Sex-Specific Transcriptomic Changes in the Villous Tissue of Placentas of Pregnant Women Using a Selective Serotonin Reuptake Inhibitor.

About 5% of pregnant women are treated with selective serotonin reuptake inhibitor (SSRI) antidepressants to treat their depression. SSRIs influence serotonin levels, a key factor in neural embryonic development, and their use during pregnancy has been associated with adverse effects on the developing embryo. However, the role of the placenta in transmitting these negative effects is not well understood. In this study, we aim to elucidate how disturbances in the maternal serotonergic system affect the villous tissue of the placenta by assessing whole transcriptomes in the placentas of women with healthy pregnancies and women with depression and treated with the SSRI fluoxetine during pregnancy. Twelve placentas of the Biology, Affect, Stress, Imaging and Cognition in Pregnancy and the Puerperium (BASIC) project were selected for RNA sequencing to examine differentially expressed genes: six male infants and six female infants, equally distributed over women treated with SSRI and without SSRI treatment. Our results show that more genes in the placenta of male infants show changed expression associated with fluoxetine treatment than in placentas of female infants, stressing the importance of sex-specific analyses. In addition, we identified genes related to extracellular matrix organization to be significantly enriched in placentas of male infants born to women treated with fluoxetine. It remains to be established whether the differentially expressed genes that we found to be associated with SSRI treatment are the result of the SSRI treatment itself, the underlying depression, or a combination of the two.

Cohort profile: the U-BIRTH study on peripartum depression and child development in Sweden.

PURPOSE: The current U-BIRTH cohort (Uppsala Birth Cohort) extends our previous cohort Biology, Affect, Stress, Imaging and Cognition (BASIC), assessing the development of children up to 11 years after birth. The U-BIRTH study aims to (1) assess the impact of exposure to peripartum mental illness on the children's development taking into account biological and environmental factors during intrauterine life and childhood; (2) identify early predictors of child neurodevelopmental and psychological problems using biophysiological, psychosocial and environmental variables available during pregnancy and early post partum. PARTICIPANTS: All mothers participating in the previous BASIC cohort are invited, and mother-child dyads recruited in the U-BIRTH study are consecutively invited to questionnaire assessments and biological sampling when the child is 18 months, 6 years and 11 years old. Data collection at 18 months (n=2882) has been completed. Consent for participation has been obtained from 1946 families of children having reached age 6 and from 698 families of children having reached age 11 years. FINDINGS TO DATE: Based on the complete data from pregnancy to 18 months post partum, peripartum mental health was significantly associated with the development of attentional control and gaze-following behaviours, which are critical to cognitive and social learning later in life. Moreover, infants of depressed mothers had an elevated risk of difficult temperament and behavioural problems compared with infants of non-depressed mothers. Analyses of biological samples showed that peripartum depression and anxiety were related to DNA methylation differences in infants. However, there were no methylation differences in relation to infants' behavioural problems at 18 months of age. FUTURE PLANS: Given that the data collection at 18 months is complete, analyses are now being undertaken. Currently, assessments for children reaching 6 and 11 years are ongoing.

Maternal early mid-pregnancy adiponectin in relation to infant birth weight and the likelihood of being born large-for-gestational-age.

This study aimed to evaluate the association of maternal adiponectin with infant birth size in 1349 pregnant women at Uppsala University Hospital, Sweden. The mean age of the women was 31.0 years, and 40.9% were nulliparous. Maternal early mid-pregnancy adiponectin was measured in microgram/mL. Linear regression models were performed to evaluate the association between adiponectin and infant birth weight. Logistic regression models were used to evaluate adiponectin in relation to the odds of giving birth to an infant large-for-gestational-age (LGA, infant birth weight standard deviation score > 90th percentile). Adjustments were made for early pregnancy BMI and diabetes mellitus. Prior adjustments, adiponectin was inversely associated with infant birth weight (ß - 17.1, 95% confidence interval (CI) - 26.8 to - 7.4 g, P < 0.001), and one microgram/mL increase in adiponectin was associated with a 9% decrease in the odds of giving birth to an LGA infant (odds ratio 0.91, CI 0.85-0.97, P = 0.006). The associations did not withstand in the adjusted models. We found a significant interaction between adiponectin and infant sex on birth size. This interaction was driven by an inverse association between maternal adiponectin and birth size in female infants, whereas no such association was found in males.

Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression.

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).

Early Mid-pregnancy Blood-Based Proteins as Possible Biomarkers of Increased Infant Birth Size in Sex-Stratified Analyses.

