The role of central serotonergic markers and estradiol changes in perinatal mental health.

OBJECTIVE: Women have an increased risk for mental distress and depressive symptoms in relation to pregnancy and birth. The serotonin transporter (SERT) may be involved in the emergence of depressive symptoms postpartum and during other sex-hormone transitions. It may be associated with cerebrospinal fluid (CSF) levels of the main serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA). In 100 healthy pregnant women, who were scheduled to deliver by cesarean section (C-section), we evaluated 5-HIAA and estradiol contributions to mental distress 5 weeks postpartum. METHODS: Eighty-two women completed the study. CSF collected at C-section was analyzed for 5-HIAA, with high performance liquid chromatography. Serum estradiol concentrations were quantified by liquid chromatography tandem mass spectrometry before C-section and postpartum. Postpartum mental distress was evaluated with the Edinburgh Postnatal Depression Scale (EPDS). Associations between EPDS, 5-HIAA, and Δestradiol were evaluated in linear regression models adjusted for age, parity and SERT genotype. RESULTS: Higher levels of postpartum mental distress symptoms were negatively associated with a large decrease in estradiol concentrations (ßΔE2  = 0.73, p = 0.007) and, on a trend level, positively associated with high antepartum 5-HIAA levels (ß5-HIAA  = 0.002, p = 0.06). CONCLUSION: In a cohort of healthy pregnant women, postpartum mental distress was higher in women with high antepartum 5-HIAA (trend) and lower in women with a large perinatal estradiol decrease. We speculate that high antepartum 5-HIAA is a proxy of SERT levels, that carry over to the postpartum period and convey susceptibility to mental distress. In healthy women, the postpartum return to lower estradiol concentrations may promote mental well-being.

Multivitamin use and risk of preeclampsia: A systematic review and meta-analysis.

INTRODUCTION: Preeclampsia is associated with adverse maternal and neonatal outcomes. It is unclear whether multivitamin use reduces the risk of preeclampsia. This systematic review and meta-analysis aimed to evaluate the association between multivitamin use and the risk of preeclampsia. MATERIAL AND METHODS: We searched PubMed, Embase and the Cochrane Library from database inception to July 2021. Randomized controlled trials (RCTs), case-control and cohort studies assessing the association between multivitamin use and risk of preeclampsia were eligible. Studies of treatment with a single micronutrient were excluded. Relative risks and 95% confidence intervals (95% CI) were calculated using random-effects models. RoB2, the Newcastle Ottawa Scale and GRADE were used to assess risk of bias and quality of evidence. The protocol was registered in PROSPERO (no. CRD42021214153). RESULTS: Six studies were included (33 356 women). Only two RCTs were found, both showing a significantly decreased risk of preeclampsia in multivitamin users. These studies were not compatible for meta-analysis due to clinical heterogeneity. A meta-analysis of observational studies using a random-effects model showed an unchanged risk of preeclampsia following multivitamin use (relative risk 0.85, 95% CI 0.69-1.03). The quality of evidence according to GRADE was very low. CONCLUSIONS: Very weak evidence suggests that multivitamin use might reduce the risk of preeclampsia; however, more research is needed. Large RCTs should be prioritized. The results of this review do not allow any final conclusions to be drawn regarding a preventive effect of multivitamin use in relation to preeclampsia.

Psychological well-being and worries among pregnant women in the first trimester during the early phase of the COVID-19 pandemic in Denmark compared with a historical group: A hospital-based cross-sectional study.

INTRODUCTION: A pandemic may negatively influence psychological well-being in the individual. We aimed to assess the potential influence of the first national lockdown in Denmark (March to June 2020) due to the COVID-19 pandemic on psychological well-being and the content and degree of worries among pregnant women in early pregnancy. MATERIAL AND METHODS: In this hospital-based cross-sectional study based on self-reported data we compared psychological well-being and worries among women who were pregnant during the first phase of the pandemic (COVID-19 group) (n = 685), with women who were pregnant the year before (Historical group) (n = 787). Psychological well-being was measured by the five-item World Health Organization Well-being Index (WHO-5), using a score ≤50 as indicator of reduced psychological well-being. Differences in WHO-5 mean scores and in the prevalence of women with score ≤50 were assessed using general linear and log-binomial regression analyses. The Cambridge Worry Scale was used to measure the content and degree of major worries. To detect differences between groups, Pearson's Chi-square test was used. RESULTS: We found no differences in mean WHO-5 score between groups (mean difference) 0.1 (95% CI -1.5 to 1.6) or in the prevalence of women with WHO-5 score ≤50 (prevalence ratio 1.04, 95% CI 0.83-1.29) in adjusted analyses. A larger proportion of women in the COVID-19 group reported major worries about Relationship with husband/partner compared with the Historical group (3% [n = 19] vs 1% [n = 6], p = 0.04), and 9.2% in the COVID-19 group worried about the possible negative influence of the COVID-19 restrictions. CONCLUSIONS: Our findings indicate that national restrictions due to the COVID-19 pandemic did not influence the psychological well-being or the content and degree of major worries among pregnant women. However, a larger proportion of women in the COVID-19 group reported major worries concerning Relationship with husband/partner compared with the Historical group and 9.2% in the COVID-19 group worried about the possible negative influence of the COVID-19 restrictions.

