Introduction: The future health of the offspring can be influenced by longstanding maternal anxiety and depression disorders during pregnancy. The present study aimed to explore the effect of psychiatric disorders during pregnancy on placental epigenetics. Methods: We measured DNA methylation patterns in term-placentas of women either suffering longstanding anxiety and depression symptoms (Index group, with overt symptoms), or a healthy population (Control, none/ only mild symptoms). Whole genome DNA methylation profiling was performed using the TruSeq (R) Methyl Capture EPIC Library Prep Kit (Illumina, San Diego, CA, USA) for library preparation and NGS technology for genomic DNA sequencing.Results: The results of high-throughput DNA methylation analysis revealed that the Index group had differential DNA methylation at epigenome-wide significance (p < 0.05) in 226 genes in the placenta. Targeted enrichment analyses identified hypermethylation of genes associated with psychiatric disorders (BRINP1, PUM1), and ion homeostasis (COMMD1), among others. The ECM (extracellular matrix)-receptor interaction pathway was significantly dysregulated in the Index group compared to the Control. In addition, DNA methylation/mRNA integration analyses revealed that four genes with key roles in neurodevelopment and other important processes (EPB41L4B, BMPR2, KLHL18, and UBAP2) were dysregulated at both, DNA methylation and transcriptome levels in the Index group compared to Control.Discussion: The presented results increase our understanding of how maternal psychiatric disorders may affect the newborn through placental differential epigenome, suggesting DNA methylation status as a biomarker when aiming to design new preventive techniques and interventions.

During pregnancy, the immune system is modified to allow developmental tolerance of the semi-allogeneic fetus and placenta to term. Pregnant women suffering from stress, anxiety, and depression show dysfunctions of their immune system that may be responsible for fetal and/or newborn disorders, provided that placental gene regulation is compromised. The present study explored the effects of maternal chronic self-perceived stress, anxiety, and depression during pregnancy on the expression of immune-related genes and pathways in term placenta. Pregnancies were clinically monitored with the Beck Anxiety Inventory (BAI) and Edinburgh Postnatal Depression Scale (EPDS). A cutoff threshold for BAI/EPDS of 10 divided patients into two groups: Index group (>10, n = 11) and a Control group (<10, n = 11), whose placentae were sampled at delivery. The placental samples were subjected to RNA-Sequencing, demonstrating that stress, anxiety, and depression during pregnancy induced a major downregulation of placental transcripts related to immune processes such as T-cell regulation, interleukin and cytokine signaling, or innate immune responses. Expression differences of main immune-related genes, such as CD46, CD15, CD8 alpha & beta ILR7 alpha, and CCR4 among others, were found in the Index group (P < 0.05). Moreover, the key immune-like pathway involved in humoral and cellular immunity named "Primary immunodeficiency" was significantly downregulated in the Index group compared with Controls. Our results show that mechanisms ruling immune system functions are compromised at the maternal-fetal interface following self-perceived depressive symptoms and anxiety during pregnancy. These findings may help unveil mechanisms ruling the impact of maternal psychiatric symptoms and lead to new prevention/intervention strategies in complicated pregnancies. Summary Sentence Mechanisms ruling immune system functions are compromised at the maternal-fetal interface following self-perceived depressive symptoms and anxiety during pregnancy.

Background: It is crucial to provide care based on individual needs. Swedish health care is obliged to give care on equal conditions for the entire population. The person with the greatest need should be given the most care, and the health care system should strive to be cost-efficient. Medical and technical advances have been significant during the last decades and the recent Covid-19 pandemic has caused a shift in health care, from in-person visits to virtual visits. The majority of pregnant women with a low risk assessment have an uncomplicated antenatal course without adverse events. These women probably receive excessive and unnecessary antenatal care. This study will investigate if an antenatal care program for healthy pregnant women with a low risk for adverse outcomes could be safely monitored with fewer in-person visits to a midwife, and with some of them replaced by virtual visits.