The objective of this study was to evaluate the associations of 92 maternal blood-based proteins with increased infant birth size. The study was performed at the Uppsala University Hospital, Sweden, and included 857 mother and child dyads. The mean age of the women was 30.3 years, and 53.2% were nulliparous. Blood samples were collected at mean 18 + 2 weeks' gestation, and the Olink cardiovascular II panel was used to measure 92 proteins, either known to be or suspected to be markers of cardiovascular and inflammatory disease in humans. Multiple linear regression models adjusted for maternal age, parity, pre-conception BMI, height, and smoking were performed to evaluate the association of each individual protein with infant birth size. We also performed sex-stratified analyses. Eight proteins (Matrix metalloproteinase-12 (MMP-12), Prostasin (PRSS8), Adrenomedullin (ADM), Pappalysin-1 (PAPP-A), Angiotensin-converting enzyme 2 (ACE2), Sortilin (SORT1), Lectin-like oxidized LDL receptor 1 (LOX-1), and Thrombomodulin (TM)) were associated with infant birth size after false discovery rate adjustment. In the analyses including only female infants, ten proteins (MMP-12, Growth/differentiation factor 2 (GDF-2), PRSS8, SORT1, ADM, Interleukin-1 receptor antagonist protein (IL-1ra), Leptin (LEP), ACE2, TM, and Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A)) were associated with infant birth size. Two proteins (PAPP-A and PRSS8) were associated with infant birth size among male infants. Our study suggests several proteins as potential biomarkers for increased birth weight, and our findings could act as a base for future research to identify new potential markers that could be added to improve screening for large infants.

Pregnancy-related hormones and COMT genotype: Associations with maternal working memory.

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.

Physical and Sedentary Activities in Association with Reproductive Outcomes among Couples Seeking Infertility Treatment: A Prospective Cohort Study.

BACKGROUND: The aim of this study was to investigate the association of physical activity (PA) with assisted reproductive technology (ART) treatment and pregnancy outcomes among couples seeking infertility treatment. METHODS: This prospective cohort study was carried out among 128 infertile individuals (64 couples), entering the infertility clinic for ART procedures. Baseline PA (before entering any treatment) was assessed using accelerometry for both women and men. For every couple the infertility treatment outcomes were recorded. RESULTS: The couples that required invasive ART procedures such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) spent less time in vigorous PA (-73 min/week per couple, woman + man) than those couples who became spontaneously pregnant after entering the study (p = 0.001). We observed no significant associations between the time spent in physical activities and positive pregnancy test or live birth. CONCLUSIONS: Our results do not support a positive nor negative relation between the time the couples spent in physical activities and the chances of getting pregnant or having a baby among patients seeking infertility treatment. However, couples undergoing invasive ART procedures did less vigorous PA than couples that became spontaneously pregnant, suggesting that PA may interfere with their reproductive health.

Polycystic ovary syndrome and extremely preterm birth: A nationwide register-based study.

INTRODUCTION: Women with polycystic ovary syndrome (PCOS) have increased risk of pregnancy complications, including preterm birth before 37 weeks. However, if this increased risk also includes extremely preterm births (<28 weeks) is unknown. Such information is important to identify women at risk and tailor antenatal care, since child morbidity and mortality become more prevalent with increasing prematurity. AIMS: To investigate the association between PCOS and extremely preterm birth, and whether onset of PCOS-related preterm birth is predominantly spontaneous or medically indicated. MATERIAL AND METHODS: This was a nationwide register-based cohort study in Sweden. The study population was all live singleton births registered in the Swedish Medical Birth Register 2005-2014 (n = 1 046 448). Women with and without PCOS were compared by severity of preterm birth [extremely (22+0 to 27+6 weeks), very (28+0 to 31+6 weeks) and moderately (32+0 to 36+6 weeks)] and delivery onset mode (spontaneous or medically indicated). Multinomial logistic regression was performed to estimate adjusted odds ratios (aOR) with 95% confidence intervals (CI). Adjustments were made for maternal age, parity, body mass index, smoking, country of birth and year of delivery. RESULTS: During the study period, 1.3% of the women giving birth had PCOS diagnosis. They had an overall higher preterm birth rate than women without PCOS (6.7% and 4.8%, respectively). Women with PCOS had increased odds of preterm birth of all severities, with the highest odds for extremely preterm birth (aOR 2.3; 95% CI 1.7-3.0), particularly of spontaneous onset (aOR 2.7; 95% CI 2.0-3.6). CONCLUSIONS: Women with PCOS had more than a two-fold increased risk of extremely preterm birth with spontaneous onset than women without such diagnosis. This can be important in antenatal risk assessment of preterm birth in women with PCOS. Future research is warranted to investigate the biological mechanisms behind preterm birth in women with PCOS.

Maternal perinatal depressive symptoms trajectories and impact on toddler behavior - the importance of symptom duration and maternal bonding.

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.

The effect of antenatal depression and antidepressant treatment on placental tissue: a protein-validated gene expression study.