Growth Differentiation Factor 15 during pregnancy and postpartum as captured in blood, cerebrospinal fluid and placenta: A cohort study on associations with maternal mental health.

INTRODUCTION: Growth Differentiation Factor 15 (GDF15) increases substantially during pregnancy and is primarily produced by the placenta. Elevated levels of GDF15 have been associated with mental health problems in non-perinatal populations, higher corticosterone levels, and decreased estrogen receptor activity. However, the role of GDF15 in mental health during the perinatal transition remains unknown. This longitudinal study is the first to evaluate pregnancy levels of GDF15 in cerebrospinal fluid (cGDF15), plasma (pGDF15) and placenta GDF15 mRNA, along with mapping plasma GDF15 (pGDF15) level changes from late pregnancy to early postpartum. Moreover, we aimed to evaluate the association between pregnancy cGDF15 levels and cortisol early postpartum, evaluate the association between pregnancy cGDF15 levels and mental health in pregnancy and postpartum, and evaluate the association between pGDF15 and estrogens and high-sensitivity C-reactive protein (CRP). METHODS: We included data from 95 women scheduled for a planned cesarean section and obtained cerebrospinal fluid (CSF) and plasma levels of GDF15. We quantified GDF15 mRNA levels in placenta biopsies. Estrogens, high-sensitivity CRP, and mental health measures were further collected on the day or one day before the cesarean section. At five weeks postpartum, mental health measures and saliva samples for cortisol analyses were collected. Correlation analyses for GDF15 in CSF, plasma, and placenta mRNA were performed, along with association analyses for pregnancy cGDF15, Cortisol Awakening Response, and mental health outcomes. RESULTS: We demonstrated a strong correlation between cGDF15 and pGDF15 (r=0.52; p<0.001) and found that both cGDF15 and pGDF15 correlated with placenta GDF15 mRNA*placental weight (r=0.62, p<0.001 and r=0.44, p=0.008, respectively). During late pregnancy, both estradiol (E2) and estriol (E3) were significantly associated with pGDF15 levels (E2: p=0.002; E3: p(corrected)<0.001). Finally, we found that cGDF15 levels were not associated with self-reported mental well-being or the Cortisol Awakening Response or absolute cortisol at awakening postpartum. CONCLUSION: This novel study points to the unique hormonal landscape during the perinatal transition and the specific role of GDF15 in pregnancy, which appears uncoupled with perinatal mental health and cortisol outcomes. Our data also strongly imply that the overall amount of circulating GDF15 in late pregnancy is closely related to placenta size.

The cortisol awakening response is blunted in healthy women early postpartum.

INTRODUCTION: The dynamic capacity of the hypothalamic-pituitary-adrenal (HPA) axis supports healthy adaptions to stress and play a key role in maintaining mental health. Perinatal adaptations in the HPA-axis dynamics in terms of the Cortisol Awakening Response (CAR), may be involved in dysregulation of perinatal mental health. We aimed to determine if CAR and absolute evening cortisol early postpartum differed from non-perinatal women and evaluate the association between the CAR and maternal mental well-being. METHODS: The CAR was computed as the area under the curve with respect to increase from baseline from serial home-sampling of saliva across 0-60 minutes from awakening. We evaluated differences in CAR and absolute evening cortisol between postpartum women (N=50, mean postpartum days: 38, SD: ±11) and non-perinatal women (N=91) in a multiple linear regression model. We also evaluated the association between CAR and maternal mental well-being in a multiple linear regression model. RESULTS: We found that healthy postpartum women had a blunted CAR (p<0.001) corresponding to 84% reduction and 80% lower absolute evening cortisol (p<0.001) relative to non-perinatal healthy women. In the postpartum group, there was a trend-level association between lower CAR and higher scores on the WHO Well-Being Index (WHO-5) (p=0.048) and lower Edinburgh Postnatal Depression Scale (EPDS) scores (p=0.04). CONCLUSION: Our data emphasize the unique hormonal landscape during the postpartum period in terms of blunted CAR and lower absolute evening cortisol in healthy women early postpartum compared to non-perinatal. Our findings show a potential association between a reduced CAR and improved mental well-being during early motherhood, which suggests that reduced CAR might reflect healthy adjustment to early motherhood.

