Antidepressant treatment modifies the association between maternal breastfeeding experience and HPA axis activation

Presented at The Pregnancy Meeting, San Franscisco, CA

Alison M. Stuebe, Roger Mills-Koonce, Samantha Meltzer-Brody, Chelsea Strange, Karen Grewen

Objective: Longer breastfeeding duration is associated with lower rates of postpartum depression, but the underlying mechanism is not known. We sought to quantify the association between maternal experience of breastfeeding and HPA axis activity.

Study Design: We analyzed data from the Mood, Mother, and Infant Study. Feeding intention was assessed in the 3rd trimester, and mood symptoms, antidepressant use, and breastfeeding intensity were assessed monthly in the first postpartum year. Breastfeeding experience was assessed using the Maternal Breastfeeding Evaluation Scale (MBSES). Maternal hair was collected at 6 months and analyzed utilizing liquid chromatography-tandem mass spectrometry to assess cortisol and cortisone levels over the prior 3 months. We used T tests, Pearson correlation, and linear regression to quantify associations between hair corticosteroids and antidepressant use, mood symptoms, breastfeeding intensity, and breastfeeding experience.

Results: Hair steroid levels were available for 179 participants, among whom 44 were taking antidepressants at 6 months postpartum. Antidepressant use was associated with higher hair cortisone than non-use (mean (se) 8.68 (0.97) vs. 6.36 (0.33), T test p=0.03), but not with cortisol or cortisol-to-cortisone ratio (p >0.05, Table). Hair cortisone was correlated with weight at the 6 month visit, and inversely correlated with breastfeeding intensity and MBSES, but it was not associated with mood symptoms. In multivariable regression models, we found that antidepressant use modified the association between MBSES and hair cortisone (interaction p=0.02, figure). Among women using antidepressants, a more positive experience of breastfeeding was associated with lower hair cortisone, whereas among women not using antidepressants, breastfeeding experience was not related to hair cortisone levels.

Conclusion: Among women being treated for depression, we found that maternal experience of breastfeeding was inversely correlated with hair cortisone levels. These data suggest that the affective experience moderates the effect of breastfeeding on maternal physiology.

Genome-wide gene expression changes in postpartum depression point towards an altered immune landscape

D. Mehta, K. Grewen, B. Pearson, S. Wani, L. Wallace, A. K. Henders, et al.

Maternal postpartum depression (PPD) is a significant public health concern due to the severe negative impact on maternal and child health and well-being. In this study, we aimed to identify genes associated with PPD. To do this, we investigated genome-wide gene expression profiles of pregnant women during their third trimester of pregnancy and tested the association of gene expression with perinatal depressive symptoms. A total of 137 women from a cohort from the University of North Carolina, USA were assessed. The main phenotypes analysed were Edinburgh Postnatal Depression Scale (EPDS) scores at 2 months postpartum and PPD (binary yes/no) based on an EPDS cutoff of 10. Illumina NextSeq500/550 transcriptomic sequencing from whole blood was analysed using the edgeR package. We identified 71 genes significantly associated with postpartum depression scores at 2 months, after correction for multiple testing at 5% FDR. These included several interesting candidates including TNFRSF17, previously reported to be significantly upregulated in women with PPD and MMP8, a matrix metalloproteinase gene, associated with depression in a genome-wide association study. Functional annotation of differentially expressed genes revealed an enrichment of immune response-related biological processes. Additional analysis of genes associated with changes in depressive symptoms from recruitment to 2 months postpartum identified 66 genes significant at an FDR of 5%. Of these genes, 33 genes were also associated with depressive symptoms at 2 months postpartum. Comparing the results with previous studies, we observed that 15.4% of genes associated with PPD in this study overlapped with 700 core maternal genes that showed significant gene expression changes across multiple brain regions (P = 7.9e-05) and 29-53% of the genes were also associated with estradiol changes in a pharmacological model of depression (P values range = 1.2e-4-2.1e-14). In conclusion, we identified novel genes and validated genes previously associated with oestrogen sensitivity in PPD. These results point towards the role of an altered immune transcriptomic landscape as a vulnerability factor for PPD.

