top of page




Sörensen F, Kimmel MC, Brenner V, Krägeloh-Mann I, Skalkidou A, Mahjani B, Fransson E. (2023). Interactions of perinatal depression versus anxiety and infants' early temperament trajectories. Child Dev.

This study examines the interplay between maternal depression/anxiety and infant temperament's developmental trajectory in 1687 Swedish-speaking mother-infant dyads from Uppsala County (2009-2019), Sweden. The sample includes a high proportion of university-educated individuals and a low share of foreign-born participants. Maternal depressive and anxiety symptoms were assessed using the Edinburgh Postnatal Depression Scale during gestational weeks 17 and 32 and postpartum at week 6. Multinomial regression explored associations between maternal variables and infant temperament trajectories at 6 weeks, 12 months, and 18 months. Prenatal anxiety is associated with the high-rising infant difficult temperament trajectory, while prenatal depression/anhedonia is associated with the stable-medium trajectory, attenuated postpartum. Associations between infant temperament and maternal mood depended on timing (pre/postpartum) and symptom type (depression/anhedonia vs. anxiety).

Björvang RD, Liakea I, Carpentsier B, Kozinszky Z, Skalkidou A, Fransson E. (2023). Association of Diabetes Mellitus in Pregnancy and Perinatal Depression. Psychosom Med.

Objective: Diabetes is frequently linked with depression, and both conditions are common complications during pregnancy. However, research findings exploring the relationship between diabetes mellitus in pregnancy (DMP) and perinatal depression (PND) have been inconsistent. Thus, this study seeks to examine the association between DMP and PND in a prospective population-based cohort. Methods: Women aged 18 to 48 years ( n = 4459) were identified from the Biology, Affect, Stress, Imaging and Cognition study. The diagnosis of DMP was based on International Classification of Diseases code O24 from medical records and was classified as pregestational, gestational, or unspecified diabetes. PND was assessed using psychometric instruments, clinical interviews, and/or register data and categorized into antepartum or postpartum depression. Multivariable logistic regressions were used to study the associations of DMP with antepartum and postpartum depression. The association between DMP and continuous depression scores, antepartum and postpartum, was investigated with multivariable linear regressions. Results: Of 4459 pregnancies, 949 women had antepartum depression (21.2%) and 1123 had postpartum depression (25%). DMP had a prevalence of 1.2%. Women with DMP had twofold higher odds for postpartum depression compared with women without DMP. Although no association was observed between DMP and antepartum depression, DMP was associated with higher antepartum depression scores. Conclusions: Our study shows an association between DMP and PND, which might be considered a risk factor when screening for high-risk groups.

Guintivano J, Byrne EM, Kiewa J, Yao S, Bauer AE, Aberg KA, Adams MJ, Campbell A, Campbell ML, Choi KW, Corfield EC, Havdahl A, Hucks D, Koen N, Lu Y, Mægbæk ML, Mullaert J, Peterson RE, Raffield LM, Sallis HM, Sealock JM, Walker A, Watson HJ, Xiong Y, Yang JMK, Anney RJL, Gordon-Smith K, Hubbard L, Jones LA, Mihaescu R, Nyegaard M, Pardiñas AF, Perry A, Saquib N, Shadyab AH, Viktorin A, Andreassen OA, Bigdeli TB, Davis LK, Dennis CL, Di Florio A, Dubertret C, Feng YA, Frey BN, Grigoriadis S, Gloaguen E, Jones I, Kennedy JL, Krohn H, Kunovac Kallak T, Li Y, Martin NG, McIntosh AM, Milgrom J, Munk-Olsen T, Oberlander T, Olsen CM, Ramoz N, Reichborn-Kjennerud T, Robertson Blackmore E, Rubinow D, Skalkidou A, Smoller JW, Stein DJ, Stowe ZN, Taylor V, Tebeka S, Tesli M, Van Lieshout RJ, van den Oord EJCG, Vigod SN, Werge T, Westlye LT, Whiteman DC, Zar HJ; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Wray N, Meltzer-Brody S, Sullivan P. (2023). Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression. Am J Psychiatry.

Objective: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. Method: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. Results: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. Conclusions: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).

Akhter T, Hedeland M, Bergquist J, Ubhayasekera K, Larsson A, Kullinger M, Skalkidou A. (2023). Plasma levels of arginines at term pregnancy in relation to mode of onset of labor and mode of childbirth. Am J Reprod Immunol.

Problem: The exact biochemical mechanisms that initiate labor are not yet fully understood. Nitric oxide is a potent relaxant of uterine smooth muscles until labor starts, and its precursor is L-arginine. Asymmetric (ADMA) and symmetric (SDMA) dimethylarginines, are potent NO-inhibitors. However, arginines (dimethylarginines and L-arginine) are scarcely studied in relation to labor and childbirth. We aimed to investigate arginines in women with spontaneous (SLVB) and induced (ILVB) term labor with vaginal birth and in women undergoing elective caesarean section (ECS). Method of study: Women at gestational week 16-18 were recruited to the population-based prospective cohort study BASIC at the Uppsala University Hospital, Sweden. Plasma samples taken at start of labor were analyzed for arginines, from SLVB (n = 45), ILVB (n = 45), and ECS (n = 45), using Ultra-High Performance Liquid Chromatography. Between-group differences were assessed using Kruskal-Wallis and Mann-Whitney U-test. Results: Women with SLVB and ILVB had higher levels of ADMA (p < .0001), SDMA (p < .05) and lower L-arginines (p < .01), L-arginine/ADMA (p < .0001), and L-arginine/SDMA (p < .01, respectively <.001) compared to ECS. However, ILVB had higher ADMA (p < .0001) and lower L-arginine (p < .01), L-arginine/ADMA (p < .0001), and L-arginine/SDMA (p < .01) compared to SLVB. Results are adjusted for gestational length at birth and cervical dilatation at sampling. Conclusion: Our novel findings of higher levels of dimethylarginines in term vaginal births compared to ECS give insights into the biochemical mechanisms of labor. These findings might also serve as a basis for further studies of arginines in complicated pregnancies and labor.



Lager S, Gidén K, Axfors C, Sigvardsson F, Kollia N, Nylander I, Fransson E, Skalkidou A. (2022). Alcohol consumption habits and associations with anxiety or depressive symptoms postpartum in women with high socioeconomic status in Sweden. Arch Womens Ment Health.

Postpartum depression and anxiety are common among new mothers. It is well-established that in the general population alcohol use is associated with depression and anxiety. Linking alcohol consumption to symptoms of postpartum depression (PPDS) or postpartum anxiety (PPAS) is presently less established. This study aims to determine if alcohol consumption pre-pregnancy, 6 weeks postpartum, 6 months postpartum, or changes in alcohol consumption are associated with PPDS or PPAS. Longitudinal data on 3849 women from a Swedish perinatal cohort were analyzed using logistic regression analyses for associations between alcohol consumption and symptoms of anxiety or depression, as assessed with the Edinburgh Postnatal Depression Scale. There was no association between pre-pregnancy drinking habits and PPDS (p = 0.588, n = 2479) or PPAS (p = 0.942; n = 2449) at 6 weeks postpartum. Similarly, no associations were observed between concurrent drinking habits at 6 weeks postpartum and PPAS (p = 0.070, n = 3626), 6 months postpartum and PPDS (0.647, n = 3461) or PPAS (p = 0.700, n = 3431). However, there was an association between drinking habits at 6 weeks postpartum and concurrent PPDS (p = 0.047, n = 3659). In conclusion, robust associations were not found between postpartum alcohol consumption and mood symptoms. This lack of association between poor mental health and risk behaviors in new mothers could be interpreted as a result of long-term policy work and high participation in Swedish maternity care. Future studies need to address these research questions in more diverse socio-cultural contexts.

Qiu X, Wu Y, Sun Y, Levis B, Tian J, Boruff JT, Cuijpers P, Ioannidis JPA, Markham S, Ziegelstein RC, Vigod SN, Benedetti A, Thombs BD; DEPRESsion Screening Data (DEPRESSD) EPDS Group. (2023). Individual participant data meta-analysis to compare EPDS accuracy to detect major depression with and without the self-harm item. Sci Rep.

Item 10 of the Edinburgh Postnatal Depression Scale (EPDS) is intended to assess thoughts of intentional self-harm but may also elicit concerns about accidental self-harm. It does not specifically address suicide ideation but, nonetheless, is sometimes used as an indicator of suicidality. The 9-item version of the EPDS (EPDS-9), which omits item 10, is sometimes used in research due to concern about positive endorsements of item 10 and necessary follow-up. We assessed the equivalence of total score correlations and screening accuracy to detect major depression using the EPDS-9 versus full EPDS among pregnant and postpartum women. We searched Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, and Web of Science from database inception to October 3, 2018 for studies that administered the EPDS and conducted diagnostic classification for major depression based on a validated semi-structured or fully structured interview among women aged 18 or older during pregnancy or within 12 months of giving birth. We conducted an individual participant data meta-analysis. We calculated Pearson correlations with 95% prediction interval (PI) between EPDS-9 and full EPDS total scores using a random effects model. Bivariate random-effects models were fitted to assess screening accuracy. Equivalence tests were done by comparing the confidence intervals (CIs) around the pooled sensitivity and specificity differences to the equivalence margin of δ = 0.05. Individual participant data were obtained from 41 eligible studies (10,906 participants, 1407 major depression cases). The correlation between EPDS-9 and full EPDS scores was 0.998 (95% PI 0.991, 0.999). For sensitivity, the EPDS-9 and full EPDS were equivalent for cut-offs 7-12 (difference range - 0.02, 0.01) and the equivalence was indeterminate for cut-offs 13-15 (all differences - 0.04). For specificity, the EPDS-9 and full EPDS were equivalent for all cut-offs (difference range 0.00, 0.01). The EPDS-9 performs similarly to the full EPDS and can be used when there are concerns about the implications of administering EPDS item 10.Trial registration: The original IPDMA was registered in PROSPERO (CRD42015024785).

Bränn E, Skalkidou A, Schwarz J, Papadopoulos FC, Sundström Poromaa I, Fransson E. (2022). Longitudinal assessment of inflammatory markers in the peripartum period by depressive symptom trajectory groups. Brain Behav Immun Health.

Objective: Mechanisms driving temporal fluctuations of inflammatory markers during pregnancy, and how these might differ between distinct perinatal depressive trajectories, are not well understood. The aim of this study was to investigate cytokines levels over the course of pregnancy in women with different trajectories of depressive symptoms peripartum, and relate the levels to levels of non-pregnant controls. Methods: Based on the Edinburgh Postnatal Depression Scale and/or selective serotonin reuptake inhibitors use, 131 women were categorized into: no (n = 65); antepartum (APD, n = 19), postpartum (PPD, n = 17) and persistent (n = 30) depressive symptoms. Plasma samples (n = 386) were analyzed for levels of interleukin (IL)-8, IL-18, Tumor necrosis factor-α, macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor A (VEGF-A) and fractalkine, at four different time-points (twice during pregnancy, during childbirth, and postpartum) using Bio-Plex Pro Human Cytokine Assays. Generalized linear mixed models were applied to analyze the associations between cytokine levels, time-point, perinatal depressive symptom trajectory group and their interaction. Results: For all markers but VEGF-A, pregnancy was associated with higher cytokine levels compared to the non-pregnant controls, with delivery being the most prominent time-point. For M-CSF, IL-18 and VEGF-A, levels were back to the non-pregnant status at postpartum week 8. An effect of perinatal depressive symptom trajectory groups on cytokine levels was found for VEGF-A. Women with PPD and women with APD had lower levels of VEGF-A throughout the study period compared to women with persistent depression, and women with PPD had lower levels compared to non-depressed women. Conclusions: Lower levels of VEGF-A were noted among women in some trajectories of depressive symptoms peripartum. The peripartum period is a time of tremendous immune system adaptations. Standardization of time-points for cytokine measurements in studies of perinatal depression are important in order to draw valid conclusions on the role of the immune system in perinatal depression.

Kallak TK, Fransson E, Bränn E, Berglund H, Lager S, Comasco E, Lyle R, Skalkidou A. (2022). Maternal prenatal depressive symptoms and toddler behavior: an umbilical cord blood epigenome-wide association study. Transl Psychiatry.

Children of mothers with prenatal depressive symptoms (PND) have a higher risk of behavioral problems; fetal programming through DNA methylation is a possible underlying mechanism. This study investigated DNA methylation in cord blood to identify possible "at birth" signatures that may indicate susceptibility to behavioral problems at 18 months of age. Cord blood was collected from 256 children of mothers who had self-reported on symptoms of depression during pregnancy and the behavior of their child at 18 months of age. Whole genome DNA methylation was assessed using Illumina MethylationEPIC assay. The mother and child pairs were categorized into four groups, based on both self-reported depressive symptoms, PND or Healthy control (HC), and scores from the Child Behavior checklist (high or low for internalizing, externalizing, and total scores). Adjustments were made for batch effects, cell-type, and clinical covariates. Differentially methylated sites were identified using Kruskal-Wallis test, and Benjamini-Hochberg adjusted p values < 0.05 were considered significant. The analysis was also stratified by sex of the child. Among boys, we observed higher and correlated DNA methylation of one CpG-site in the promoter region of TPP1 in the HC group, with high externalizing scores compared to HC with low externalizing scores. Boys in the PND group showed lower DNA methylation in NUDT15 among those with high, compared to low, internalizing scores; the DNA methylation levels of CpGs in this gene were positively correlated with the CBCL scores. Hence, the differentially methylated CpG sites could be of interest for resilience, regardless of maternal mental health during pregnancy. The findings are in a relatively healthy study cohort, thus limiting the possibility of detecting strong effects associated with behavioral difficulties. This is the first investigation of cord blood DNA methylation signs of fetal programming of PND on child behavior at 18 months of age and thus calls for independent replications.

Liakea I, K C A, Bränn E, Fransson E, Sundström Poromaa I, Papadopoulos FC, Skalkidou A. (2022). Working Memory During Late Pregnancy: Associations With Antepartum and Postpartum Depression Symptoms. Front Glob Womens Health.