Multivitamin intake and the risk of congenital heart defects: A cohort study.

OBJECTIVE: Congenital heart disease (CHD) is the most common type of congenital birth defect, but little is known about possible modifiable behavioral risk factors. The study aimed to assess whether intake of periconceptional or postconceptional multivitamin was associated with a decreased risk of CHD in the offspring. STUDY DESIGN: The study population comprised 15,567 women from the Copenhagen Pregnancy Cohort with complete data on multivitamin intake before and during pregnancy, who gave birth to live-born singletons from October 2012 to October 2016. Main outcome measure was CHD defined according to the International Classification of Diseases (ICD), 10th revision. Cases of CHD were classified into five subgroups based on the clinical phenotype: 1) Conotruncal defects, 2) Left ventricular outflow tract obstruction, 3) Right ventricular outflow tract obstruction, 4) Septal defects, and 5) Other CHD. Multivariate logistic regression analyses were performed with adjustment for maternal age, chronic disease, assisted reproductive technology, smoking status, and alcohol consumption. RESULTS: Of the 15,567 included women, 31.9 % reported a daily multivitamin intake in the periconceptional period, 53.7 % in the postconceptional period, and 14.4 % women did not report a daily multivitamin intake. The prevalence of CHD in the population was 0.7 % (n = 112). Periconceptional and postconceptional multivitamin intake was not associated with risk of overall CHD in offspring: Adjusted OR was 0.64 (95 % CI 0.36-1.13) and 0.77 (95 % CI 0.47-1.30), respectively. CONCLUSION: The current large cohort study did not show a preventive effect of multivitamin intake in the periconceptional or postconceptional period on the risk of CHD in the offspring.

Evaluation of the Effect of Supervised Group Exercise on Self-Reported Sleep Quality in Pregnant Women with or at High Risk of Depression: A Secondary Analysis of a Randomized Controlled Trial.

Poor sleep quality is common during pregnancy. Our objective was to evaluate the effect of supervised group physical exercise on self-reported sleep quality in pregnant women with or at high risk of depression, and secondly, to describe the association between sleep quality and psychological well-being during pregnancy and postpartum. This was a secondary analysis of a randomized controlled trial (n = 282) (NCT02833519) at Rigshospitalet, Denmark. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI), psychological well-being by the five-item WHO Well-Being Index (WHO-5). The intention-to-treat analysis showed no difference in mean global PSQI score neither at 29−34 weeks, 6.56 (95% CI: 6.05−7.07) in the intervention group and 7.00 (95% CI: 6.47−7.53) in the control group, p = 0.2, nor at eight weeks postpartum. Women with WHO-5 ≤ 50 reported higher mean global PSQI scores at baseline, 7.82 (95% CI: 7.26−8.38), than women with WHO-5 score > 50, mean 5.42 (95% CI: 5.02−5.82), p < 0.0001. A significant difference was also present post-intervention and eight weeks postpartum. No significant effect of group exercise regarding self-reported sleep quality was seen at 29−34 weeks of gestation or postpartum. Low psychological well-being was associated with poor sleep quality during pregnancy and postpartum.

Iron supplementation during the first trimester of pregnancy after a national change of recommendation: a Danish cross-sectional study.

In 2013, the Danish Health Authorities recommended a change in prophylactic iron supplementation to 40-50 mg/d from gestational week 10. Hence, the aims of the present study were (1) to estimate the prevalence of women who follow the Danish recommendation on iron supplementation during the last 3 weeks of the first trimester of pregnancy and (2) to identify potential sociodemographic, reproductive and health-related pre-pregnancy predictors for iron supplementation during the first trimester. We conducted a cross-sectional study with data from the hospital-based Copenhagen Pregnancy Cohort. Characteristics were analysed by descriptive statistics and multivariable logistic regression analysis was performed to examine the associations between predictors and iron supplementation during the last 3 weeks of the first trimester. The study population consisted of 23 533 pregnant women attending antenatal care at Copenhagen University Hospital - Rigshospitalet from October 2013 to May 2019. The prevalence of iron supplementation according to recommendations was 49⋅1 %. The pre-pregnancy factors of ≥40 years of age, the educational level below a higher degree and a vegetarian or vegan diet were identified as predictors for iron supplementation during the first trimester of pregnancy. Approximately half of the women were supplemented with the recommended dose of iron during the first trimester of pregnancy. We identified pre-pregnancy predictors associated with iron supplementation. Interventions that target women of reproductive age are needed. An enhanced focus on iron supplementation during pregnancy should be incorporated in pre-pregnancy and interpregnancy counselling.