PMID: 33664235

Associations of postpartum depression symptoms and infant feeding with Hypothalamic Pituitary Adrenal (HPA) axis reactivity

Presented at The Pregnancy Meeting, Grapevine, TX

Anna E. Bauer, Kathryn Wouk, Karen Grewen, Nisha C. Gottfredson, Samantha Meltzer-Brody, Cathi Propper, Roger Mills-Koonce, Brenda Pearson, Julia Whitley, Alison M. Stuebe

Objective: Both oxytocin and depression have been shown to blunt the HPA axis response to stressors. We aimed to determine whether postpartum depression symptoms, infant feeding, and their interaction are associated with HPA axis dysregulation, indexed by loss of expected associations in adrenocorticotropic (ACTH)-cortisol (CRT) coupling.
Study Design: Women intending to breastfeed were recruited in the 3rd trimester of pregnancy, oversampling for past or current anxiety/depression. At 2 months postpartum, dyads attended a lab visit. Following peripheral IV placement, women chose to breast or bottle-feed their infants, as they would at home. After a 10-minute post-feed rest, women participated in the Trier Social Stress Test (TSST), a standardized social stressor that includes a speech and a math task. Blood samples for ACTH and CRT were collected 10 minutes after feeding, during each task, and at 10, 20, and 30 minutes of recovery. Multilevel models were used to evaluate whether associations between ACTH at time j and CRT at time j+1 differed between women with or without current depression symptoms (Beck Depression Inventory ≥14 vs. < 14) and infant feeding type (breast vs. bottle).
Results: A total of 222 women were enrolled; 205 completed the 2 month visit, and 165 breastfed before the TSST (80.5%). Breastfeeding women had lower ACTH (p=0.01) and CRT (p=0.02) than bottle-feeding women, but no differences in ACTH-CRT coupling (p=0.15). ACTH (p=0.37), CRT (p=0.93), and ACTH-CRT coupling (p=0.09) were similar in women with and without depression symptoms. There was a significant interaction (p=0.03) between depression symptoms and infant feeding on ACTH-CRT coupling. Symptomatic women who breastfed had lower ACTH-CRT coupling responses compared with those who bottle-fed, but there were no differences by feeding in asymptomatic women (figure).
Conclusion: We found that breastfeeding blunted HPA axis response only among women with depression symptoms but not among women without. The influence of breastfeeding and oxytocin on HPA axis reactivity may play a role in the pathophysiology of perinatal mood disorders.

Oxytocin during breastfeeding and maternal mood symptoms

Whitley J, Wouk K, Bauer AE, Grewen K, Gottfredson NC, Meltzer-Brody S, Propper C, Mills-Koonce R, Pearson B, Stuebe A.

This study aimed to quantify the relationship between postpartum depression and anxiety, oxytocin, and breastfeeding. We conducted a longitudinal prospective study of mother-infant dyads from the third trimester of pregnancy to 12 months postpartum. A sample of 222 women were recruited to complete the Beck Depression Inventory II and Spielberger State-Trait Anxiety Inventory-state subscale, participate in observed infant feeding sessions at 2 and 6 months postpartum, and provide venous blood samples during feeding. Maternal venous oxytocin levels in EDTA-treated plasma and saliva were determined by enzyme immunoassay with extraction and a composite measure of area under the curve (AUC) was used to define oxytocin across a breastfeeding session. Linear regression was used to estimate associations between postpartum depression and anxiety as predictors and oxytocin AUC during breastfeeding as the outcome at both 2 and 6 months postpartum. Mixed models accounting for correlations between repeated oxytocin measures were used to quantify the association between current depression and/or anxiety symptoms and oxytocin profiles during breastfeeding. We found no significant differences in oxytocin AUC across a feed between depressed or anxious women and asymptomatic women at either 2 or 6 months postpartum. Repeated measures analyses demonstrated no differences in oxytocin trajectories during breastfeeding by symptom group but possible differences by antidepressant use. Our study suggests that external factors may influence the relationship between oxytocin, maternal mood symptoms, and infant feeding.

PMID: 31911347

The Mood, Mother, and Infant Study: Associations Between Maternal Mood in Pregnancy and Breastfeeding Outcome.

Epublished ahead of print in Breastfeeding Medicine, August 2019

Stuebe AM, Meltzer-Brody S, Propper C, Pearson B, Beiler P, Elam M, Walker C, Mills-Koonce R, Grewen K

Purpose: We sought to determine the role of depression and anxiety in breastfeeding cessation.

Materials and Methods:Participants underwent a baseline visit with a structured clinical interview in the third trimester of pregnancy. Monthly phone interviews assessed current mood symptoms and infant feeding status. We assessed the association between baseline mood and infant feeding outcomes using Cox proportional hazards regression, adjusting for infant feeding intention and sociodemographic confounders.