Background: Few studies, with conflicting results, report on the association between memory performance and depressive symptoms during the perinatal period. In this study, we aimed to evaluate whether memory performance during late pregnancy is associated with antepartum (APD) and postpartum depression (PPD) symptoms. Method: We conducted a prospective follow-up of 283 pregnant women, nested within a large cohort of women enrolled in the BASIC study in Uppsala University hospital between 2009 and 2019. The Wechsler Digit Span Task (forward-DSF, backward-DSB and total score-DST) was performed to evaluate short-term memory/attention (DSF) and working memory (DSB) around the 38th gestational week; the Edinburgh Postnatal Depression Scale (EPDS), evaluating depressive symptoms, was filled out at 17, 32, 38 gestational weeks, as well as at 6 weeks postpartum. Unadjusted and multivariate logistic regression was used to assess the association between performance on the Digit Span Task and outcome, namely depressive symptoms (using a cut-off of 12 points on the EPDS) at 38 gestational weeks, as well as at 6 weeks postpartum. Results: APD symptoms were not significantly associated with DSF (p = 0.769) or DSB (p = 0.360). APD symptoms were significantly associated with PPD symptoms (p < 0.001). Unadjusted regression modeling showed that DSF in pregnancy was a significant predictor of PPD symptoms (OR 1.15; 95% CI, 1.00, 1.33, p = 0.049), and remained a significant predictor when adjusted for confounders (education and feeling rested at assessment; OR 1.21, 95% CI 1.03, 1.42, p = 0.022). DSF was a predictor of PPD symptoms only for women without a pre-pregnancy history of depression (OR 1.32; 95% CI 1.04, 1.67, p = 0.024) and also those without APD (OR 1.20, 95% CI 1.01, 1.43, p = 0.040). Conclusion: There was no significant association between working and short-term memory performance and APD symptoms. Among all women, but especially non-depressed earlier in life and/or at antepartum, those scoring high on the forward memory test, i.e., short-term memory, had a higher risk for PPD. Future studies are required to further explore the pathophysiology behind and the predictive value of these associations.

Tu HF, Skalkidou A, Lindskog M, Gredebäck G. (2021). Maternal childhood trauma and perinatal distress are related to infants' focused attention from 6 to 18 months. Sci Rep.

Maternal distress is repeatedly reported to have negative impacts on the cognitive development in children and is linked to neurodevelopmental disorders (e.g. attention-deficit/hyperactivity disorder and autism spectrum disorder). However, studies examining the associations between maternal distress and the development of attention in infancy are few. This study investigated the longitudinal relationships between maternal distress (depressive symptoms, anxiety symptoms, and exposure to childhood trauma) and the development of focused attention in infancy in 118 mother-infant dyads. We found that maternal exposure to non-interpersonal traumatic events in childhood was associated with the less focused attention of the infants to audio-visual stimuli at 6, 10, and 18 months. In addition, exposure to interpersonal traumatic events in childhood was identified as a moderator of the negative effect of maternal anxiety during the 2nd trimester on the development of focused attention in infants. We discuss the possible mechanisms accounting for these cross-generational effects. Our findings underscore the importance of maternal mental health to the development of focused attention in infancy and address the need for early screening of maternal mental health during pregnancy.

Welander NZ, Mwinyi J, Asif S, Schiöth HB, Skalkidou A, Fransson E. (2021). Migraine as a risk factor for mixed symptoms of peripartum depression and anxiety in late pregnancy: A prospective cohort study. J Affect Disord.

Background: Migraine has been identified as a risk factor for peripartum depression. However, little is known about the contribution of anxiety to this association or potential changes throughout the peripartum period. Methods: In a sample of 4,831 women from the Biology, Affect, Stress, Imaging and Cognition cohort in Sweden, participants were asked about history of migraine prior to pregnancy. The participants completed the Edinburgh Postnatal Depression Scale (EPDS) at gestational weeks 17 and 32 and postpartum week 6. Multinomial logistic regression analyses were used to assess associations between migraine and symptoms of depression, anxiety or mixed depression and anxiety, while adjusting for potential confounders. Results: In crude estimates, migraine was associated with separate and mixed symptoms of depression and anxiety at most time points. After adjustments, migraine was associated with anxiety at week 17 (adjusted odds ratio: 1.69; 95% confidence interval: 1.11-2.54) and with mixed depression and anxiety at week 32 (adjusted odds ratio: 1.45; 95% confidence interval: 1.06-1.99). None of the other associations remained statistically significant after adjustments. Limitations: Migraine history was self-reported. Symptoms of depression and anxiety were based on the screening tool EPDS and not on clinical diagnoses. Conclusions: The results demonstrate that migraine may be a risk factor for anxiety in mid- pregnancy and mixed symptoms of peripartum depression and anxiety in late pregnancy. Inflammatory and hormonal factors may underlie the association between migraine, depression and anxiety across the peripartum period.


Amiel Castro R, Kunovac Kallak T, Sundström Poromaa I, Willebrand M, Lager S, Ehlert U, Skalkidou A. (2021). Pregnancy-related hormones and COMT genotype: Associations with maternal working memory. Psychoneuroendocrinology.

Women experience different degrees of subjective cognitive changes during pregnancy. The exact mechanism underlying these changes is unknown, although endocrine alterations and genetics may be contributing factors. We investigated whether multiple pregnancy-related hormones were associated with working memory function assessed with the Digit Span Test (DST) in late pregnancy. Moreover, we examined whether the catechol-O-methyltransferase (COMT) genotype, previously related to working memory, was an effect modifier in this association. In this population-based panel study, we recorded psychiatric history, medication use, socio-demographic characteristics, and psychological well-being, gathered blood and saliva samples, and administered the DST at gestational weeks 35-39 (N = 216). We conducted multivariate linear regressions with DST as outcome, with different hormones and COMT genotype, adjusting for covariates including maternal age, BMI, education, depressive symptoms, and parity. We repeated these analyses excluding women with elevated depressive symptoms. Higher DST total scores were associated with increased free estradiol concentrations (B = 0.01, p = 0.03; B = 0.01, p = 0.02) in all participants and in participants without depressive symptoms, respectively, whereas DST forward was positively associated with free estradiol only in women without depressive symptoms (B = 0.01, p = 0.04). Lower total testosterone concentrations (B = -0.03, p = 0.01) enhanced DST backward performance in non-depressed women. Maternal higher education was significantly associated with the DST subscales in all participants. No significant differences emerged when considering the COMT genotype. Our results suggest differential associations of free estradiol and total testosterone levels with working memory function in late pregnancy.


Bränn, E., Malavaki, C., Fransson, E., Ioannidi, M., Henriksson, H., Papadopoulos, F., Chrousos, G., Klapa, M., & Skalkidou, A. (2021). Metabolic Profiling Indicates Diversity in the Metabolic Physiologies Associated With Maternal Postpartum Depressive Symptoms. Frontiers in Psychiatry, 12, 862.

Postpartum depression (PPD) is a devastating disease requiring improvements in diagnosis and prevention. Blood metabolomics identifies biological markers discriminatory between women with and those without antenatal depressive symptoms. Whether this cutting-edge method can be applied to postpartum depressive symptoms merits further investigation. As a substudy within the Biology, Affect, Stress, Imagine and Cognition Study, 24 women with PPD symptom (PPDS) assessment at 6 weeks postpartum were included. Controls were selected as having a score of ≤ 6 and PPDS cases as ≥12 on the Edinburgh Postnatal Depression Scale. Blood plasma was collected at 10 weeks postpartum and analyzed with gas chromatography–mass spectrometry metabolomics. Variations of metabolomic profiles within the PPDS samples were identified. One cluster showed altered kidney function, whereas the other, a metabolic syndrome profile, both previously associated with depression. Five metabolites (glycerol, threonine, 2-hydroxybutanoic acid, erythritol, and phenylalanine) showed higher abundance among women with PPDSs, indicating perturbations in the serine/threonine and glycerol lipid metabolism, suggesting oxidative stress conditions. Alterations in certain metabolites were associated with depressive pathophysiology postpartum, whereas diversity in PPDS physiologies was revealed. Hence, plasma metabolic profiling could be considered in diagnosis and pathophysiological investigation of PPD toward providing clues for treatment. Future studies require standardization of various subgroups with respect to symptom onset, lifestyle, and comorbidities.

Kimmel, M. C., Fransson, E., Cunningham, J. L., Brann, E., Grewen, K., Boschiero, D., Chrousos, G. P., Meltzer-Brody, S., Skalkidou, A. (2021) Heart rate variability in late pregnancy: exploration of distinctive patterns in relation to maternal mental health. Transl Psychiatry 11(1), 286.

Exploration of photoplethysmography (PPG), a technique that can be translated to the clinic, has the potential to assess the autonomic nervous system (ANS) through heart rate variable (HRV) in pregnant individuals. This novel study explores the complexity of mental health of individuals in a clinical sample responding to a task in late pregnancy; finding those with several types of past or current anxiety disorders, greater trait anxiety, or greater exposure to childhood traumatic events had significantly different HRV findings from the others in the cohort. Lower high frequency (HF), a measure of parasympathetic activity, was found for women who met the criteria for the history of obsessive-compulsive disorder (OCD) (p = 0.004) compared with women who did not meet the criteria for OCD, and for women exposed to greater than five childhood traumatic events (p = 0.006) compared with those exposed to four or less childhood traumatic events. Conversely higher low frequency (LF), a measure thought to be impacted by sympathetic system effects, and the LF/HF ratio was found for those meeting criteria for a panic disorder (p = 0.006), meeting criteria for social phobia (p = 0.002), had elevated trait anxiety (p = 0.006), or exposure to greater than five childhood traumatic events (p = 0.004). This study indicates further research is needed to understand the role of PPG and in assessing ANS functioning in late pregnancy. Study of the impact of lower parasympathetic functioning and higher sympathetic functioning separately and in conjunction at baseline and in relation to tasks during late pregnancy has the potential to identify individuals that require more support and direct intervention.

Bränn, E., Fransson, E., Wikman, A., Kollia, N., Nguyen, D., Lilliecreutz, C., & Skalkidou, A. (2021). Who do we miss when screening for postpartum depression? A population-based study in a Swedish region. Journal of affective disorders, 287, 165–173.

Universal screening for postpartum depression is crucial for early detection, interventions and support. The aim of this study was to describe the proportion of, and explore risk factors for, women not being offered screening, as well as for declining an offer or not being screened due to any other unknown reason. Socioeconomic, obstetrical and neonatal data, extracted from the Swedish Pregnancy Registry, for 9,959 pregnancies recorded for the Östergötland county between 2016 and 2018 were linked to Edinburgh Postnatal Depression Scale (EPDS) screening results at 6-8 weeks postpartum, extracted from medical records. Risk factors were assessed using logistic regression models and with a nomogram for easy visualization. In total, there were no recorded offers of EPDS screening in the medical records for 30.0% of women at the postpartum follow-up. Women born outside of Sweden and women reporting poor self-rated health were at increased risk of not being offered screening for postpartum depression. There is a possibility that women were offered screening or were screened, but this was incorrectly or never recorded in medical records.The majority of women were offered screening for postpartum depression, but there is room for improvement in order to achieve universal screening. Awareness among healthcare providers of the risk factors for not screening might increase adherence to guidelines for universal screening. Overcoming barriers for screening and raising the topic of mental-health issues for postpartum women should be prioritized.


Andersson, S., Bathula, D. R., Iliadis, S. I., Walter, M., & Skalkidou, A. (2021). Predicting women with depressive symptoms postpartum with machine learning methods. Scientific reports, 11(1), 7877

Postpartum depression (PPD) is a detrimental health condition that affects 12% of new mothers. Despite negative effects on mothers' and children's health, many women do not receive adequate care. Preventive interventions are cost-efficient among high-risk women, but our ability to identify these is poor. We leveraged the power of clinical, demographic, and psychometric data to assess if machine learning methods can make accurate predictions of postpartum depression. Data were obtained from a population-based prospective cohort study in Uppsala, Sweden, collected between 2009 and 2018 (BASIC study, n = 4313). Sub-analyses among women without previous depression were performed. The extremely randomized trees method provided robust performance with highest accuracy and well-balanced sensitivity and specificity (accuracy 73%, sensitivity 72%, specificity 75%, positive predictive value 33%, negative predictive value 94%, area under the curve 81%). Among women without earlier mental health issues, the accuracy was 64%. The variables setting women at most risk for PPD were depression and anxiety during pregnancy, as well as variables related to resilience and personality. Future clinical models that could be implemented directly after delivery might consider including these variables in order to identify women at high risk for postpartum depression to facilitate individualized follow-up and cost-effectiveness.


Kallak, T. K., Bränn, E., Fransson, E., Johansson, Å., Lager, S., Comasco, E., Lyle, R., & Skalkidou, A. (2021). DNA methylation in cord blood in association with prenatal depressive symptoms. Clinical epigenetics, 13(1), 78.

Prenatal symptoms of depression (PND) and anxiety affect up to every third pregnancy. Children of mothers with mental health problems are at higher risk of developmental problems, possibly through epigenetic mechanisms together with other factors such as genetic and environmental. We investigated DNA methylation in cord blood in relation to PND, taking into consideration a history of depression, co-morbidity with anxiety and selective serotonin reuptake inhibitors (SSRI) use, and stratified by sex of the child. Mothers (N = 373) prospectively filled out web-based questionnaires regarding mood symptoms and SSRI use throughout pregnancy. Cord blood was collected at birth and DNA methylation was measured using Illumina MethylationEPIC array at 850 000 CpG sites throughout the genome. Differentially methylated regions were identified using Kruskal-Wallis test, and Benjamini-Hochberg adjusted p-values < 0.05 were considered significant. No differential DNA methylation was associated with PND alone; however, differential DNA methylation was observed in children exposed to comorbid PND with anxiety symptoms compared with healthy controls in ABCF1 (log twofold change - 0.2), but not after stratification by sex of the child. DNA methylation in children exposed to PND without SSRI treatment and healthy controls both differed in comparison with SSRI exposed children at several sites and regions, among which hypomethylation was observed in CpGs in the promoter region of CRBN (log2 fold change - 0.57), involved in brain development, and hypermethylation in MDFIC (log2 fold change 0.45), associated with the glucocorticoid stress response. Although it is not possible to assess if these methylation differences are due to SSRI treatment itself or to more severe depression, our findings add on to existing knowledge that there might be different biological consequences for the child depending on whether maternal PND was treated with SSRIs or not.