How often will midwives and obstetricians experience obstetric emergencies or high-risk deliveries: a national cross-sectional study.

OBJECTIVE: To estimate how often midwives, specialty trainees and doctors specialised in obstetrics and gynaecology are attending to specific obstetric emergencies or high-risk deliveries (obstetric events). DESIGN: A national cross-sectional study. SETTING: All hospital labour wards in Denmark. PARTICIPANTS: Midwives (n=1303), specialty trainees (n=179) and doctors specialised in obstetrics and gynaecology (n=343) working in hospital labour wards (n=21) in Denmark in 2018. METHODS: Categories of obstetric events comprised of Apgar score <7/5 min, eclampsia, emergency caesarean sections, severe postpartum haemorrhage, shoulder dystocia, umbilical cord prolapse, vaginal breech deliveries, vaginal twin deliveries and vacuum extraction. Data on number of healthcare professionals were obtained through the Danish maternity wards, the Danish Health Authority and the Danish Society of Obstetricians and Gynaecologists. We calculated the time interval between attending each obstetric event by dividing the number of events occurred with the number of healthcare professionals. OUTCOME MEASURES: The time interval between attending a specific obstetric event. RESULTS: The average time between experiencing obstetric events ranged from days to years. Emergency caesarean sections, which occur relatively frequent, were attended on average every other month by midwives, every 9 days for specialty trainees and every 17 days by specialist doctors. On average, rare events like eclampsia were experienced by midwives only every 42 years, every 6 years by specialty trainees and every 11 years by specialist doctors. CONCLUSIONS: Some obstetric events occur extremely rarely, hindering the ability to obtain and maintain the clinical skills to manage them through clinical practice alone. By assessing the frequency of a healthcare professionals attending an obstetric emergency, our study contributes to assessing the need for supplementary educational initiatives and interventions to learn and maintain clinical skills.

Lifestyle Habits among Pregnant Women in Denmark during the First COVID-19 Lockdown Compared with a Historical Period-A Hospital-Based Cross-Sectional Study.

The first national lockdown in Denmark due to the COVID-19 pandemic was declared on 11 March 2020. From this date, national restrictions were imposed. We aimed to assess the potential influence of this first nationwide lockdown on exercise, alcohol consumption, and smoking in early pregnancy. Using a cross-sectional study based on routinely collected patient-reported data, we compared the lifestyle habits of women who were pregnant during the first phase of the pandemic (COVID-19 group) (n = 685) with those of women who were pregnant the year before (Historical group) (n = 787). We found a reduction in any exercise (PR = 0.91, 95% CI (0.84 to 0.99), in adherence to national recommendations of exercise (PR = 0.89, 95% CI (0.80 to 0.99), in cycling (15% vs. 28%, p < 0.0001), and swimming (0.3% vs. 3%, p = 0.0002) in the COVID-19 group compared with the Historical group. The prevalence of binge drinking was reduced in the COVID-19 group compared with the Historical group (PR = 0.80, 95% CI (0.68 to 0.93). In contrast, the prevalence of any weekly alcohol consumption and smoking cessation during pregnancy was similar between groups. Our findings indicate that national restrictions due to the COVID-19 pandemic influenced the lifestyle habits of pregnant women and should be addressed in antenatal counseling.

Short-term oestrogen as a strategy to prevent postpartum depression in high-risk women: protocol for the double-blind, randomised, placebo-controlled MAMA clinical trial.