Results: We enrolled 222 mother-infant dyads in late pregnancy, of whom 206 completed assessments through 12 months postpartum. We enriched our study with symptomatic women by enrolling 87 women with current depression or anxiety (Current), 64 women with a history of depression or anxiety (Past), and 71 women with no psychiatric history (Never). In multivariable-adjusted analyses, baseline diagnosis was not associated with breastfeeding outcome, but baseline symptoms of depression (Beck Depression Inventory ≥11) or anxiety (Spielberger State Anxiety ≥40) were associated with earlier introduction of formula (depression: adj hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.01-2.30; anxiety: 1.70, 95% CI 1.01-2.87); and any cessation of breastfeeding (depression: adj HR 2.02, 95% CI 1.23-3.31; anxiety: 1.83, 95% CI 1.00-3.33), as were depression symptoms among women who were being treated with antidepressants, compared with untreated asymptomatic women (formula: adj HR 2.27, 95% CI 1.29-4.02; cessation: 2.32, 95% CI 1.17-4.61). History of childhood trauma (adj HR 1.34, 95% CI 1.12-1.61), disordered eating symptoms (adj HR 1.22, 95% CI 1.02-1.46), and poor sleep quality in pregnancy (adj HR 1.32, 95% CI 1.09-1.60) were independently associated with earlier introduction of formula.

Conclusions: Baseline mood symptoms were independently associated with earlier formula introduction and cessation of breastfeeding. History of childhood trauma, disordered eating symptoms and poor sleep quality were associated with earlier formula introduction. Targeted support may enable women with these symptoms to achieve their feeding goals.

PMID:31424266

Positive Emotions During Infant Feeding and Breastfeeding Outcomes.

Epublished in the Journal of Human Lactation, May 2019

Wouk K, Gottfredson NC, Tucker C, Pence BW, Meltzer-Brody S, Zvara B, Grewen K, Stuebe AM.

BACKGROUND: Few studies have examined the role of maternal emotions in breastfeeding outcomes.

RESEARCH AIM: We aimed to determine the extent to which positive maternal emotions during human milk feeding at 2 months were associated with time to any and exclusive human milk feeding cessation and overall breastfeeding experience.

METHODS: A sample of 192 women intending to breastfeed for at least 2 months was followed from the third trimester until 12 months postpartum. Positive emotions during infant feeding at 2 months were measured using the modified Differential Emotions Scale. Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHR) for time to any and exclusive human milk feeding cessation associated with a 1-point increase in positive emotions. Linear regression was used to estimate the association between positive emotions and maternal breastfeeding experience reported at 12 months.

RESULTS: Among those human milk feeding at 2 months, positive emotions during feeding were not associated with human milk feeding cessation by 12 months (aHR = 0.94, 95% CI [0.64, 1.31]). However, among women exclusively human milk feeding at 2 months, a 1-point increase in positive emotions was associated with a 35% lower hazard of introducing formula or solid foods by 6 months (aHR = 0.65, 95% CI [0.46, 0.92]). Positive emotions were associated with a significantly more favorable maternal report of breastfeeding experience at 12 months. Results were similar in sensitivity analyses using maternal feelings about breastfeeding in the first week as the exposure.

CONCLUSIONS: A positive maternal emotional experience of feeding is associated with breastfeeding outcomes.

PMID: 31059653

Disordered eating symptoms and maternal emotional experience of breastfeeding

Presented at the Breastfeeding and Feminism International Meeting, Chapel Hill, NC March 2019

Alison M. Stuebe, Samantha Meltzer-Brody, Brenda Pearson, Kathryn Wouk, Karen Grewen

Background: Symptoms of disordered eating and body image are common, and may worsen following childbirth. The relationship between disordered eating symptoms and maternal emotional experience of breastfeeding has not been explored.

Methods: Women intending to breastfeed at least two months were recruited into the Mood, Mother and Infant cohort study in the 3rd trimester of pregnancy. Psychiatric history was assessed at enrollment via Structured Clinical Interview, including past or current eating disorder diagnosis, with oversampling of women with a history or current diagnosis of major depressive or anxiety disorder. Eating disorder symptoms were quantified at enrollment and at 2, 6 and 12 months postpartum using the Eating Disorder Examination Questionnaire (EDE-Q), which assesses restraint, eating concern, weight concern, and shape concern, as well as a global score. Early breastfeeding experience was assessed at 1 month with the question, “How would you say you felt about breastfeeding during the first week you were breastfeeding?” (Likert scale, 1=Disliked very much, 5=Liked very much). Emotions during feeding at 2, 6 and 12 months were quantified with the modified Differential Emotions Scale (mDES), which asks women to indicate the greatest amount that they experienced 10 positive emotions and 10 negative emotions while feeding their baby during the past week. We measured overall breastfeeding experience at 12 months using the Maternal Breastfeeding Evaluation Scale (MBFES), including 3 subscales of Maternal Enjoyment/Role Attainment, Infant Satisfaction/Growth, and Lifestyle/Maternal Body Image. We used Spearman correlations to quantify the association between EDE-Q scores and measures of maternal breastfeeding experience, and we used mixed models to assess the association between MBFES score and EDE-Q trajectory from enrollment through 12 months postpartum.