Bhandari PM, Levis B, Neupane D, Patten SB, Shrier I, Thombs BD, Benedetti A; Depression Screening Data (DEPRESSD) EPDS Group. (2021). Data-driven methods distort optimal cutoffs and accuracy estimates of depression screening tools: a simulation study using individual participant data. J Clin Epidemiol.

Objective: To evaluate, across multiple sample sizes, the degree that data-driven methods result in (1) optimal cutoffs different from population optimal cutoff and (2) bias in accuracy estimates. Study design and setting: A total of 1,000 samples of sample size 100, 200, 500 and 1,000 each were randomly drawn to simulate studies of different sample sizes from a database (n = 13,255) synthesized to assess Edinburgh Postnatal Depression Scale (EPDS) screening accuracy. Optimal cutoffs were selected by maximizing Youden's J (sensitivity+specificity-1). Optimal cutoffs and accuracy estimates in simulated samples were compared to population values. Results: Optimal cutoffs in simulated samples ranged from ≥ 5 to ≥ 17 for n = 100, ≥ 6 to ≥ 16 for n = 200, ≥ 6 to ≥ 14 for n = 500, and ≥ 8 to ≥ 13 for n = 1,000. Percentage of simulated samples identifying the population optimal cutoff (≥ 11) was 30% for n = 100, 35% for n = 200, 53% for n = 500, and 71% for n = 1,000. Mean overestimation of sensitivity and underestimation of specificity were 6.5 percentage point (pp) and -1.3 pp for n = 100, 4.2 pp and -1.1 pp for n = 200, 1.8 pp and -1.0 pp for n = 500, and 1.4 pp and -1.0 pp for n = 1,000. Conclusions: Small accuracy studies may identify inaccurate optimal cutoff and overstate accuracy estimates with data-driven methods.

Wu Y, Levis B, Ioannidis JPA, Benedetti A, Thombs BD; DEPRESsion Screening Data (DEPRESSD) Collaboration. (2021). Probability of Major Depression Classification Based on the SCID, CIDI, and MINI Diagnostic Interviews: A Synthesis of Three Individual Participant Data Meta-Analyses. Psychother Psychosom.

Introduction: Three previous individual participant data meta-analyses (IPDMAs) reported that, compared to the Structured Clinical Interview for the DSM (SCID), alternative reference standards, primarily the Composite International Diagnostic Interview (CIDI) and the Mini International Neuropsychiatric Interview (MINI), tended to misclassify major depression status, when controlling for depression symptom severity. However, there was an important lack of precision in the results. Objective: To compare the odds of the major depression classification based on the SCID, CIDI, and MINI. Methods: We included and standardized data from 3 IPDMA databases. For each IPDMA, separately, we fitted binomial generalized linear mixed models to compare the adjusted odds ratios (aORs) of major depression classification, controlling for symptom severity and characteristics of participants, and the interaction between interview and symptom severity. Next, we synthesized results using a DerSimonian-Laird random-effects meta-analysis. Results: In total, 69,405 participants (7,574 [11%] with major depression) from 212 studies were included. Controlling for symptom severity and participant characteristics, the MINI (74 studies; 25,749 participants) classified major depression more often than the SCID (108 studies; 21,953 participants; aOR 1.46; 95% confidence interval [CI] 1.11-1.92]). Classification odds for the CIDI (30 studies; 21,703 participants) and the SCID did not differ overall (aOR 1.19; 95% CI 0.79-1.75); however, as screening scores increased, the aOR increased less for the CIDI than the SCID (interaction aOR 0.64; 95% CI 0.52-0.80). Conclusions: Compared to the SCID, the MINI classified major depression more often. The odds of the depression classification with the CIDI increased less as symptom levels increased. Interpretation of research that uses diagnostic interviews to classify depression should consider the interview characteristics.

Levis B, Negeri Z, Sun Y, Benedetti A, Thombs BD; DEPRESsion Screening Data (DEPRESSD) EPDS Group. (2020). Accuracy of the Edinburgh Postnatal Depression Scale (EPDS) for screening to detect major depression among pregnant and postpartum women: systematic review and meta-analysis of individual participant data. BMJ.

Objective: To evaluate the Edinburgh Postnatal Depression Scale (EPDS) for screening to detect major depression in pregnant and postpartum women.

Design: Individual participant data meta-analysis. Data sources: Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, and Web of Science (from inception to 3 October 2018). Eligibility criteria for selecting studies: Eligible datasets included EPDS scores and major depression classification based on validated diagnostic interviews. Bivariate random effects meta-analysis was used to estimate EPDS sensitivity and specificity compared with semi-structured, fully structured (Mini International Neuropsychiatric Interview (MINI) excluded), and MINI diagnostic interviews separately using individual participant data. One stage meta-regression was used to examine accuracy by reference standard categories and participant characteristics. Results: Individual participant data were obtained from 58 of 83 eligible studies (70%; 15 557 of 22 788 eligible participants (68%), 2069 with major depression). Combined sensitivity and specificity was maximised at a cut-off value of 11 or higher across reference standards. Among studies with a semi-structured interview (36 studies, 9066 participants, 1330 with major depression), sensitivity and specificity were 0.85 (95% confidence interval 0.79 to 0.90) and 0.84 (0.79 to 0.88) for a cut-off value of 10 or higher, 0.81 (0.75 to 0.87) and 0.88 (0.85 to 0.91) for a cut-off value of 11 or higher, and 0.66 (0.58 to 0.74) and 0.95 (0.92 to 0.96) for a cut-off value of 13 or higher, respectively. Accuracy was similar across reference standards and subgroups, including for pregnant and postpartum women. Conclusions: An EPDS cut-off value of 11 or higher maximised combined sensitivity and specificity; a cut-off value of 13 or higher was less sensitive but more specific. To identify pregnant and postpartum women with higher symptom levels, a cut-off of 13 or higher could be used. Lower cut-off values could be used if the intention is to avoid false negatives and identify most patients who meet diagnostic criteria.

Eckerdal P, Kollia N, Karlsson L, Skoog-Svanberg A, Wikström AK, Högberg U, Skalkidou A. (2020). Epidural Analgesia During Childbirth and Postpartum Depressive Symptoms: A Population-Based Longitudinal Cohort Study. Anesth Analg. Mar;130(3):615-624. 

Background: Severe pain has been linked to depression, which raises the question of whether epidural analgesia (EDA) during childbirth is associated with a reduced risk of postpartum depression (PPD). This association has been explored previously, but the studies were restricted by small sample sizes and the inability to control for relevant confounders. This study aimed to investigate the association between the administration of EDA and the development of PPD after adjusting for sociodemographic, psychosocial, and obstetric variables. Methods: Data were retrieved from the Biology, Affect, Stress, Imaging and Cognition (BASIC) project (2009-2017), a population-based longitudinal cohort study of pregnant women conducted at Uppsala University Hospital, Sweden. The outcome was PPD at 6 weeks postpartum, defined as a score of ≥12 points on the Edinburgh Postnatal Depression Scale (EPDS). Information was collected through medical records and self-reported web-based questionnaires during pregnancy and 6 weeks after childbirth. Only primiparous women with spontaneous start of childbirth were included (n = 1503). The association between EDA and PPD was examined in multivariable logistic regression models, adjusting for sociodemographic, psychosocial, and obstetric variables. Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). Results: Of the 1503 women included in the analysis, 800 (53%) reported use of EDA during childbirth. PPD at 6 weeks postpartum was present in 193 (13%) women. EDA was not associated with higher odds of PPD at 6 weeks postpartum after adjusting for suspected confounders (age, fear of childbirth, antenatal depressive symptoms; adjusted OR [aOR] = 1.22; 95% CI, 0.87-1.72). Conclusions: EDA was not associated with the risk of PPD at 6 weeks postpartum after adjusting for sociodemographic, psychosocial, and obstetric variables. However, these findings do not preclude a potential association between PPD and childbirth pain or other aspects of EDA that were not assessed in this study.


Astor, K., Lindskog, M., Forssman, L., Kenward, B., Fransson, M., Skalkidou, A., Tharner, A., Cassé, J., & Gredebäck, G. (2020). Social and emotional contexts predict the development of gaze following in early infancy. Royal Society open science, 7(9):201178

The development of gaze following begins in early infancy and its developmental foundation has been under heavy debate. Using a longitudinal design (N = 118), we demonstrate that attachment quality predicts individual differences in the onset of gaze following, at six months of age, and that maternal postpartum depression predicts later gaze following, at 10 months. In addition, we report longitudinal stability in gaze following from 6 to 10 months. A full path model (using attachment, maternal depression and gaze following at six months) accounted for 21% of variance in gaze following at 10 months. These results suggest an experience-dependent development of gaze following, driven by the infant's own motivation to interact and engage with others (the social-first perspective).

Fransson E, Sörensen F, Kunovac Kallak T, Ramklint M, Eckerdal P, Heimgärtner M, Krägeloh-Mann I, Skalkidou A. (2020). Maternal perinatal depressive symptoms trajectories and impact on toddler behavior - the importance of symptom duration and maternal bonding. J Affect Disord.

Background: Maternal perinatal depression is a public health problem affecting mothers and children worldwide. This study aimed to increase the knowledge regarding the impact of timing of maternal depression on child behavioral difficulties at 18 months, taking into consideration child gender and maternal bonding. Methods: Data from a Swedish population-based longitudinal mother-infant study (n = 1,093) were used for linear regression modeling. Associations between antenatal depression, postpartum depression, persistent depression and child behavioral problems were assessed. Results: Maternal antenatal and persistent depression were associated with higher Child Behavior Checklist scores. Girls were affected to a greater degree. Postpartum bonding mediated most of the negative effects of postpartum and persistent depression on child behavior; not the effects of antenatal depression, however. Limitations: Child behavioral problems were reported by the mother. Information regarding paternal depressive symptoms was lacking. Conclusion: Different onset and timing of maternal depression showed distinct associations with child behavioral problems. The effects of antenatal depression were not mediated by maternal bonding, indicating underlying mechanisms possibly related to fetal programming. Screening of depressive symptoms even during pregnancy would be important in routine care in order to early identify and treat depression.

Asif, S., Mulic-Lutvica, A., Axfors, C., Eckerdal, P., Iliadis, S. I., Fransson, E. and Skalkidou, A. (2020) Severe obstetric lacerations associated with postpartum depression among women with low resilience - a Swedish birth cohort study. BJOG 127(11).

OBJECTIVE: Women's levels of resilience and attitudes towards perineal lacerations vary greatly. Some women see them as part of the birthing process, while others react with anger, depressed mood or even self-harm thoughts. A previous study has reported increased risk of postpartum depressive (PPD) symptoms in women with severe perineal lacerations. The aim of this study was to assess the association between severe obstetric perineal lacerations and PPD. A secondary objective was to assess this association among women with low resilience. DESIGN: Nested cohort study. SETTING: Uppsala, Sweden. SAMPLE: Vaginally delivered women with singleton pregnancies (n = 2,990). METHODS: The main exposure was obstetric perineal lacerations. Resilience was assessed in gestational week 32 using the Swedish version of the Sense of Coherence Scale (SOC-29). A digital acyclic graph (DAG) was used to identify possible confounders and mediators. Logistic regression was used to estimate odds ratios and 95% confidence intervals. A sub-analysis was run after excluding women with normal or high resilience. MAIN OUTCOME MEASURES: Postpartum depression, assessed with the Depression Self-Reporting Scale (DSRS), completed at six weeks postpartum. RESULTS: There was no significant association between severe obstetric perineal lacerations and PPD at six weeks postpartum. However, a significant association was found between severe lacerations and PPD in women with low resilience (OR =4.8 95% CI = 1.2-20), persisting even after adjusting for confounding factors. CONCLUSION: Health care professionals might need to identify women with low resilience, as they are at increased risk for PPD after a severe perineal laceration.

Skalkidou A, Sundström-Poromaa I, Wikman A, Hesselman S, Wikström AK, Elenis E. (2020). SSRI use during pregnancy and risk for postpartum haemorrhage: a national register-based cohort study in Sweden. BJOG.

Objective: Evaluate whether selective serotonin reuptake inhibitor (SSRI) use during pregnancy, as well as prior or current untreated psychiatric illness is associated with postpartum haemorrhage (PPH). Design: National register-based cohort study based on data from the Swedish Pregnancy Register. Setting: Sweden, nationwide coverage. Population: A total of 31 159 pregnant women with singleton deliveries after gestational week 22+0 between January 2013 and July 2017. Methods: Pregnant women with self-reported SSRI use at any time point during pregnancy were compared with non-SSRI-treated women with prior or current psychiatric illness, as well as wiith healthy women with no psychiatric illness or reporting SSRI use.

Main outcome measures: Postpartum haemorrhage defined as blood loss >1000 ml during the first 2 hours postpartum reported by the delivering midwife or obstetrician. Results: Postpartum haemorrhage prevalence was 7.0% among healthy women, 7.6% among women with prior or current psychiatric illness and 9.1% among women treated with SSRI. The unadjusted odds for PPH among women with prior or current psychiatric illness and women on SSRI treatment were increased by 9 and 34%, respectively, compared with healthy unmedicated women without a history of psychiatric illness (odds ratio [OR] 1.09, 95% CI 1.04-1.14 and OR 1.34, 95% CI 1.24-1.44, respectively). The estimates remained unchanged after adjustment for several confounders (such as maternal age, body mass index [BMI], parity, prior caesarean section, smoking, occupation and country of birth) and potential covariates (such as delivery mode, polyhydramnion, preterm delivery, labour dystocia and infant birthweight >4000 g). Conclusions: Higher risk for PPH was observed both among women treated with SSRI during pregnancy and among women with prior or current psychiatric illness.

