a three year period. • 14% of mothers had antenatal depression diagnosis. • 3.7% took antidepressants during pregnancy. • Compared neonatal outcomes in women diagnosed with depression with no SRI-use to women diagnosed with depression who took SRIs during pregnancy and group with no depression, no SRI-use. Oberlander, Arch Gen Psychiatry 2006:63(8)

35. Neonatal Outcomes Evaluated • Birth weight • Percentage born < 37 weeks • Length of hospitalization > 3 days • Incidence of adverse neonatal symptoms: respiratory distress jaundice feeding difficulties neonatal seizures

36. Maternal characteristics used for matching to reduce confounders • Number visits to psychiatrist • Numbers of times diagnosed depressed • Number of additional mental health diagnoses • Prescriptions for antipsychotics or TCAs • Number of prenatal visits • Income • Age

37. Study Results • Women who took SRIs during pregnancy were substantially different from depressed women who did not take SRIs during pregnancy. • Diagnosed as have depression 4X more than unexposed depressed group. • Visited psychiatrists 5X more than unexposed depressed group. • 3X more likely to have an another mental health diagnosis than unexposed dep group. (Indirect measures of mental illness severity.)

38. After matching for confounding variables: Depressed mothers who took SRIs during pregnancy did not differ in rates of preterm deliveries, average birth weights, feeding problems, jaundice or frequency of neonatal seizures from depressed mothers who did not take SRIs. Their infants were more likely to experience two adverse neonatal outcomes compared to mothers not taking SRIs: • respiratory distress • % of birth weights below the 10th percentile (very small difference)

39. “ . . . findings may suggest that previous studies failed to account for maternal illness severity, thereby attributing adverse neonatal outcomes to SSRI exposure rather than to maternal depression” for most adverse neonatal outcomes. Increased risk of respiratory distress did not disappear when confounding variables taken into account so it is likely a true effect of SRI-exposure.

40. Depression versus SRI-exposure during pregnancy outcome study Prospective, observational study assessed women at 3 times during pregnancy for depression. (N=238) • No depression, no SRI (N=131) • Continuous SRI-exposure (N=14) • Partial SRI-exposure (N=23) • Continuous depression, no SRI (N=14) • Intermittent depression, no SRI (N=22) SRI-exposure confirmed by serum levels. Wisner, American Journal of Psychiatry 2009; 166; 557-566

41. Untreated depressed women had significantly more severe depression ratings and worse global function than treated women. Untreated depressed women were more likely to have > one alcoholic beverage per week. Tobacco use was the same among all groups.

42. Both of the groups exposed to continuous depression alone and continuous depression plus SRIs had rates of preterm birth exceeding 20% with the same proportion of late-and early-preterm births. Non-depressed, non-exposed group had a 6 to 7% preterm birth rate.

43. Rates of Preterm Birth adjusted for Maternal Age and Race No SRI, no depression ----- Continuous SRI-exposure 5.43 Continuous depression, no SRI 3.71 Partial SRI-exposure 0.86 Intermittent depression, no SRI 1.04

44. What are the study’s implications? Factors independently related to active depression and SRI-treatment during pregnancy are associated with preterm birth and the effects are the same order of magnitude. OR

45. A factor common to pregnant women with depression who stay off medications and those who choose continuous medication treatment is related to preterm birth. “The underlying depressive disorder and its sequela may constitute a long-term disease risk- factor independent” of depression symptom levels during pregnancy.

46. The observation that partial-depression exposed and partial SRI-exposed groups did not have higher rates of preterm births suggest that “the chronicity or the severity of depression affect reproductive outcomes” rather than SRI-exposure alone.

47. Final Thoughts • There is a false dichotomy between the interest of the infant and the interest of the mother. • Need to consider depression during pregnancy like any other chronic health problem during pregnancy – there are consequences to mother and baby of treating as well as not treating the condition. Both set of risks must be taken into account when making treatment decisions.