Results: Data were available for 206 women, of whom 25 (12.1%) had a history of an eating disorder diagnosis. Higher baseline EDE-Q score and both shape and weight concern subscales were correlated with not liking breastfeeding in the first week (p<0.05). The EDE-Q score and all 4 subscales were associated with more negative emotions during feeding at 2, 6, and 12 months (p<.01), with the exception of the EDE-Restraint subscale and negative emotions at 6 months. EDE-Q score was also associated with lower MBFES scores on all 3 subscales (p=.02, .002, <.0001), as well as lower total score (p<.001). We found the strongest negative correlation between the EDE-Q Shape Concern subscale and the MBES Lifestyle / Maternal Body Image subscale (r=0.45, p<.0001). In mixed models adjusting for maternal body mass index and past or current depression or anxiety, MBFES scores in the highest tertile were associated with lower EDE-Q scores from enrollment through 12 months postpartum (group p<.01).

Conclusion: Symptoms of disordered eating and body image were associated with negative maternal experiences of breastfeeding. Woman-centered strategies to address these concerns in the context of infant feeding and the perinatal period may improve the lived experience of breastfeeding.

Perinatal mood disorders modify the association between infant feeding and cortisol response to stress

Presented at the Society for Maternal Fetal Medicine, Las Vegas, NV, February 2019.

Alison M. Stuebe, Samantha Meltzer-Brody, Roger Mills-Koonce, Brenda Pearson, Julia Whitley, Karen Grewen

Objective: Oxytocin has been shown to blunt the HPA axis response to stressors. We conducted a longitudinal prospective cohort study to test the hypothesis that perinatal mood disorders are associated with dysregulation of the effects of breastfeeding, a physiologic stimulus for oxytocin, on maternal HPA axis activity.

Study Design: Women intending to breastfeed were recruited in the 3rd trimester of pregnancy. Psychiatric history was assessed at enrollment via Structured Clinical Interview, with oversampling of women with past or current anxiety or depression. Women with an active psychiatric diagnosis at enrollment comprised the prenatal depression/anxiety (PNDA) group. At 2 months postpartum, dyads attended a lab visit. Following peripheral IV placement, women chose to breast or bottle-feed their infants, as they would at home. After a 10-minute post-feed rest, women participated in the Trier Social Stress Test (TSST), a standardized social stressor that includes a speech task and a math task. Blood samples for Cortisol (CRT) were collected 10 minutes after feeding, during the speech and math tasks, and at 10, 20 and 30 minutes of recovery. Repeated measures analysis was used to test the extent to which infant feeding (breast vs. bottle) and PNDA or current depression symptoms, indexed by Beck Depression Inventory >11, were associated with CRT levels during the TSST. P values <0.05 were considered statistically significant.

Results: A total of 222 women were enrolled; 208 completed the 2-month visit, of whom 175 breastfed before the TSST (84.1%). PNDA modified the association between feeding type and CRT levels (group p=0.02, group x time p =0.07) , adjusting for current antidepressant use (figure). We similarly found that current depression symptoms modified the association between feeding type and CRT levels (group p=0.05, group x time p =0.02), adjusting for current antidepressant use. Women with perinatal mood symptoms who were bottle-feeding had the highest CRT levels during the TSST, whereas women with PNDA who were breastfeeding had the lowest CRT levels.

Conclusion: Among women with PNDA, we found larger infant-feeding associated differences in HPA axis response than among women without PNDA. Dysregulation of oxytocin’s effect on HPA axis reactivity may play a role in the pathophysiology of perinatal mood disorders.

Perinatal depression and anxiety and oxytocin

Presented at the Society for Maternal Fetal Medicine, Las Vegas, NV, February 2019

Alison M. Stuebe, Samantha Meltzer-Brody, Roger Mills-Koonce, Brenda Pearson, Julia Whitley, Karen Grewen

Objective: We conducted a longitudinal prospective cohort study to test the hypothesis that perinatal depression is associated with reduced oxytocin during mother-infant interaction.