Edvinsson, A., Hoyer, A., Hansson, M., Kallak, T. K., Sundstrom-Poromaa, I., Skalkidou, A., Lager, S. (2020) Placental glucocorticoid receptors are not affected by maternal depression or SSRI treatment. Ups J Med Sci. 1-7

Background: Prenatal depression is common, with an estimate that up to one in five pregnant women suffers from depressive symptoms. Maternal depression is associated with poor pregnancy outcomes such as preterm birth and low birth-weight. Such outcomes possibly affect offspring development. Previous studies suggest placental RNA levels of the glucocorticoid receptor are altered by maternal depression or anxiety; this stress may affect the placenta of male and female foetuses differently. However, it is unknown if the protein levels and activity of this receptor are additionally affected in women with depressive symptoms or being pharmacologically treated for depression.Methods: In this study, we investigated whether the glucocorticoid receptor (NR3C1) in the placenta is affected by maternal depression and/or selective serotonin reuptake inhibitor (SSRIs) treatment. Placentas from 45 women with singleton, term pregnancies were analysed by Western blot to determine glucocorticoid receptor levels, and by DNA-binding capacity to measure glucocorticoid receptor activation.Results: There were no differences in levels of the glucocorticoid receptor or activity between groups (control, depressive symptoms, and SSRI treatment; n = 45). Similarly, there was no difference in placental glucocorticoid receptor levels or activity dependent upon foetal sex.Conclusion: Maternal depression and SSRI treatment do not affect the glucocorticoid receptors in the placenta.

Axfors, C., Bränn, E., Henriksson, HE., Hellgren, C., Kunovac Kallak, T., Fransson, E., Lager, S., 2, Iliadis SI.,, Sylvén S., Papadopoulos FC., Ekselius L., Sundström-Poromaa I., Skalkidou A. (2019) Cohort Profile: The Biology, Affect, Stress, Imaging and Cognition (Basic) Study on Perinatal Depression in a Population-Based Swedish Cohort.  BMJ Open 9, no. 10.

PURPOSE: With the population-based, prospective Biology, Affect, Stress, Imaging and Cognition (BASIC) cohort, we aim to investigate the biopsychosocial aetiological processes involved in perinatal depression (PND) and to pinpoint its predictors in order to improve early detection.

PARTICIPANTS: From September 2009 to November 2018, the BASIC study at Uppsala University Hospital, Sweden, has enrolled 5492 women, in 6478 pregnancies, of which 46.3% first-time pregnancies and with an average age of 31.5 years. After inclusion around gestational week 16-18, participants are followed-up with data collection points around gestational week 32, at childbirth, as well as three times postpartum: after 6 weeks, 6 months and 1 year. At the last follow-up, 70.8% still remain in the cohort.

FINDINGS TO DATE: In addition to internet-based surveys with self-report instruments, participants contribute with biological samples, for example, blood samples (maternal and from umbilical cord), biopsies (umbilical cord and placenta) and microbiota samples. A nested case-control subsample also takes part in cognitive and emotional tests, heart rate variability tests and bioimpedance tests. Subprojects have identified various correlates of PND of psychological and obstetric origin in addition to factors of the hypothalamic-pituitary-adrenal axis and immune system.

FUTURE PLANS: In parallel with the completion of data collection (final follow-up November 2019), BASIC study data are currently analysed in multiple subprojects. Since 2012, we are conducting an ongoing follow-up study on the participants and their children up to 6 years of age (U-BIRTH). Researchers interested in collaboration may contact Professor Alkistis Skalkidou (corresponding author) with their request to be considered by the BASIC study steering committee.

Axfors C, Eckerdal P, Volgsten H, Wikström AK, Ekselius L, Ramklint M, Sundström Poromaa I, Skalkidou A. (2019). Investigating the association between neuroticism and adverse obstetric and neonatal outcomes. Sci Rep.

Neuroticism is not only associated with affective disorders but also with certain somatic health problems. However, studies assessing whether neuroticism is associated with adverse obstetric or neonatal outcomes are scarce. This observational study comprises first-time mothers (n = 1969) with singleton pregnancies from several cohorts based in Uppsala, Sweden. To assess neuroticism-related personality, the Swedish universities Scales of Personality was used. Swedish national health registers were used to extract outcomes and confounders. In logistic regression models, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the outcomes by an increase of 63 units of neuroticism (equalling the interquartile range). Analyses were adjusted for maternal age, educational level, height, body mass index, year of delivery, smoking during pregnancy, involuntary childlessness, and psychiatric morbidity. Main outcomes were mode of delivery, gestational diabetes mellitus, gestational hypertension, preeclampsia, induction of delivery, prolonged delivery, severe lacerations, placental retention, postpartum haemorrhage, premature birth, infant born small or large for gestational age, and Apgar score. Neuroticism was not independently associated with adverse obstetric or neonatal outcomes besides gestational diabetes. For future studies, models examining sub-components of neuroticism or pregnancy-specific anxiety are encouraged.

Petursdottir Maack, H., Skalkidou, A., Sjoholm, A., Eurenius-Orre, K., Mulic-Lutvica, A., Wikstrom, A. K., Sundstrom Poromaa, I. (2019) Maternal body mass index moderates antenatal depression effects on infant birthweight. Sci Rep. 9(1):6213.

Obesity and depression are two common medical problems that pregnant women present with in antenatal care. Overweight and obesity at the beginning of the pregnancy, and excessive weight gain during pregnancy, are independent explanatory variables for fetal birthweight and independent risk factors for giving birth to a large for gestational age (LGA) infant. However, the effect of co-morbid depression has received little attention. This study set out to investigate if maternal body mass index (BMI) in early pregnancy moderates antenatal depression effects on infant birthweight. 3965 pregnant women participated in this longitudinal cohort study, where cases (n = 178) had Edinburgh Postnatal Depression Scale (EPDS) score ≥ 17 in gestational week 17 or 32, and remaining women (n = 3787) were used as controls. The influence of maternal BMI and antenatal depressive symptoms on standardized birthweight was evaluated by analysis of covariance, with adjustment for relevant confounders. Depressed women with BMI 25.0 kg/m2 or more gave birth to infants with significantly greater standardized birthweight than non-depressed overweight women, whereas the opposite pattern was noted in normal weight women (BMI by antenatal depressive symptoms interaction; F(1,3839) = 6.32; p = 0.012. The increased birthweight in women with co-prevalent overweight and depressive symptoms was not explained by increased weight gain during the pregnancy. Maternal BMI at the beginning of pregnancy seems to influence the association between antenatal depressive symptoms and infant birthweight, but in opposite directions depending on whether the pregnant women is normal weight or overweight. Further studies are needed to confirm our finding.

Breedh, J., Comasco, E., Hellgren, C., Papadopoulos, F. C., Skalkidou, A., Poromaa, I. S. (2019). Hypothalamic-pituitary-adrenal axis responsiveness, startle response, and sensorimotor gating in late pregnancy. Psychoneuroendocrinology. 106:1-8.

During pregnancy, the hypothalamic-pituitary-adrenal (HPA) axis, the main regulator of the stress response, undergoes dramatic changes. The acoustic startle response (ASR) and the prepulse inhibition (PPI) of the startle response are neurophysiological research tools and objective measures of an individual's response to an emotional context or stressor. The ASR and PPI are influenced by psychiatric diseases characterized by anxiety symptoms and are sensitive to cortisol. Hence, the ASR and the PPI can be used to investigate the effects of pregnancy-induced endocrine changes and their contribution to affective disorders. The present study sought to investigate the association between measures of HPA-axis responsiveness, startle reactivity and sensorimotor gating during pregnancy that to date remains unknown. The eye-blink component of the ASR, and its prepulse inhibition, were measured in 107 late third trimester pregnant women. Saliva samples were collected to assess the cortisol awakening response (CAR), a measure of HPA-axis activity. Blood was sampled to measure serum levels of cortisol, cortisone and the cortisone to cortisol ratio. Ongoing anxiety disorders, sleep duration, smoking, and age were considered as potential confounders in the statistical analyses. CAR reactivity, measured as area under the curve (AUC) increase and above baseline, was positively associated with baseline startle magnitude [Cohen's d = 0.27; F (1, 105) = 4.99; p = 0.028, and Cohen's d = 0.30; F (1, 105) = 6.25; p = 0.014, respectively] as well as PPI at 86 dB [Cohen's d = 0.29; F (1, 105) = 5.93; p = 0.017; and Cohen's d = 0.34; F (1, 105) = 8.38; p = 0.005, respectively]. The observed positive correlation between startle magnitude in pregnant women and greater increase in cortisol during the awakening response may be interpreted as heightened neurophysiological reactivity, likely associated with dysregulation of the stress system.

Skalkidou, A., Poromaa, I. S., Iliadis, S. I., Huizink, A. C., Hellgren, C., Freyhult, E., Comasco, E. (2019). Stress-related genetic polymorphisms in association with peripartum depression symptoms and stress hormones: A longitudinal population-based study. Psychoneuroendocrinology 103:296-305

Individual differences in the response of the stress system to hormonal changes during pregnancy and the postpartum period render some women susceptible to developing depression. The present study sought to investigate peripartum depression and stress hormones in relation to stress-related genotypes. The Edinburgh Postnatal Depression Scale was used to assess peripartum depressive symptoms in a sample of 1629 women, followed from pregnancy week seventeen to six months postpartum. Genotypes of ninety-four haplotype-tag single nucleotide polymorphisms (SNPs) in sixteen genes of the hypothalamus-pituitary-adrenal axis pathway were analyzed and data on psychosocial and demographic factors was collected. In sub-studies, salivary cortisol awakening response in gestational week 35-39, salivary evening cortisol levels in gestational week 36 and postpartum week 6, and blood cortisol and cortisone levels in gestational week 35-39 were analyzed. SNP-set kernel association tests were performed at the gene-level, considering psychosocial and demographic factors, followed by post-hoc analyses of SNPs of significant genes. Statistically significant findings at the 0.05 p-level included SNPs in the hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) gene in relation to self-rated depression scores in postpartum week six among all participants, and serpin family A member 6 (SERPINA6) gene at the same time-point among women with de novo onset of postpartum depression. SNPs in these genes also associated with stress hormone levels during pregnancy. The present study adds knowledge to the neurobiological basis of peripartum depression by systematically assessing SNPs in stress-regulatory genes and stress-hormone levels in a population-based sample of women.

Bränn, E., Edvinsson, Å., Rostedt Punga, A., Sundström-Poromaa, I., Skalkidou, A. (2019). Inflammatory and anti-inflammatory markers in plasma: from late pregnancy to early postpartum. Sci Rep. 9(1):1863

During pregnancy, the woman's body undergoes tremendous changes in immune system adaptation. The immunological shifts that occur in pregnancy can partially be explained by alterations in hormonal levels. Furthermore, during pregnancy, many autoimmune diseases go into remission, only to flare again in the early postpartum period. Given these important changes in the clinical course of a number of autoimmune disorders, surprisingly little has been done to investigate the inflammatory profile changes across pregnancy and the postpartum period. Thus, the aim of this study was to describe how inflammatory and anti-inflammatory markers change from late pregnancy to the early postpartum period, using a multiplexed assay consisting of both well-known as well as exploratory proteins. Two-hundred-and-ninety women were included in this study and donated a total of 312 blood samples; 198 in late pregnancy (~gw38) and 114 in the postpartum period (~w8). The plasma blood samples were analyzed for 92 immune system related protein markers using Proseek Multiplex Inflammation I panel, a high-sensitivity assay based on proximity extension assay technology. Fifty-six inflammatory and anti-inflammatory markers were significantly different between pregnancy and the postpartum, of which 50 survived corrections for multiple comparisons. Out of these 50 markers, 41 decreased from pregnancy to postpartum, while the remaining 9 increased in the postpartum period. The top five markers with the greatest decrease in the postpartum period were Leukemia inhibitory factor receptor (LIF-R), Latency-associated peptide Transforming growth factor beta-1 (LAP TGF-beta-1), C-C motif chemokine 28 (CCL28), Oncostatin M (OSM) and Fibroblast growth factor 21 (FGF21). Top three markers that increased in the postpartum period were Tumor necrosis factor ligand superfamily member 11 (TRANCE), Tumor necrosis factor ligand superfamily member 12 (TWEAK), and C-C motif chemokine/Eotaxin (CCL11). This study revealed that the majority of the markers decreased from pregnancy to postpartum, and only a few increased. Several of the top proteins that were higher in pregnancy than postpartum have anti-inflammatory and immune modulatory properties promoting pregnancy progress. These results clearly reflect the tremendous change in the immune system in the pregnancy to postpartum transition.

Wikman, A., Axfors, C., Iliadis, S. I., Cox, J., Fransson, E., Skalkidou, A. (2019). Characteristics of women with different perinatal depression trajectories. J Neurosci Res.

Maternal perinatal depression (PND), a common mental disorder with a prevalence of over 10%, is associated with long-term health risks for both mothers and offspring. This study aimed at describing characteristics related to background and lifestyle, pregnancy, delivery, and postpartum of different PND trajectories defined according to the onset of depressive symptoms. Participants were drawn from a large population-based cohort study in Uppsala, Sweden (n = 2,466). Five trajectory groups of depressive symptom onset were created using the Edinburgh Postnatal Depression Scale ≥13 (pregnancy) or ≥12 points (postpartum): (a) healthy (60.6%), (b) pregnancy depression (8.5%), (c) early postpartum onset (10.9%), (d) late postpartum onset (5.4%), and (e) chronic depression (14.6%). In multinomial logistic regressions, the associations between trajectories and the included characteristics were tested using the healthy trajectory as reference. Background characteristics (younger age, lower education, unemployment) were primarily associated with pregnancy depression and chronic depression. Characteristics associated with all PND trajectories were smoking prior to pregnancy, migraine, premenstrual mood symptoms, intimate partner violence, interpersonal trauma, negative delivery expectations, pregnancy nausea, and symphysiolysis. Nulliparity, instrumental delivery, or a negative delivery experience was associated with early postpartum onset. Postpartum factors (e.g., infantile colic, lack of sleep, low partner support, and bonding difficulties) were associated with early and late postpartum onset together with chronic depression. The findings suggest that different PND trajectories have divergent characteristics, which could be used to create individualized treatment options. To find the most predictive characteristics for different PND trajectories, studies with even larger and more diverse samples are warranted.