Methods: This is a non-inferiority trial where a stepped wedge cluster randomized controlled design will be used. Data collection includes register data and questionnaires that concern antenatal, obstetric and neonatal outcomes, patient- and caregiver-reported experiences, healthcare-economy, and implementation aspects. The modified antenatal care (MAC) study is performed in parts of the southeast of Sweden, which has approximately 8200 childbirths annually. At the start of the study, all antenatal care centers included in the study will use the same standard antenatal care (SAC) program. In the MAC program the in-person visits to a midwife will be reduced to four instead of eight, with two additional virtual meetings compared with the SAC program.

Discussion: This presented study protocol is informed by research knowledge. The protocol is expected to provide a good structure for future studies on changed antenatal care programs that introduce virtual visits for healthy pregnant women with a low risk for adverse outcomes, without risking quality, safety, and increased costs.

Introduction Identification of pregnant women suffering from depression or other mental disorders is a challenge for antenatal caregivers. The purpose of this case-control study was to describe mental disorders and the risk factors for mental disorders in women with depressive symptoms assessed with the Edinburgh Postnatal Depression Scale during the first trimester and to compare them with pregnant women without depressive symptoms. Material and methods In total, 2271 women answered the Edinburgh Postnatal Depression Scale at the first antenatal visit with a midwife. An Edinburgh Postnatal Depression Scale score of 13 or higher was considered to be screen-positive and these women were further assessed. Screen-negative pregnant women, matched for age and parity, were chosen as controls. Results In total, 149 (6.6%) women were found to be screen-positive. The majority (126, 85%) had at least one mental disorder or risk factor for mental disorder, such as depression (36.0%), anxiety (14.8%), or severe fear of childbirth (20.8%). The screen-positive women were more often smokers (16.1% vs 1.3%), unemployed (19.9% vs 1.3%), or on sick leave (25.3% vs 14.1%) during pregnancy and more often used selective serotonin reuptake inhibitor during pregnancy (14.2% vs 2.7%) compared with the screen-negative women (P<.001). Among the screen-negative women (n = 150) only three (2%) presented with symptoms of depression during pregnancy. Conclusions The Edinburgh Postnatal Depression Scale seems to be a valuable screening tool to detect depressive symptoms as well as other mental disorders during early pregnancy.

Objective To investigate hair cortisol concentrations (HCC) monthly in pregnant women and to explore the effect of parity. Design Prospective cohort study from gestational week (GW) 26, at childbirth and postpartum. Setting An antenatal care clinic in southeast Sweden. Sample 390 pregnant women. Methods Cortisol was measured using radioimmunoassay in methanol extracts of ground hair samples. Main outcome measures Hair cortisol concentrations. Results Both primi- and multiparae exhibited an increase in HCC throughout pregnancy. Primiparae had significantly higher HCC in the latter part of the last trimester compared with multiparae (1 month P = 0.003, 2 months P = 0.038). The use of psychotropic medication in the first trimester correlated to HCC postpartum (P < 0.001). HCC in GW 14-17 was associated with HCC in GW 18-21 (primiparae and multiparae, P < 0.001), GW 22-25 (primiparae P = 0.036, multiparae P = 0.033), and 2 months postpartum (primiparae P = 0.049). HCC in GW 18-21 was associated with GW 22-25 in both primiparae (P < 0.001) and multiparae (P < 0.001) as well as 2 months prior to childbirth among primiparae (<0.037). In general, all estimates of HCC in pregnancy and postpartum showed a significant association between HCC for a specific month and the HCC in the previous month (all P < 0.001), except for the association of HCC among primiparae in GW 22-25 and 3 months prior to childbirth. Conclusions Increased cortisol concentrations in hair were observed during pregnancy, which decreased 3 months prior to childbirth in multiparae. The results indicate a quicker suppression of the hypothalamic CRH (corticotropin-releasing hormone) production by placenta CRH in multiparous women.