BACKGROUND: Antenatal depression affects 10-20% of pregnant women. Around 2-4% of European pregnant women use antidepressant treatment, most commonly selective serotonin reuptake inhibitors (SSRIs). Poor pregnancy outcomes, such as preterm birth and low birth weight, have been described in women with antenatal depression and in pregnant women on SSRI treatment. However, the effects of antenatal depression and antidepressant treatment on the placenta are largely unknown. The aim of this work was to compare placental gene and protein expression in healthy women, women with untreated antenatal depression and women on antidepressant treatment during pregnancy. METHODS: Placental samples from 47 controls, 25 depressed and 45 SSRI-treated women were analysed by means of qPCR using custom-designed TaqMan low-density arrays (TLDAs) for 44 genes previously known to be involved in the pathophysiology of depression, and expressed in the placenta. Moreover, placental protein expression was determined by means of immunohistochemistry in 37 healthy controls, 13 women with untreated depression and 21 women on antidepressant treatment. Statistical comparisons between groups were performed by one-way ANOVA or the Kruskal-Wallis test. RESULTS: Nominally significant findings were noted for HTR1A and NPY2R, where women with untreated depression displayed higher gene expression than healthy controls (p < 0.05), whereas women on antidepressant treatment had similar expression as healthy controls. The protein expression analyses revealed higher expression of HTR1A in placentas 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.

Second Trimester Maternal Leptin Levels Are Associated with Body Mass Index and Gestational Weight Gain but not Birth Weight of the Infant.

INTRODUCTION: Obesity is increasing among the pregnant population. Leptin has an important role in the regulation of energy balance and hunger. The aim of this study was to investigate the association between maternal leptin levels with maternal obesity, gestational weight gain (GWG), single nucleotide polymorphisms (SNPs) within the leptin gene, and the age-adjusted birth weight of the child. MATERIAL AND METHODS: Maternal leptin levels (n = 740) and SNPs (n = 504) were analyzed in blood samples taken within the Uppsala Biobank of Pregnant women at pregnancy weeks 16-19. RESULTS: Maternal leptin levels differed significantly between body mass index (BMI) groups. Normal weight women had the lowest median leptin levels and levels increased with each BMI group. Leptin SNP genotype was not associated with leptin levels or BMI. There was also no association between maternal leptin levels and age-adjusted birth weight of the child except for a negative association between leptin levels and birth weight in the morbid obese group. DISCUSSION/CONCLUSION: Maternal BMI was identified as the best positive explanatory factor for maternal leptin levels. Leptin was a strong positive explanatory factor for GWG. Birth weight of children of uncomplicated pregnancies was, however, dependent on maternal height, BMI, GWG, and parity but not leptin levels, except for in morbid obese women where a negative association between maternal leptin levels and birth weight was found. We speculate that this indicates altered placental function, not manifested in pregnancy complication. We conclude that maternal leptin levels do not affect the birth weight of the child more than BMI, GWG, and parity.

Cohort profile: the Biology, Affect, Stress, Imaging and Cognition (BASIC) study on perinatal depression in a population-based Swedish cohort.

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.

Vasoactive intestinal peptide is upregulated in women with endometriosis and chronic pelvic pain.

PROBLEM: Chronic pelvic pain (CPP) causes compromised the quality of life in women with endometriosis and is often attributed to local inflammation and ingrowth of nerve fibers. In this pilot study, we aimed to investigate whether the inflammation-related vasoactive intestinal peptide (VIP) and interleukin (IL)-6 were increased in affected patients. METHOD OF STUDY: Endometrial and endometriotic tissue biopsy specimens, and serum and peritoneal fluid (PF) samples, were obtained from 85 endometriosis patients and 53 controls. VIP and IL-6 analysis and measurement of microvessel density in tissue were performed using immunohistochemistry, Western blotting, RT-qPCR, and ELISA. RESULTS: Compared with controls, VIP transcript and protein levels were increased in endometrium from endometriosis patients and further elevated in patients with CPP. In addition, microvessel density, a measurement of angiogenic activity, was increased in the endometrium and in endometriosis lesions in the same subset of patients. Serum and PF levels of VIP and IL-6 were higher in women with endometriosis and CPP compared with endometriosis patients who reported no chronic pain. CONCLUSION: Vasoactive intestinal peptide is upregulated in endometriosis patients reporting chronic pain. Increased microvessel density in tissue and peritoneal fluid concentrations of IL-6 indicate an elevated inflammation in the pelvic microenvironment of these patients.

Physical activity, fatness, educational level and snuff consumption as determinants of semen quality: findings of the ActiART study.

In this study, the association between physical activity and other potential determinants, objectively measured by accelerometry, was examined. Sixty-two men attending an infertility clinic participated in the study. Obese men (body mass index ≥ 30) and those with a waist circumference 102 cm or more had lower semen volume than the other men (P < 0.05). Higher values in sperm parameters were observed in participants who completed university studies and those who did not consume snuff, compared with the other participants (P < 0.05). Finally, men who spent an average number of 10 min-bouts of moderate-to-vigorous physical activity had significantly better semen quality than those who engaged in low or high numbers of bouts of activity (P < 0.05). No associations were found for sedentary or moderate-to-vigorous physical activity time when it was not sustained over 10 min, i.e. not in bouts. Men who have average levels of physical activity over sustained periods of 10 min are likely to have better semen quality than men who engage in low or high levels of such activity. Similarly, high levels of total and central adiposity, low educational level and snuff consumption are negatively related to semen quality.