Levis B, McMillan D, Sun Y, He C, Rice DB, Krishnan A, Wu Y, Azar M, Sanchez TA, Chiovitti MJ, Bhandari PM, Neupane D, Saadat N, Riehm KE, Imran M, Boruff JT, Cuijpers P, Gilbody S, Ioannidis JPA, Kloda LA, Patten SB, Shrier I, Ziegelstein RC, Comeau L, Mitchell ND, Tonelli M, Vigod SN, Aceti F, Alvarado R, Alvarado-Esquivel C, Bakare MO, Barnes J, Beck CT, Bindt C, Boyce PM, Bunevicius A, Couto TCE, Chaudron LH, Correa H, de Figueiredo FP, Eapen V, Fernandes M, Figueiredo B, Fisher JRW, Garcia-Esteve L, Giardinelli L, Helle N, Howard LM, Khalifa DS, Kohlhoff J, Kusminskas L, Kozinszky Z, Lelli L, Leonardou AA, Lewis BA, Maes M, Meuti V, Nakić Radoš S, Navarro García P, Nishi D, Okitundu Luwa E-Andjafono D, Robertson-Blackmore E, Rochat TJ, Rowe HJ, Siu BWM, Skalkidou A, Stein A, Stewart RC, Su KP, Sundström-Poromaa I, Tadinac M, Tandon SD, Tendais I, Thiagayson P, Töreki A, Torres-Giménez A, Tran TD, Trevillion K, Turner K, Vega-Dienstmaier JM, Wynter K, Yonkers KA, Benedetti A, Thombs BD. (2019). Comparison of major depression diagnostic classification probability using the SCID, CIDI, and MINI diagnostic interviews among women in pregnancy or postpartum: An individual participant data meta-analysis. Int J Methods Psychiatr Res.

Objectives: A previous individual participant data meta-analysis (IPDMA) identified differences in major depression classification rates between different diagnostic interviews, controlling for depressive symptoms on the basis of the Patient Health Questionnaire-9. We aimed to determine whether similar results would be seen in a different population, using studies that administered the Edinburgh Postnatal Depression Scale (EPDS) in pregnancy or postpartum. Methods: Data accrued for an EPDS diagnostic accuracy IPDMA were analysed. Binomial generalised linear mixed models were fit to compare depression classification odds for the Mini International Neuropsychiatric Interview (MINI), Composite International Diagnostic Interview (CIDI), and Structured Clinical Interview for DSM (SCID), controlling for EPDS scores and participant characteristics. Results: Among fully structured interviews, the MINI (15 studies, 2,532 participants, 342 major depression cases) classified depression more often than the CIDI (3 studies, 2,948 participants, 194 major depression cases; adjusted odds ratio [aOR] = 3.72, 95% confidence interval [CI] [1.21, 11.43]). Compared with the semistructured SCID (28 studies, 7,403 participants, 1,027 major depression cases), odds with the CIDI (interaction aOR = 0.88, 95% CI [0.85, 0.92]) and MINI (interaction aOR = 0.95, 95% CI [0.92, 0.99]) increased less as EPDS scores increased. Conclusion: Different interviews may not classify major depression equivalently.

Cato, K., Sylven, S. M., Georgakis, M. K., Kollia, N., Rubertsson, C., Skalkidou, A.Antenatal depressive symptoms and early initiation of breastfeeding in association with exclusive breastfeeding six weeks postpartum: a longitudinal population-based study.BMC Pregnancy Childbirth. 19(1):49

BACKGROUND: Depressive symptoms negatively impact on breastfeeding duration, whereas early breastfeeding initiation after birth enhances the chances for a longer breastfeeding period. Our aim was to investigate the interplay between depressive symptoms during pregnancy and late initiation of the first breastfeeding session and their effect on exclusive breastfeeding at six weeks postpartum.

METHODS: In a longitudinal study design, web-questionnaires including demographic data, breastfeeding information and the Edinburgh Postnatal Depression Scale (EPDS) were completed by 1217 women at pregnancy weeks 17-20, 32 and/or at six weeks postpartum. A multivariable logistic regression model was fitted to estimate the effect of depressive symptoms during pregnancy and the timing of the first breastfeeding session on exclusive breastfeeding at six weeks postpartum.

RESULTS: Exclusive breastfeeding at six weeks postpartum was reported by 77% of the women. Depressive symptoms during pregnancy (EPDS> 13); (OR:1.93 [1.28-2.91]) and not accomplishing the first breastfeeding session within two hours after birth (OR: 2.61 [1.80-3.78]), were both associated with not exclusively breastfeeding at six weeks postpartum after adjusting for identified confounders. Τhe combined exposure to depressive symptoms in pregnancy and late breastfeeding initiation was associated with an almost 4-fold increased odds of not exclusive breastfeeding at six weeks postpartum.

CONCLUSIONS: Women reporting depressive symptoms during pregnancy seem to be more vulnerable to the consequences of a postponed first breastfeeding session on exclusive breastfeeding duration. Consequently, women experiencing depressive symptoms may benefit from targeted breastfeeding support during the first hours after birth.

Henriksson, HE., Malavaki, C., Bränn, E., Drainas, V., Lager, S., Iliadis, SI., Papadopoulos, FC., Sundström Poromaa, I., Chrousos, GP., Klapa, MI., Skalkidou, A. (2019) Blood plasma metabolic profiling of pregnant women with antenatal depressive symptoms. Transl Psychiatry. 2019 Aug 23;9(1):204.

Antenatal depression affects ~9-19% of pregnant women and can exert persistent adverse effects on both mother and child. There is a need for a deeper understanding of antenatal depression mechanisms and the development of tools for reliable diagnosis and early identification of women at high risk. As the use of untargeted blood metabolomics in the investigation of psychiatric and neurological diseases has increased substantially, the main objective of this study was to investigate whether untargeted gas chromatography-mass spectrometry (GC-MS) plasma metabolomics in 45 women in late pregnancy, residing in Uppsala, Sweden, could indicate metabolic differences between women with and without depressive symptoms. Furthermore, seasonal differences in the metabolic profiles were explored. When comparing the profiles of cases with controls, independently of season, no differences were observed. However, seasonal differences were observed in the metabolic profiles of control samples, suggesting a favorable cardiometabolic profile in the summer vs. winter, as indicated by lower glucose and sugar acid concentrations and lactate to pyruvate ratio, and higher abundance of arginine and phosphate. Similar differences were identified between cases and controls among summer pregnancies, indicating an association between a stressed metabolism and depressive symptoms. No depression-specific differences were apparent among depressed and non-depressed women, in the winter pregnancies; this could be attributed to an already stressed metabolism due to the winter living conditions. Our results provide new insights into the pathophysiology of antenatal depression, and warrant further investigation of the use of metabolomics in antenatal depression in larger cohorts.

Henriksson, HE., White, RA., Iliadis, SI., Fransson, E., Papadopoulos, FC., Sundström-Poromaa, I., Skalkidou, A. (2019) Spring peaks and autumn troughs identified in peripheral inflammatory markers during the peripartum period. Sci Rep. 9(1):15328

Seasonal variations have recently been described in biomarkers, cell types, and gene expression associated with the immune system, but so far no studies have been conducted among women in the peripartum period. It is of note that pregnancy complications and outcomes, as well as autoimmune diseases, have also been reported to exhibit seasonal fluctuations. We report here a clear-cut seasonal pattern of 23 inflammatory markers, analysed using proximity-extension assay technology, in pregnant women. The inflammatory markers generally peaked in the spring and had a trough in the autumn. During the postpartum period we found seasonality in one inflammatory marker, namely monocyte chemotactic protein 4 (MCP-4). Our findings suggest that seasonal variations in peripheral inflammatory markers are only observed during pregnancy. The results of this study could be valuable to professionals working within the field of immunology-related areas, and provide insight for the understanding of obstetric complications.

Edvinsson, Å., Hellgren, C., Kunovac Kallak, T., Åkerud, H., Skalkidou, A., Stener-Victorin, E., Fornes, R., Spigset, O., Lager, S., Olivier, J., Sundström-Poromaa, I. (2019). The effect of antenatal depression and antidepressant treatment on placental tissue: a protein-validated gene expression study. BMC Pregnancy and Childbirth, 19(1).

Background: Antenatal depression affects 10–20% of pregnant women. Around 2–4% of European pregnant womenuse antidepressant treatment, most commonly selective serotonin reuptake inhibitors (SSRIs). Poor pregnancyoutcomes, such as preterm birth and low birth weight, have been described in women with antenatal depression andin pregnant women on SSRI treatment. However, the effects of antenatal depression and antidepressant treatment onthe placenta are largely unknown. The aim of this work was to compare placental gene and protein expression inhealthy women, women with untreated antenatal depression and women on antidepressant treatment duringpregnancy. Methods: Placental samples from 47 controls, 25 depressed and 45 SSRI-treated women were analysed by means ofqPCR using custom-designed TaqMan low-density arrays (TLDAs) for 44 genes previously known to be involved in thepathophysiology of depression, and expressed in the placenta. Moreover, placental protein expression was determinedby means of immunohistochemistry in 37 healthy controls, 13 women with untreated depression and 21 women onantidepressant treatment. Statistical comparisons between groups were performed by one-way ANOVA or the Kruskal–Wallis test. Results: Nominally significant findings were noted forHTR1AandNPY2R, where women with untreated depressiondisplayed higher gene expression than healthy controls (p< 0.05), whereas women on antidepressant treatment hadsimilar expression as healthy controls. The protein expression analyses revealed higher expression of HTR1A inplacentas from women on antidepressant treatment, than in placentas from healthy controls (p<0.05). Conclusion: The differentially expressed HTR1A, both at the gene and the protein level that was revealed in this study,suggests the involvement of HTR1A in the effect of antenatal depression on biological mechanisms in the placenta.More research is needed to elucidate the role of depression and antidepressant treatment on the placenta, and,further, the effect on the fetus

Bränn, E., E. Fransson, R. A. White, F. C. Papadopoulos, A. Edvinsson, M. Kamali-Moghaddam, J. L. Cunningham, I. Sundstrom-Poromaa, and A. Skalkidou. (2018) Inflammatory Markers in Women with Postpartum Depressive Symptoms. Journal of Neuroscience Research 

Postpartum depression (PPD) is a devastating disorder affecting not only more than 10% of all women giving birth, but also the baby, the family, and the society. Compiling evidence suggests the involvement of the immune system in the pathophysiology of major depression; yet, the immune response in perinatal depression is not as well studied. The aim of this study was to investigate the alterations in peripheral levels of inflammatory biomarkers in 169 Swedish women with and without depressive symp‐ toms according to the Edinburgh postnatal depression scale or the M.I.N.I neuropsy‐ chiatric interview at eight weeks postpartum. Among the 70 markers analyzed with multiplex proximity extension assay, five were significantly elevated in women with postpartum depressive symptoms in the adjusted LASSO logistic regression analysis: Tumor necrosis factor ligand superfamily member (TRANCE) (OR‐per 1 SD in‐ crease = 1.20), Hepatocyte growth factor (HGF) (OR = 1.17) Interleukin (IL)‐18 (OR = 1.06), Fibroblast growth factor 23 (FGF‐23) (OR = 1.25), and C‐X‐C motif chemokine 1 (CXCL1) (OR 1.11). These results indicate that women with PPD have elevated levels of some inflammatory biomarkers. It is, therefore, plausible that PPD is associated with a compromised adaptability of the immune system.

Iliadis, S., Axfors, C., Johansson, S., Skalkidou, A., & Mulic-Lutvica, A. (2018). Women with prolonged nausea in pregnancy have increased risk for depressive symptoms postpartum. Scientific Reports, 8(1), 1-9.

The aim of this population-based, longitudinal study was to assess the association between nausea and vomiting in pregnancy (NVP) and perinatal depressive symptoms. Pregnant women (N = 4239) undergoing routine ultrasound at gestational week (GW) 17 self-reported on NVP and were divided into those without nausea (G0), early (≤17 GW) nausea without medication (G1), early nausea with medication (G2), and prolonged (>17 GW) nausea (G3). The Edinburgh Postnatal Depression Scale at GW 17 and 32 (cut-off ≥13) and at six weeks postpartum (cut-off ≥12) was used to assess depressive symptoms. Main outcome measures were depressive symptoms at GW 32 and at six weeks postpartum. NVP was experienced by 80.7%. The unadjusted logistic regression showed a positive association between all three nausea groups and depressive symptoms at all time-points. After adjustment, significant associations with postpartum depressive symptoms remained for G3, compared to G0 (aOR = 1.66; 95% CI 1.1–2.52). After excluding women with history of depression, only the G3 group was at higher odds for postpartum depressive symptoms (aOR = 2.26; 95% CI 1.04–4.92). Inconclusion, women with prolonged nausea have increased risk of depressive symptoms at six weeks postpartum, regardless of history of depression.

Henriksson, White, Sylvén, Papadopoulos, & Skalkidou. (2018). Meteorological parameters and air pollen count in association with self-reported peripartum depressive symptoms. European Psychiatry, 54, 10-18.