Aim/hypothesis Environmental factors are believed to contribute to the risk of developing type 1 diabetes. The aim of this study was to investigate how size for gestational age affects the risk of developing childhood type 1 diabetes.

Methods Using the Swedish paediatric diabetes quality register and the Swedish medical birth register, children with type 1 diabetes diagnosed between 2000 and 2012 (n = 9376) were matched with four control children (n = 37,504). Small for gestational age (SGA) and large for gestational age (LGA) were defined according to Swedish national standards. Data were initially analysed using Pearsons chi(2) and thereafter by single and multiple logistic regression models.

Results An equal proportion of children were born appropriate for gestational age, but children with type 1 diabetes were more often born LGA and less often born SGA than control children (4.7% vs 3.5% and 2.0% vs 2.6%, respectively, p < 0.001). In the multiple logistic regression analysis, being born LGA increased (adjusted OR 1.16 [95% CI 1.02, 1.32]) and SGA decreased (adjusted OR 0.76 [95% CI 0.63, 0.92]) the risk for type 1 diabetes, regardless of maternal BMI and diabetes.

Conclusions/interpretation Size for gestational age of Swedish children affects the risk of type 1 diabetes, with increased risk if the child is born LGA and decreased risk if the child is born SGA. Being born LGA is an independent risk factor for type 1 diabetes irrespective of maternal BMI and diabetes. Thus, reducing the risk for a child being born LGA might to some extent reduce the risk for type 1 diabetes.

Objective: To investigate the impact of major depressive disorder (MDD) and antidepressant medication before and during pregnancy on obstetric and neonatal outcomes. Study design: A national register-based cohort study of pregnant women born in Sweden, and their first child born in 2012-2015 (n = 262 329). Women diagnosed with MDD and who had redeemed an antidepressant one year before becoming pregnant ("before pregnancy") and women who were diagnosed with MDD and who had redeemed an antidepressant both before and during pregnancy ("before and during pregnancy") were compared with each other and with women who had neither been diagnosed with MDD nor been prescribed antidepressants (population controls). Results: In comparison to population controls, the "before pregnancy" and the "before and during pregnancy" groups had increased likelihoods of operative childbirth (aOR = 1.19, 95 % CI 1.12-1.27, aOR = 1.38, 95 % CI 1.28-1.48 respectively), and with an increased likelihood for the child being admitted to a neonatal intensive care unit (NICU) (aOR = 1.51, 95 % CI 1.17-1.95, aOR = 1.55, 95 % CI 1.14-2.11). Children born to mothers in the "before and during pregnancy" group had an increased likelihood of preterm birth (aOR = 1.72, 95 % CI 1.52-1.95,), while children to mothers in the "before pregnancy" group had an increased likelihood of low birthweight (aOR = 1.15, 95 % CI 1.00-1.33) compared to population controls. Women in the "before and during pregnancy" group had an increased likelihood for hyperemesis during pregnancy (aOR =1.93, 95 % CI = 1.60-2.32), having an operative childbirth (aOR =1.17, 95 % CI = 1.06-1.29) or a preterm birth (aOR = 1.53, 95 % CI = 1.28-1.81) compared to the "before pregnancy" group. Conclusions: Women with MDD and antidepressant medication prior to becoming pregnant are at increased risk for adverse obstetric and neonatal outcomes compared to women without an MDD. Continuation of antidepressant medication during pregnancy somewhat increased the risk for adverse obstetric and neonatal outcomes. (C) 2020 Published by Elsevier B.V.