Study Design: Women intending to breastfeed were recruited in the 3rd trimester of pregnancy. Psychiatric history was assessed at enrollment via Structured Clinical Interview, with oversampling of women with a history or current diagnosis of major depressive disorder or anxiety disorders. Women with an active psychiatric diagnosis at enrollment comprised the prenatal depression/anxiety (PNDA) group. Dyads attended lab visits for a feeding session at 2 and 6 months postpartum; mothers fed their infants as they would at home. Venous maternal blood samples were collected via antecubital IV at baseline, at minutes 1, 4, 7, and 10 of feeding, and 10 minutes after feeding. OT levels were determined by enzyme immunoassay with extraction. Mood symptoms were quantified using the Beck Depression Inventory-II (BDI-II), the Spielberg State-Trait Anxiety Inventory (STAI), and the Edinburgh Postnatal Depression Scale (EPDS). Repeated measures analyses were used to compare OT levels by feeding type and PNDA, adjusting for current symptom score and antidepressant use. P values <.05 were considered statistically significant.

Results: A total of 222 women were enrolled, of whom 208 completed the 2-month visit and 204 completed the 6-month visit. During the 2 month visit, 84.1% breastfed (N=175), and at 6 months, 70.6% breastfed (N=144). Women without PNDA were more likely to breastfeed at the 6 month visit (74.5 vs. 61.0%, p=0.06). At 2 months postpartum, OT levels were highest among breastfeeding women with PNDA and lowest among bottle-feeding women with PNDA, adjusting for current mood symptoms and antidepressant use (group p=0.07, group x time p =0.001, figure). We similarly found that PNDA modified the association between feeding and OT levels at 6 months, adjusting for current mood symptoms and antidepressant use (group p=0.002, group x time p=0.0002, figure).

Conclusion: At 2 months, breastfeeding women with PNDA had the highest OT levels, whereas bottle-feeding women with PNDA had the lowest OT levels. We speculate that this differential OT response to infant feeding may mediate associations between depression and early weaning.

Maternal perception of birth trauma and its association with postpartum mood and parenting stress

Presented at the Society for Maternal Fetal Medicine, Las Vegas, NV, February 2019.

Alison Goulding, Karen Grewen, Samantha Meltzer-Brody, Brenda Pearson, Alison Stuebe

Objective: We sought to examine the association between traumatic birth and measures of mood and parenting stress through 12 months postpartum.

Study Design: We conducted a secondary analysis of participants in the Mood, Mother and Infant (MMI) Study. Women intending to breastfeed were recruited in the 3rdtrimester for a longitudinal cohort study, oversampling for women with current/past depression or anxiety.  A structured clinical interview was performed at baseline to assess for history or current diagnosis of major depressive or anxiety disorders. Baseline anxiety and depression symptoms were measured using the Beck Depression Inventory (BDI) and the Spielberger State-Trait Anxiety Inventory (STAI). Mood was measured at baseline and monthly with the Edinburgh Postnatal Depression Scale (EPDS), and at 2, 6, and 12 months postpartum with the BDI, STAI, and Parenting Stress Index (PSI). Maternal post-traumatic stress disorder (PTSD) symptoms were assessed at 2 months postpartum using the modified Perinatal PTSD Questionnaire (PPQ); birth PTSD was defined using the established threshold of PPQ score ≥ 19. We used repeated measures analysis to quantify the association between birth PTSD and postpartum mood and parenting stress through 12 months postpartum, adjusting for prenatal PPD risk and mood symptoms.

Results: Data were available from 209 women, of whom 15 (7.2%) had birth PTSD. Compared to women without birth PTSD, these women had higher prenatal STAI-Trait (mean 45.1 vs. 33.6, p=0.01) and BDI (mean 18.4 vs. 8.6, p<0.01) scores. In repeated measures analysis adjusting for prenatal STAI-Trait score, BDI score and PPD risk status, we found that birth PTSD was independently associated with higher postpartum EPDS (group p=0.03, group x time p=0.01), BDI (group p<0.0001), state anxiety (group p=0.002, group x time p=0.01) and PSI (group p=0.002) scores through 12 months postpartum.

Conclusions: In our sample, 7% of women had birth PTSD. A traumatic birth experience was associated with postpartum anxiety and depression symptoms and parenting stress, independent of prenatal risk. These findings support efforts to minimize traumatic experiences during childbirth, and to provide additional support to women who endorse PTSD symptoms following birth.