Background: Meteorological parameters and air pollen count have been associated withaffective disorders and suicide. Regarding peripartum depression, the literature is restricted and inconclusive. Methods: This cross-sectional study included women (pregnant, n = 3843; postpartum, n = 3757) who participated in the BASIC (Biology, Affect, Stress, Imaging, and Cognition) study 2010–2015 and the UPPSAT (Uppsala-Athens) study (postpartum, n = 1565) in 2006–2007. Cases were defined according to presence of depressive symptoms during pregnancy (gestational week 32) and 6 weeks postpartum, using the Edinburgh Postnatal Depression Scale (EPDS). Exposure of sunshine, temperature, precipitation, snow coverage, and air pollen counts of durations of 1, 7, and 42 days prior to the outcome were studied for associations with depressive symptoms, using negative binomial regression. Results: Prior to Bonferroni correction, the concentration of mugwort pollen, both one week and six weeks before the EPDS assessment at gestational week 32, was inversely associated with depressive symptoms in pregnancy, both before and after adjustment for season. No associationswere found between the exposure to meteorological parameters and pollen and depressive symptoms, at the same day of depressive symptoms’ assessment, the previous week, or the six weeks prior to assessment, either during pregnancy or postpartum after Bonferroni correction. Conclusions: There was no evidence that neither short-term nor long-term exposure to meteorological parameters or air pollen counts were associated with self-reported peripartum depressive symptoms inUppsala, Sweden.

Elenis, E., Skalkidou, A., Skoog-Svanberg, A., Sydsjo, G., Stavreus-Evers, A., & Akerud, H. (2018). HRG C633T polymorphism and risk of gestational hypertensive disorders: a pilot study. BMC Med Genet, 19(1), 44.

BACKGROUND: Preeclampsia and gestational hypertensive disorders are thought to occur due to endothelial cell dysfunction and abnormal placentation, triggered by angiogenesis-related factors yet undetermined. The aim of this study was to investigate whether a genetic polymorphism (SNP) of Histidine-rich glycoprotein (HRG), HRG C633T SNP, is associated with gestational hypertensive disorders. METHODS: It was performed a nested case-control study from the BASIC Cohort of Uppsala University Hospital comprising 92 women diagnosed with gestational hypertensive disorders without other comorbidities and 200 women with full term uncomplicated pregnancies, all genotyped regarding HRG C633T SNP. RESULTS: The genetic analysis of the study sample showed that C/C genotype was more prevalent among controls. The presence of the T-allele showed a tendency towards an increased risk of gestational hypertensive disorders. After clustering the study participants based on their genotype, it was observed that the odds for gestational hypertensive disorders among heterozygous C/T or homozygous T/T carriers were higher compared to homozygous C/C carriers [OR 1.72, 95% CI (1.04-2.84)]. The association remained significant even after adjustment for maternal age, BMI and parity. CONCLUSIONS: The HRG C633T genotype seems to be associated with gestational hypertensive disorders, and as part of a greater algorithm, might contribute in the future to the prediction of the individual susceptibility to the condition.

Eckerdal, P., Georgakis, M. K., Kollia, N., Wikstrom, A. K., Hogberg, U., & Skalkidou, A. (2018). Delineating the association between mode of delivery and postpartum depression symptoms: a longitudinal study. Acta Obstet Gynecol Scand, 97(3), 301-311.

INTRODUCTION: Although a number of perinatal factors have been implicated in the etiology of postpartum depression, the role of mode of delivery remains controversial. Our aim was to explore the association between mode of delivery and postpartum depression, considering the potentially mediating or confounding role of several covariates. MATERIAL AND METHODS: In a longitudinal-cohort study in Uppsala, Sweden, with 3888 unique pregnancies followed up postpartum, the effect of mode of delivery (spontaneous vaginal delivery, vacuum extraction, elective cesarean section, emergency cesarean section) on self-reported postpartum depression symptoms (Edinburgh Postnatal Depression Scale >/=12) at 6 weeks postpartum was investigated through logistic regression models and path analysis. RESULTS: The overall prevalence of postpartum depression was 13%. Compared with spontaneous vaginal delivery, women who delivered by emergency cesarean section were at higher risk for postpartum depression 6 weeks after delivery in crude (odds ratio 1.45, 95% confidence interval 1.04-2.01) but not in adjusted analysis. However, the path analysis revealed that emergency cesarean section and vacuum extraction were indirectly associated with increased risk of postpartum depression, by leading to postpartum complications, self-reported physical symptoms postpartum, and therefore a negative delivery experience. In contrast, history of depression and fear of delivery increased the odds of postpartum depression and led more frequently to elective cesarean section; however, it was associated with a positive delivery experience. CONCLUSIONS: Mode of delivery has no direct impact on risk of postpartum depression; nevertheless, several modifiable or non-modifiable mediators are present in this association. Women delivering in an emergency setting by emergency cesarean section or vacuum extraction, and reporting negatively experienced delivery, constitute a high-risk group for postpartum depression.

Axfors, C., Sylven, S., Ramklint, M., & Skalkidou, A. (2017). Adult attachment's unique contribution in the prediction of postpartum depressive symptoms, beyond personality traits. J Affect Disord, 222, 177-184.

BACKGROUND: Personality traits such as neuroticism can help identify pregnant women at risk of postpartum depressive symptoms (PPDS). However, it is unclear whether attachment style could have an additional contribution to this risk elevation. This study aimed to examine the overlap of adult attachment insecurity and neuroticism/trait anxiety as PPDS predictors, taking into account baseline depressive symptoms. METHODS: A Swedish population-based sample of pregnant women reported on adult attachment and either neuroticism (n = 1063) or trait anxiety (n = 555). Depressive symptoms were assessed at baseline, and at six weeks and six months postpartum. Correlations between attachment and neuroticism/trait anxiety were calculated. Generalized linear models of PPDS tested the effect of attachment anxiety and avoidance, adjusting for neuroticism/trait anxiety and baseline depression. Logistic regression models with combined high attachment anxiety and neuroticism/trait anxiety visualized their value as risk factors beyond antenatal depression. RESULTS: Attachment and neuroticism/trait anxiety were highly correlated (r = .55-.77). Attachment anxiety exerted a partially independent effect on PPDS at six weeks (p < .05) and at six months (p < .05) adjusting for neuroticism. Among antenatally non-depressed, combined high attachment anxiety and high neuroticism or trait anxiety was predictive of PPDS at both assessment points. LIMITATIONS: Low acceptance rate, exclusive use of self-reports. CONCLUSIONS: Beyond personality, attachment anxiety had a small independent effect on the risk of PPDS. Combining items of adult attachment and neuroticism/trait anxiety could prove useful in antenatal screening for high risk of PPDS.

Axfors, C., Sylven, S., Skalkidou, A., & Ramklint, M. (2017). Psychometric properties of the attachment style questionnaire in Swedish pregnant women: short and full versions. J Reprod Infant Psychol, 35(5), 450-461.

OBJECTIVES: (i) To evaluate the reliability and factor structure of the Attachment Style Questionnaire - Short Form (ASQ-SF) for use in pregnant women and (ii) to compare the reliability and factor structure of the short- and full version-ASQ among pregnant women. BACKGROUND: Adult attachment insecurity is currently included as a major risk factor in studies of perinatal health. None of the self-report measures with a Swedish translation have been psychometrically evaluated in a pregnant cohort. METHODS: A population-based cohort of 1631 pregnant women answered the ASQ in late pregnancy. Internal consistency (item-subscale correlations, Cronbach's alpha, and alpha if item deleted) was evaluated for the seven available subscales. Confirmatory factor analysis (CFA) was run to examine the factor structure of the short form compared with the full-version. Test-retest correlations were assessed in a subgroup (n = 48). RESULTS: All mean item-subscale correlations for the ASQ-SF were > 0.30. Cronbach's alpha's for ASQ-SF dimensions were as follows: Avoidance (0.87); Anxiety (0.89); Discomfort with Closeness (0.85); Relationships as Secondary (0.54); Confidence (0.83); Need for Approval (0.76); and Preoccupation with Relationships (0.77). No item removal substantively increased subscale alpha's. The CFA demonstrated better model fit for the ASQ-SF than for the full-version ASQ, while other reliability measures were similar. Test-retest correlations ranged from 0.65 to 0.84. CONCLUSION: The ASQ-SF showed similar psychometric properties in pregnant women as in the general population and had good reliability, but the optimal factor structure needs to be studied further. Results support the usage of the ASQ-SF in pregnant cohorts.

Edvinsson, A., Skalkidou, A., Hellgren, C., Gingnell, M., Ekselius, L., Willebrand, M., & Sundstrom Poromaa, I. (2017). Different patterns of attentional bias in antenatal and postpartum depression. Brain Behav, 7(11), e00844.

Background: Biased information processing in attention, memory, and interpretation is proposed to be central cognitive alterations in patients with major depressive disorder, but studies in women with peripartum depression are scarce. Because of the many similarities with depression in nonperipartum states as regards symptom profile and risk factors, we hypothesized that women with antenatal and postpartum depression would display attentional bias to negatively and positively valenced words. Methods: One hundred and seventy-seven pregnant and 157 postpartum women were included. Among these, 40 suffered from antenatal depressive disorder and 33 from postpartum depressive disorder. An emotional Stroop task with neutral, positive, negative, and negatively valenced obstetric words was used. Results: No significant difference in emotional interference scores was noted between women with antenatal depression and nondepressed pregnant women. In contrast, women with postpartum depression displayed shorter reaction times to both positive (p = .028) and negative (p = .022) stimuli, compared with neutral words. Pregnant women on antidepressant treatment displayed longer reaction times to negatively valenced obstetric words in comparison with untreated depressed women (p = .012), and a trend toward greater interference in comparison with controls (p = .061). Conclusions: In contrast with the hypothesis, we found no evidence of attentional bias to emotionally valenced stimuli in women with untreated peripartum depression. However, the shorter reaction times to emotional stimuli in women with postpartum depression may indicate emotional numbing, which in turn, is a functional impairment that may have repercussions for child development and well-being. Our findings emphasize the need to identify and treat women with postpartum depression at the earliest possible time point to ensure swift recovery and support for the family.

Hellgren, C., Comasco, E., Skalkidou, A., & Sundstrom-Poromaa, I. (2017). Allopregnanolone levels and depressive symptoms during pregnancy in relation to single nucleotide polymorphisms in the allopregnanolone synthesis pathway. Horm Behav, 94, 106-113.

Allopregnanolone, a neurosteroid whose levels rise throughout gestation, putatively stabilizes antenatal mood. The present study aimed to investigate associations of plasma allopregnanolone to antenatal depressive symptoms, as well as to genetic and obstetric factors. Allopregnanolone plasma levels from 284 pregnant women were measured around gestational week 18. Haplotype tag single nucleotide polymorphisms in the aldo-keto reductase family 1, members C2 and C4 (AKR1C2, AKR1C4), and steroid 5 alpha-reductase 1 and 2 (SRD5A1, and SRD5A2) genes were genotyped in a larger sample of pregnant women (n=1351). The Edinburgh Postnatal Depression Scale (EPDS) was administered via web-questionnaires in gestational weeks 17 and 32. Demographic and obstetric data was retrieved from web-questionnaires and medical records. There was no association between allopregnanolone levels and depressive symptoms. Furthermore, no associations between allopregnanolone level and synthesis pathway genotypes were found after accounting for multiple comparisons. However, exploratory analyses suggested that the women who were homozygous for the minor allele of the AKR1C2 polymorphism rs1937863 had nominally lower allopregnanolone levels and lower depression scores in gestational week 17, but also the highest increase in depression scores between week 17 and 32. Additionally, higher body mass index was associated with lower allopregnanolone levels. The results do not support second trimester plasma allopregnanolone as a mood stabilizing factor. However, we speculate that AKR1C2 variation may alter the susceptibility to depressive symptoms through effects on central allopregnanolone synthesis. Another implication of this study is that the relationship between neuroactive steroids and obesity in pregnancy deserves to be investigated.

Kallak, T. K., Hellgren, C., Skalkidou, A., Sandelin-Francke, L., Ubhayasekhera, K., Bergquist, J., Axelsson, O., Comasco, E., Campbell, R. E., & Sundstrom Poromaa, I. (2017). Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain. Eur J Endocrinol, 177(4), 379-388.

OBJECTIVE: Prenatal androgen exposure has been suggested to play a role in polycystic ovary syndrome. Given the limited information on what maternal characteristics influence maternal testosterone levels, and the even less explored routes by which female fetus androgen exposure would occur, the aim of this study was to investigate the impact of maternal age, BMI, weight gain, depressed mood and aromatase SNPs on testosterone levels in maternal serum and amniotic fluid of female fetuses. METHODS: Blood samples from pregnant women (n = 216) obtained in gestational weeks 35-39, and pre-labor amniotic fluid samples from female fetuses (n = 56), taken at planned Caesarean section or in conjunction with amniotomy for induction of labor, were analyzed. Maternal serum testosterone and amniotic fluid testosterone and cortisol were measured by tandem mass spectrometry. RESULTS: Multiparity (beta = -0.28, P < 0.001), self-rated depression (beta = 0.26, P < 0.001) and weight gain (beta = 0.18, P < 0.05) were independent explanatory factors for the maternal total testosterone levels. Maternal age (beta = -0.34, P < 0.001), weight gain (beta = 0.19, P < 0.05) and amniotic fluid cortisol levels (beta = 0.44, P < 0.001) were independent explanatory factors of amniotic fluid testosterone in female fetuses, explaining 64.3% of the variability in amniotic fluid testosterone. WIDER IMPLICATIONS OF THE FINDINGS: Young maternal age and excessive maternal weight gain may increase the prenatal androgen exposure of female fetuses. Further studies are needed to explore this finding.