Objectives: Oxytocin is the drug of choice in preventing postpartum hemorrhage (PPH). The aim was to compare the peroperative- and total blood loss within two hours and PPH after planned cesarean section (CS) when receiving 2.5 IU vs 5.0 IU of oxytocin in different risk groups for PPH. Study design: A pilot study including 927 women undergoing planned CS where women receiving 2.5 IU of oxytocin were compared to women receiving 5.0 IU of oxytocin. Main outcome measures: Data comparing peroperative blood loss, total blood loss within two hours and PPH were analyzed. Results: The women receiving 2.5 IU of oxytocin had a slightly higher peroperative blood loss, compared to the 5.0 IU group (476 ml vs 426 ml, p = 0.029). The total blood loss two hours after surgery showed no significant difference between the groups (626 ml vs 595 ml, p = 0.230). In the 2.5 IU group 13% had a blood loss > 1000 ml vs 10% in the 5 IU group (aOR 1.64, 95% CI = 1.05-2.56). When the women considered to be at high risk for postpartum hemorrhage were excluded, we found no difference in the likelihood for postpartum hemorrhage between the groups (aOR 1.13, 95% CI = 0.64-1.99). Conclusions: Women undergoing planned CS and receiving 2.5 IU of oxytocin had a slightly higher risk for postpartum hemorrhage in this study. However, a lower dose of 2.5 IU of oxytocin seems to be a safe option in planned CS for women without known risk factors for postpartum hemorrhage, but further research is needed to confirm these findings.

Anxiety, chronical stress, and depression during pregnancy are considered to affect the offspring, presumably through placental dysregulation. We have studied the term placentae of pregnancies clinically monitored with the Becks Anxiety Inventory (BAI) and Edinburgh Postnatal Depression Scale (EPDS). A cutoff threshold for BAI/EPDS of 10 classed patients into an Index group (>10,n= 23) and a Control group (<10,n= 23). Cortisol concentrations in hair (HCC) were periodically monitored throughout pregnancy and delivery. Expression differences of main glucocorticoid pathway genes, i.e., corticotropin-releasing hormone (CRH), 11 beta-hydroxysteroid dehydrogenase (HSD11B2), glucocorticoid receptor (NR3C1), as well as other key stress biomarkers (Arginine Vasopressin, AVP and O-GlcNAc transferase, OGT) were explored in medial placentae using real-time qPCR and Western blotting. Moreover, gene expression changes were considered for their association with HCC, offspring, gender, and birthweight. A significant dysregulation of gene expression for CRH, AVP, and HSD11B2 genes was seen in the Index group, compared to controls, while OGT and NR3C1 expression remained similar between groups. Placental gene expression of the stress-modulating enzyme 11 beta-hydroxysteroid dehydrogenase (HSD11B2) was related to both hair cortisol levels (Rho = 0.54;p< 0.01) and the sex of the newborn in pregnancies perceived as stressful (Index,p< 0.05). Gene expression of CRH correlated with both AVP (Rho = 0.79;p< 0.001) and HSD11B2 (Rho = 0.45;p< 0.03), and also between AVP with both HSD11B2 (Rho = 0.6;p< 0.005) and NR3C1 (Rho = 0.56;p< 0.03) in the Control group but not in the Index group; suggesting a possible loss of interaction in the mechanisms of action of these genes under stress circumstances during pregnancy.

Background and purpose - The incidence of Perthes disease as reported in the literature varies widely between and within countries. The etiology of the disease is still unknown. Both environmental and genetic factors have been suggested to play a part in either causing the disease or increasing the susceptibility of an individual. We determined the incidence of Perthes disease in Sweden and investigated possible relationships to parental socioeconomic status, ethnicity, marital status, mothers age when giving birth, parity, number of siblings, and smoking habits. Patients and methods - Six Swedish population-based registers were used, together covering all children born in Sweden from 1973 through 1993. Results - The incidence of Perthes disease in Sweden was 9.3 per 100,000 subjects. The ratio between boys and girls was 3.1:1. The educational level of the father and the mother of a child with Perthes disease was lower than in the controls. The incidence was lower when the fathers were in the highest income bracket (above the 90(th) percentile). A higher proportion of parents of Nordic lineage had children with Perthes disease than parental pairs with one or both who were not of such lineage. Interpretation - This study confirms that there is an association between the incidence of Perthes disease and the socioeconomic status of the parents.