Gambadauro, P., S. Iliadis, E. Brann and A. Skalkidou (2017). Conception by means of in vitro fertilization is not associated with maternal depressive symptoms during pregnancy or postpartum. Fertil Steril

OBJECTIVE: To study whether conception by means of in vitro fertilization (IVF) is associated with maternal depressive symptoms during pregnancy or postpartum. DESIGN: Longitudinal observational study. SETTING: University hospital. PATIENT(S): A total of 3,283 women with singleton pregnancies receiving antenatal care and delivering in Uppsala from 2010 to 2015. INTERVENTION(S): A web-based self-administered structured questionnaire including sociodemographic, clinical and pregnancy-related items, and the Edinburgh Postnatal Depression Scale (EPDS) was delivered at 17 and 32 gestational weeks and at 6 weeks and 6 months postpartum. MAIN OUTCOME MEASURE(S): Prevalence of significant depressive symptoms (EPDS >/=12) and EPDS scores. RESULT(S): A total of 167 women (5%) had conceived via IVF and 3,116 (95%) had a spontaneous pregnancy. IVF mothers were more frequently >/=35 years of age (46.1% vs. 22.6%) and primiparous (71.7% vs. 49.9%) and had a higher cesarean delivery rate (22.4% vs. 14.2%). Demographic and clinical characteristics were otherwise similar between the two groups. Significant depressive symptoms were reported by 12.8%, 12.4%, 13.8%, and 11.9% of women at 17 and 32 gestational weeks and 6 weeks and 6 months postpartum, respectively. The prevalence of depressive symptoms and the EPDS scores during pregnancy and postpartum were similar between women conceiving spontaneously or through IVF. The mode of conception was not associated with significant depressive symptoms at any time point, even when adjusting for several possible confounders in multivariable logistic regression analysis. CONCLUSION(S): Despite the psychologic distress characterizing subfertility and its treatment, conception by means of IVF is not associated with maternal depressive symptoms during pregnancy or postpartum.

Henriksson, H. E., S. M. Sylven, T. K. Kallak, F. C. Papadopoulos and A. Skalkidou (2017). Seasonal patterns in self-reported peripartum depressive symptoms. Eur Psychiatry 43, 99-108.

BACKGROUND: In the peripartum period, the literature on seasonality in depression is still scarce and studies present varying findings. The aims of this study were to investigate whether seasonal patterns in postpartum depressive symptoms previously identified in a Swedish study could be replicated in a larger study, as well as to assess seasonal patterns in depressive symptoms during pregnancy. METHODS: This was a nested case-control study comprised of 4129 women who participated in the BASIC project and gave birth at Uppsala University Hospital, Uppsala, Sweden, between February 2010 and December 2015. RESULTS: Women who gave birth in October-December 2011 had an increased odds of depressive symptoms at 6 weeks postpartum, when compared with women giving birth in April-June 2011 (aOR=2.42; 95% CI: 1.12-5.26). The same pattern was found among women with a history of depression. No other seasonal patterns for depressive symptoms during pregnancy or at 6 weeks postpartum were identified. CONCLUSIONS: In general, no consistent seasonal patterns were found in peripartum depressive symptoms. Whether the seasonal patterns found in some studies during certain years may be due to other factors relating to specific years and seasons, such as extreme climatic conditions or other particular events, warrants further investigation.

Edvinsson, A., E. Brann, C. Hellgren, E. Freyhult, R. White, M. Kamali-Moghaddam, J. Olivier, J. Bergquist, A. E. Bostrom, H. B. Schioth, A. Skalkidou, J. L. Cunningham and I. Sundstrom-Poromaa (2017). Lower inflammatory markers in women with antenatal depression brings the M1/M2 balance into focus from a new direction. Psychoneuroendocrinology 80, 15-25.

BACKGROUND: Antenatal depression and use of serotonin reuptake inhibitors (SSRI) in pregnancy have both been associated with an increased risk of poor pregnancy outcomes, such as preterm birth and impaired fetal growth. While the underlying biological pathways for these complications are poorly understood, it has been hypothesized that inflammation may be a common physiological pathway. The aim of the present study was to assess peripheral inflammatory markers in healthy women, women with antenatal depression, and in women using SSRI during pregnancy. METHODS: 160 healthy pregnant controls, 59 women with antenatal depression and 39 women on treatment with SSRIs were included. The relative levels of 92 inflammatory proteins were analyzed by proximity extension assay technology. RESULTS: Overall, 23 of the inflammatory markers were significantly lower in women with antenatal depression and in women on treatment with SSRIs in comparison with the healthy controls. No difference in any of the inflammatory markers was observed between women with antenatal depression and those who were using SSRI. Top three inflammatory markers that were down-regulated in women with antenatal depression were TNF-related apoptosis-inducing ligand (TRAIL), p=0.000001, macrophage colony-stimulating factor 1 (CSF-1), p=0.000004, and fractalkine (CX3CL1), p=0.000005. Corresponding inflammatory markers in SSRI users were CSF-1, p=0.000011, vascular endothelial growth factor A (VEGF-A), p=0.000016, and IL-15 receptor subunit alpha (IL-15RA), p=0.000027. The inflammatory markers were negatively correlated with cortisone serum concentrations in controls, but not in the cases. Differential DNA methylation of was found for seven of these inflammatory markers in an independent epigenetics cohort. CONCLUSION: Women with antenatal depression or on SSRI treatment have lower levels of a number of peripheral inflammatory markers than healthy pregnant controls. Hypothetically, this could be due to dysregulated switch to the pro-M2 milieu that characterizes normal third trimester pregnancy. However, longitudinal blood sampling is needed to elucidate whether the presumably dysregulated M2 shift is driving the development of antenatal depression or is a result of the depression.

Brann, E., F. Papadopoulos, E. Fransson, R. White, A. Edvinsson, C. Hellgren, M. Kamali-Moghaddam, A. Bostrom, H. B. Schioth, I. Sundstrom-Poromaa and A. Skalkidou (2017). Inflammatory markers in late pregnancy in association with postpartum depression-A nested case-control study. Psychoneuroendocrinology 79, 146-159.

Recent studies indicate that the immune system adaptation during pregnancy could play a significant role in the pathophysiology of perinatal depression. The aim of this study was to investigate if inflammation markers in a late pregnancy plasma sample can predict the presence of depressive symptoms at eight weeks postpartum. Blood samples from 291 pregnant women (median and IQR for days to delivery, 13 and 7-23days respectively) comprising 63 individuals with postpartum depressive symptoms, as assessed by the Edinburgh postnatal depression scale (EPDS>/=12) and/or the Mini International Neuropsychiatric Interview (M.I.N.I.) and 228 controls were analyzed with an inflammation protein panel using multiplex proximity extension assay technology, comprising of 92 inflammation-associated markers. A summary inflammation variable was also calculated. Logistic regression, LASSO and Elastic net analyses were implemented. Forty markers were lower in late pregnancy among women with depressive symptoms postpartum. The difference remained statistically significant for STAM-BP (or otherwise AMSH), AXIN-1, ADA, ST1A1 and IL-10, after Bonferroni correction. The summary inflammation variable was ranked as the second best variable, following personal history of depression, in predicting depressive symptoms postpartum. The protein-level findings for STAM-BP and ST1A1 were validated in relation to methylation status of loci in the respective genes in a different population, using openly available data. This explorative approach revealed differences in late pregnancy levels of inflammation markers between women presenting with depressive symptoms postpartum and controls, previously not described in the literature. Despite the fact that the results do not support the use of a single inflammation marker in late pregnancy for assessing risk of postpartum depression, the use of STAM-BP or the novel notion of a summary inflammation variable developed in this work might be used in combination with other biological markers in the future.

Wesström, J., Skalkidou, A., Manconi, M., Fulda, S., and Sundström-Poromaa, I. (2014). Pre-pregnancy restless legs syndrome (Willis-Ekbom Disease) is associated with perinatal depression. J. Clin. Sleep Med. JCSM Off. Publ. Am. Acad. Sleep Med. 10, 527–533.

OBJECTIVES: Both restless legs syndrome ([RLS], also known as Willis-Ekbom Disease [WED]) and depression are common during pregnancy. However, no prior studies have assessed if pregnant women with RLS have an elevated risk of depression during and/or after pregnancy.

METHODS: 1,428 women who were pregnant in gestational week 16-17 were asked to participate in a longitudinal survey. They were followed by web-based questionnaires in gestational week 17 and 32, and 6 weeks after delivery. Data were also retrieved from prenatal and birth records. Two different sets of criteria were used to examine the prevalence of RLS in the cohort (International Restless Legs Syndrome Society Group standard criteria and the later developed CH-RLSQ11 questionnaire). The latter questionnaire attempts to exclude those with common "mimics" of RLS.

RESULTS: Adjusted odds ratio for depression in gestational week 17, 32, and postpartum week 6 in relation to pre-pregnancy RLS onset and moderate to severe symptom severity were 4.74 (2.30 - 9.76), 3.67 (1.85 - 7.28), and 2.58 (1.28 - 5.21), respectively. No significant associations were seen in pregnant women with de novo RLS during pregnancy. When using the standard diagnostic RLS criteria and frequency of symptoms more than 2-3 days per week, the prevalence of RLS was 12.3%. With the CH-RLSQ11 questionnaire and the same threshold for frequency of symptoms the prevalence was 6.5%.

CONCLUSION: Women with RLS onset before pregnancy with moderate or severe symptoms had an increased risk of both antenatal and postnatal depression. The self-reported prevalence of RLS during pregnancy is lower when a questionnaire dealing with "mimics" is used.

Olivier, J.D.A., Åkerud, H., Skalkidou, A., Kaihola, H., and Sundström-Poromaa, I. (2014). The effects of antenatal depression and antidepressant treatment on placental gene expression. Front. Cell. Neurosci. 8, 465.

The effects of antenatal depression and antidepressant treatment during pregnancy on both mother and child are vigorously studied, but the underlying biology for these effects is largely unknown. The placenta plays a crucial role in the growth and development of the fetus. We performed a gene expression study on the fetal side of the placenta to investigate gene expression patterns in mothers with antenatal depression and in mothers using antidepressant treatment during pregnancy. Placental samples from mothers with normal pregnancies, from mothers with antenatal depression, and from mothers using antidepressants were collected. We performed a pilot microarray study to investigate alterations in the gene expression and selected several genes from the microarray for biological validation with qPCR in a larger sample. In mothers with antenatal depression 108 genes were differentially expressed, whereas 109 genes were differentially expressed in those using antidepressants. Validation of the microarray revealed more robust gene expression differences in the seven genes picked for confirmation in antidepressant-treated women than in depressed women. Among the genes that were validated ROCK2 and C12orf39 were differentially expressed in both depressed and antidepressant-treated women, whereas ROCK1, GCC2, KTN1, and DNM1L were only differentially expressed in the antidepressant-treated women. In conclusion, antenatal depression and antidepressant exposure during pregnancy are associated with altered gene expression in the placenta. Findings on those genes picked for validation were more robust among antidepressant-treated women than in depressed women, possibly due to the fact that depression is a multifactorial condition with varying degrees of endocrine disruption. It remains to be established whether the alterations found in the gene expression of the placenta are found in the fetus as well.

Iliadis, S.I., Comasco, E., Hellgren, C., Kollia, N., Sundström Poromaa, I., and Skalkidou, A. (2017). Associations between a polymorphism in the hydroxysteroid (11-beta) dehydrogenase 1 gene, neuroticism and postpartum depression. J. Affect. Disord. 207, 141–147.

BACKGROUND: This study examined the association between a single nucleotide polymorphism in the hydroxysteroid (11-beta) dehydrogenase 1 gene and neuroticism, as well as the possible mediatory role of neuroticism in the association between the polymorphism and postpartum depressive symptoms.

METHODS: 769 women received questionnaires containing the Edinburgh Postnatal Depression Scale (EPDS) at six weeks postpartum and demographic data at pregnancy week 17 and 32 and at six weeks postpartum, as well as the Swedish universities Scales of Personality at pregnancy week 32.

RESULTS: Linear regression models showed an association between the GG genotype and depressive symptoms. When neuroticism was introduced in the model, it was associated with EPDS score, whereas the association between the GG genotype and EPDS became borderline significant. A path analysis showed that neuroticism had a mediatory role in the association between the polymorphism and EPDS score.

LIMITATIONS: The use of the EPDS, which is a self-reporting instrument.

CONCLUSIONS: Neuroticism was associated with the polymorphism and had a mediatory role in the association between the polymorphism and postpartum depression. This finding elucidates the genetic background of neuroticism and postpartum depression.

Iliadis, S.I., Sylvén, S., Hellgren, C., Olivier, J.D., Schijven, D., Comasco, E., Chrousos, G.P., Sundström Poromaa, I., and Skalkidou, A. (2016). MID-PREGNANCY CORTICOTROPIN-RELEASING HORMONE LEVELS IN ASSOCIATION WITH POSTPARTUM DEPRESSIVE SYMPTOMS. Depress. Anxiety.

BACKGROUND: Peripartum depression is a common cause of pregnancy- and postpartum-related morbidity. The production of corticotropin-releasing hormone (CRH) from the placenta alters the profile of hypothalamus-pituitary-adrenal axis hormones and may be associated with postpartum depression. The purpose of this study was to assess, in nondepressed pregnant women, the possible association between CRH levels in pregnancy and depressive symptoms postpartum.

METHODS: A questionnaire containing demographic data and the Edinburgh Postnatal Depression Scale (EPDS) was filled in gestational weeks 17 and 32, and 6 week postpartum. Blood samples were collected in week 17 for assessment of CRH. A logistic regression model was constructed, using postpartum EPDS score as the dependent variable and log-transformed CRH levels as the independent variable. Confounding factors were included in the model. Subanalyses after exclusion of study subjects with preterm birth, newborns small for gestational age (SGA), and women on corticosteroids were performed.

RESULTS: Five hundred thirty-five women without depressive symptoms during pregnancy were included. Logistic regression showed an association between high CRH levels in gestational week 17 and postpartum depressive symptoms, before and after controlling for several confounders (unadjusted OR = 1.11, 95% CI 1.01-1.22; adjusted OR = 1.13, 95% CI 1.02-1.26; per 0.1 unit increase in log CRH). Exclusion of women with preterm birth and newborns SGA as well as women who used inhalation corticosteroids during pregnancy did not alter the results.

CONCLUSIONS: This study suggests an association between high CRH levels in gestational week 17 and the development of postpartum depressive symptoms, among women without depressive symptoms during pregnancy.

Iliadis, S.I., Comasco, E., Sylvén, S., Hellgren, C., Sundström Poromaa, I., and Skalkidou, A. (2015c). Prenatal and Postpartum Evening Salivary Cortisol Levels in Association with Peripartum Depressive Symptoms. PloS One 10, e0135471.

BACKGROUND: The biology of peripartum depression remains unclear, with altered stress and the Hypothalamus-Pituitary-Adrenal axis response having been implicated in its pathophysiology.

METHODS: The current study was undertaken as a part of the BASIC project (Biology, Affect, Stress, Imaging, Cognition), a population-based longitudinal study of psychological wellbeing during pregnancy and the postpartum period in Uppsala County, Sweden, in order to assess the association between evening salivary cortisol levels and depressive symptoms in the peripartum period. Three hundred and sixty-five pregnant women from the BASIC cohort were recruited at pregnancy week 18 and instructed to complete a Swedish validated version of the Edinburgh Postnatal Depression Scale at the 36th week of pregnancy as well as the sixth week after delivery. At both times, they were also asked to provide evening salivary samples for cortisol analysis. A comprehensive review of the relevant literature is also provided.

RESULTS: Women with postpartum EPDS score ≥ 10 had higher salivary evening cortisol at six weeks postpartum compared to healthy controls (median cortisol 1.19 vs 0.89 nmol/L). A logistic regression model showed a positive association between cortisol levels and depressive symptoms postpartum (OR = 4.1; 95% CI 1.7-9.7). This association remained significant even after controlling for history of depression, use of tobacco, partner support, breastfeeding, stressful life events, and sleep problems, as possible confounders (aOR = 4.5; 95% CI 1.5-14.1). Additionally, women with postpartum depressive symptoms had higher postpartum cortisol levels compared to both women with depressive symptoms antenatally and controls (p = 0.019 and p = 0.004, respectively).

CONCLUSIONS: Women with depressive symptoms postpartum had higher postpartum cortisol levels, indicating an altered response of the HPA-axis in postpartum depression.

Iliadis, S.I., Koulouris, P., Gingnell, M., Sylvén, S.M., Sundström-Poromaa, I., Ekselius, L., Papadopoulos, F.C., and Skalkidou, A. (2015b). Personality and risk for postpartum depressive symptoms. Arch. Womens Ment. Health 18, 539–546.

Postpartum depression (PPD) is a common childbirth complication, affecting 10-15 % of newly delivered mothers. This study aims to assess the association between personality factors and PPD. All pregnant women during the period September 2009 to September 2010, undergoing a routine ultrasound at Uppsala University Hospital, were invited to participate in the BASIC study, a prospective study designed to investigate maternal well-being. Depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS) while the Depression Self-Rating Scale (DSRS) was used as a diagnostic tool for major depression. Personality traits were evaluated using the Swedish Universities Scale of Personality (SSP). One thousand thirty-seven non-depressed pregnant women were included in the study. Non-depressed women reporting high levels of neuroticism in late pregnancy were at high risk of developing postpartum depressive symptoms (PPDSs) at 6 weeks and 6 months after delivery, even after adjustment for confounders (adjusted odds ratio (aOR) = 3.4, 95 % confidence interval (CI) 1.8-6.5 and adjusted odds ratio (aOR) = 3.9, 95 % CI 1.9-7.9). The same was true for a DSRS-based diagnosis of major depression at 6 months postpartum. Somatic trait anxiety and psychic trait anxiety were associated with increased risk for PPDS at 6 weeks (aOR = 2.1, 95 % CI 1.2-3.5 and aOR = 1.9, 95 % CI 1.1-3.1), while high scores of mistrust were associated with a twofold increased risk for PPDS at 6 months postpartum (aOR 1.9, 95 % CI 1.1-3.4). Non-depressed pregnant women with high neuroticism scores have an almost fourfold increased risk to develop depressive symptoms postpartum, and the association remains robust even after controlling for most known confounders. Clinically, this could be of importance for health care professionals working with pregnant and newly delivered women.

Hellgren, C., Edvinsson, Å., Olivier, J.D., Fornes, R., Stener-Victorin, E., Ubhayasekera, S.J.K.A., Skalkidou, A., Bergquist, J., and Sundström-Poromaa, I. (2016). Tandem mass spectrometry determined maternal cortisone to cortisol ratio and psychiatric morbidity during pregnancy-interaction with birth weight. Psychoneuroendocrinology 69, 142–149.

Maternal serum cortisol has been suggested to be influenced by psychiatric morbidity, and may also influence fetal growth. However, several studies found equal cortisol levels in depressed and healthy pregnant women. Placental 11-β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) shields the fetus from maternal cortisol by conversion to cortisone, a function that may be compromised by maternal stress. We aimed to compare the serum ratio of cortisone to cortisol, in women with and without psychiatric morbidity during pregnancy. A secondary aim was to investigate whether fetal growth, approximated by infant birth weight, was associated with the cortisone to cortisol ratio. We performed tandem mass spectrometry analysis of serum cortisol and cortisone in late pregnancy in 94 women with antenatal psychiatric morbidity and 122 controls (cohort 1). We also compared the placental gene expression of HSD11B1 and 2 in another group of 69 women with psychiatric morbidity and 47 controls (cohort 2). There were no group differences in cortisol to cortisone ratio, absolute levels of cortisone and cortisol (cohort 1), or expression of HSD11B1 or 2 (cohort 2). However, cortisone to cortisol ratio was positively associated with birth weight in women with psychiatric morbidity, also after adjustment for gestational length, fetal sex, maternal height, smoking, SSRI use, and time of blood sampling (standardized β=0.35, p<0.001), with no association in the healthy controls Thus, the maternal serum cortisone to cortisol ratio does not seem to be affected by psychiatric morbidity, but psychiatric morbidity may increase fetal exposure to cortisol or other metabolic factors influencing fetal growth.

Eckerdal, P., Kollia, N., Löfblad, J., Hellgren, C., Karlsson, L., Högberg, U., Wikström, A.-K., and Skalkidou, A. (2016). Delineating the Association between Heavy Postpartum Haemorrhage and Postpartum Depression. PloS One 11, e0144274.

OBJECTIVES: To explore the association between postpartum haemorrhage (PPH) and postpartum depression (PPD), taking into account the role of postpartum anaemia, delivery experience and psychiatric history.

METHODS: A nested cohort study (n = 446), based on two population-based cohorts in Uppsala, Sweden. Exposed individuals were defined as having a bleeding of ≥1000 ml (n = 196) at delivery, and non-exposed individuals as having bleeding of <650 ml (n = 250). Logistic regression models with PPD symptoms (Edinburgh Postnatal Depression scale (EPDS) score ≥ 12) as the outcome variable and PPH, anaemia, experience of delivery, mood during pregnancy and other confounders as exposure variables were undertaken. Path analysis using Structural Equation Modeling was also conducted.

RESULTS: There was no association between PPH and PPD symptoms. A positive association was shown between anaemia at discharge from the maternity ward and the development of PPD symptoms, even after controlling for plausible confounders (OR = 2.29, 95%CI = 1.15-4.58). Path analysis revealed significant roles for anaemia at discharge, negative self-reported delivery experience, depressed mood during pregnancy and postpartum stressors in increasing the risk for PPD.

CONCLUSION: This study proposes important roles for postpartum anaemia, negative experience of delivery and mood during pregnancy in explaining the development of depressive symptoms after PPH.

Comasco, E., Gulinello, M., Hellgren, C., Skalkidou, A., Sylven, S., and Sundström-Poromaa, I. (2016). Sleep duration, depression, and oxytocinergic genotype influence prepulse inhibition of the startle reflex in postpartum women. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 26, 767–776.

The postpartum period is characterized by a post-withdrawal hormonal status, sleep deprivation, and susceptibility to affective disorders. Postpartum mothering involves automatic and attentional processes to screen out new external as well as internal stimuli. The present study investigated sensorimotor gating in relation to sleep duration, depression, as well as catecholaminergic and oxytocinergic genotypes in postpartum women. Prepulse inhibition (PPI) of the startle reflex and startle reactivity were assessed two months postpartum in 141 healthy and 29 depressed women. The catechol-O-methyltransferase (COMT) Val158Met, and oxytocin receptor (OXTR) rs237885 and rs53576 polymorphisms were genotyped, and data on sleep duration were collected. Short sleep duration (less than four hours in the preceding night) and postpartum depression were independently associated with lower PPI. Also, women with postpartum depression had higher startle reactivity in comparison with controls. The OXTR rs237885 genotype was related to PPI in an allele dose-dependent mode, with T/T healthy postpartum women carriers displaying the lowest PPI. Reduced sensorimotor gating was associated with sleep deprivation and depressive symptoms during the postpartum period. Individual neurophysiological vulnerability might be mediated by oxytocinergic genotype which relates to bonding and stress response. These findings implicate the putative relevance of lower PPI of the startle response as an objective physiological correlate of liability to postpartum depression.

Hannerfors, A.-K., Hellgren, C., Schijven, D., Iliadis, S.I., Comasco, E., Skalkidou, A., Olivier, J.D.A., and Sundström-Poromaa, I. (2015). Treatment with serotonin reuptake inhibitors during pregnancy is associated with elevated corticotropin-releasing hormone levels. Psychoneuroendocrinology 58, 104–113.

Treatment with serotonin reuptake inhibitors (SSRI) has been associated with an increased risk of preterm birth, but causality remains unclear. While placental CRH production is correlated with gestational length and preterm birth, it has been difficult to establish if psychological stress or mental health problems are associated with increased CRH levels. This study compared second trimester CRH serum concentrations in pregnant women on SSRI treatment (n=207) with untreated depressed women (n=56) and controls (n=609). A secondary aim was to investigate the combined effect of SSRI treatment and CRH levels on gestational length and risk for preterm birth. Women on SSRI treatment had significantly higher second trimester CRH levels than controls, and untreated depressed women. CRH levels and SSRI treatment were independently associated with shorter gestational length. The combined effect of SSRI treatment and high CRH levels yielded the highest risk estimate for preterm birth. SSRI treatment during pregnancy is associated with increased CRH levels. However, the elevated risk for preterm birth in SSRI users appear not to be mediated by increased placental CRH production, instead CRH appear as an independent risk factor for shorter gestational length and preterm birth.

Ahlsson, F., Åkerud, H., Schijven, D., Olivier, J., and Sundström-Poromaa, I. (2015). Gene Expression in Placentas From Nondiabetic Women Giving Birth to Large for Gestational Age Infants. Reprod. Sci. Thousand Oaks Calif 22, 1281–1288.

Gestational diabetes, obesity, and excessive weight gain are known independent risk factors for the birth of a large for gestational age (LGA) infant. However, only 1 of the 10 infants born LGA is born by mothers with diabetes or obesity. Thus, the aim of the present study was to compare placental gene expression between healthy, nondiabetic mothers (n = 22) giving birth to LGA infants and body mass index-matched mothers (n = 24) giving birth to appropriate for gestational age infants. In the whole gene expression analysis, only 29 genes were found to be differently expressed in LGA placentas. Top upregulated genes included insulin-like growth factor binding protein 1, aminolevulinate δ synthase 2, and prolactin, whereas top downregulated genes comprised leptin, gametocyte-specific factor 1, and collagen type XVII α 1. Two enriched gene networks were identified, namely, (1) lipid metabolism, small molecule biochemistry, and organismal development and (2) cellular development, cellular growth, proliferation, and tumor morphology.

Comasco, E., Hellgren, C., Olivier, J., Skalkidou, A., and Sundström Poromaa, I. (2015). Supraphysiological hormonal status, anxiety disorders, and COMT Val/Val genotype are associated with reduced sensorimotor gating in women. Psychoneuroendocrinology 60, 217–223.

Pregnancy is a period characterized by a supraphysiological hormonal status, and greater anxiety proneness, which can lead to peripartum affective symptoms with dramatic consequences not only for the woman but also for the child. Clinical psychiatry is heavily hampered by the paucity of objective and biology-based intermediate phenotypes. Prepulse inhibition (PPI) of the startle response, a neurophysiological measure of sensorimotor gating, has been poorly investigated in relation to anxiety and in pregnant women. In the present study, the PPI of healthy non-pregnant women (n = 82) and late pregnant women (n = 217) was investigated. Age, BMI, depression and anxiety symptoms, tobacco use, and antidepressant medication were considered. We investigated and provided evidence of lower PPI: (i) in healthy pregnant women compared to healthy non-pregnant controls, (ii) in pregnant women with anxiety disorders compared to healthy pregnant women, (iii) in pregnant women with anxiety disorders using SSRI compared to un-medicated pregnant women with anxiety disorders, and (iv) in healthy pregnant women carrying the COMT Val158Met Val/Val genotype compared to Met carriers. Altogether, a reduced sensorimotor gating as an effect of supraphysiological hormonal status, anxiety disorders, SSRIs, and catecholaminergic genotype, implicate the putative relevance of lower PPI as an objective biological correlate of anxiety proneness in pregnant women. These findings call for prospective studies to dissect the multifactorial influences on PPI in relation to mental health of pregnant women.

Hellgren, C., Åkerud, H., Skalkidou, A., and Sundström-Poromaa, I. (2013). Cortisol awakening response in late pregnancy in women with previous or ongoing depression. Psychoneuroendocrinology 38, 3150–3154.

Pregnancy is associated with increased basal cortisol levels, and decreased hypothalamic-pituitary-adrenal (HPA) axis reactivity. The cortisol awakening response (CAR) is a measure of HPA-axis reactivity which has been reported to be increased in patients with ongoing depressive disorder and in individuals with remitted depression. In this study, we investigated HPA-axis reactivity in pregnant women with ongoing or previous depression. The CAR was assessed by measurement of salivary cortisol at awakening and 15, 30, and 45 min post-awakening. Based on structured psychiatric interviews and repeated measurements of depressive symptoms during pregnancy, 134 women were included in one of the three groups: never depressed (n=57), depressed prior to the current pregnancy (n=39), and depressed during the current pregnancy (n=38). Given the prior findings of increased CAR in non-pregnant depressed subjects, we hypothesized that an ongoing or previous depression would result in a higher CAR. Contrary to our hypothesis, a mixed models analysis failed to yield significant group differences. Thus, our results suggest that never depressed pregnant women and women with depression during pregnancy have similar cortisol awakening responses. Furthermore, our findings suggest that the cortisol awakening response does not differ between currently healthy women with and without experience of a depressive episode during late pregnancy.

bottom of page