INTRODUCTION: Postpartum depression affects 10%-15% of women and has a recurrence rate of 40% in subsequent pregnancies. Women who develop postpartum depression are suspected to be more sensitive to the rapid and large fluctuations in sex steroid hormones, particularly estradiol, during pregnancy and postpartum. This trial aims to evaluate the preventive effect of 3 weeks transdermal estradiol treatment immediately postpartum on depressive episodes in women at high risk for developing postpartum depression. METHODS AND ANALYSIS: The Maternal Mental Health Trial is a double-blind, randomised and placebo-controlled clinical trial. The trial involves three departments of obstetrics organised under Copenhagen University Hospital in Denmark. Women who are singleton pregnant with a history of perinatal depression are eligible to participate. Participants will be randomised to receive either transdermal estradiol patches (200 µg/day) or placebo patches for 3 weeks immediately postpartum. The primary outcome is clinical depression, according to the Diagnostic and Statistical Manual of Mental Disorders-V criteria of Major Depressive Disorder with onset at any time between 0 and 6 months postpartum. Secondary outcomes include, but are not limited to, symptoms of depression postpartum, exclusive breastfeeding, cortisol dynamics, maternal distress sensitivity and cognitive function. The primary statistical analysis will be performed based on the intention-to-treat principle. With the inclusion of 220 participants and a 20% expected dropout rate, we anticipate 80% power to detect a 50% reduction in postpartum depressive episodes while controlling the type 1 error at 5%. ETHICS AND DISSEMINATION: The study protocol is approved by the Regional Committees on Health Research Ethics in the Capital Region of Denmark, the Danish Medicines Agency and the Centre for Data Protection Compliance in the Capital Region of Denmark. We will present results at scientific meetings and in peer-reviewed journals and in other formats to engage policymakers and the public. TRIAL REGISTRATION NUMBER: NCT04685148.

Women and partners' experiences of critical perinatal events: a qualitative study.

OBJECTIVE: The aim of this study was to explore women and partners' experiences following critical perinatal events. DESIGN: This is a qualitative interview study. We conducted semistructured individual interviews with women and their partners in separate rooms. Interviews were analysed thematically and validated by a transdisciplinary group of anthropologists, obstetricians and a midwife. SETTING: Department of obstetrics at a tertiary referral university hospital in Denmark. PARTICIPANTS: Women and partners who had experienced a critical perinatal event within the past 3-12 months. RESULTS: We conducted 17 interviews and identified three main themes: (1) ambivalence towards medicalisation, (2) the extended temporality of a critical birth and (3) postnatal loss of attention from healthcare professionals. Overall, participants expressed a high degree of trust in and quality of provided healthcare during the critical perinatal events. They experienced medicalisation (obstetric interventions) as a necessity, linking them to the safety of the child and their new role as responsible parents. However, some women experienced disempowerment when healthcare professionals overlooked their ability to stay actively involved during birth events. Postnatally, women and their partners experienced shortages of healthcare professional resources, absent healthcare and lack of attention. CONCLUSIONS: Women and their partners' experiences of critical perinatal events begin long before and end long after the actual moment of childbirth, challenging conventional ideas about the birth as being the pivotal event in making families. In future healthcare planning, it is important to to align expectations and guide parental involvement in birth events and to acknowledge the postnatal period as equally crucial.

Postnatal consultations with an obstetrician after critical perinatal events: a qualitative study of what women and their partners experience.

OBJECTIVE: The objective of this study was to explore women's and their partners' experiences with attending postnatal consultations with an obstetrician after critical perinatal events. DESIGN: Qualitative interview study. We did semi-structured individual narrative interviews exploring the lived experiences. Interviews were analysed using a phenomenological approach and the thematic analysis was validated by a transdisciplinary group of anthropologists, obstetricians and a midwife. SETTING: Department of obstetrics at a large hospital in Denmark. PARTICIPANTS: We did a qualitative study with 17 participants (10 women and 7 partners) who had experienced critical perinatal events. RESULTS: Five major themes were identified: (1) a need to gain understanding and make sense of the critical perinatal events, (2) a need for relational continuity, (3) the importance of discussing emotional effects as well as physical aspects of occurred events, (4) preparing for future pregnancies and (5) closure of the story.Most of the participants emphasised the importance of knowing the obstetrician undertaking the postnatal consultation. The majority of the participants described a need to discuss the emotional effects of the experience as well as the physical aspects of occurred events. The postnatal consultation served as an approach to obtain a positive closure of their birth story and to feel confident about potential future pregnancies. CONCLUSIONS: This interview-based study suggests that postnatal consultation with an obstetrician might be an important tool for women and their partners in understanding the course of events during the critical birth experience and in processing it and preparing for future pregnancies. It appears to be important to assign an obstetrician whom they already know and to encourage them to discuss not only physical aspects of what happened but also the emotional effects of the experience.

Multivitamin use and risk of preeclampsia in a high-income population: A cohort study.

OBJECTIVE: The objective of this study was to examine the association between multivitamin use in the periconceptional period and the risk of preeclampsia. STUDY DESIGN: The association was investigated in a prospective cohort study. 15,154 deliveries in women followed at a large university hospital in Denmark were included between 16 September 2012 and 31 October 2016. Pregnant women were sent a questionnaire containing items related to socio-demographic-, lifestyle- and health factors. The responses on multivitamin use were merged with the preeclampsia diagnosis from the Danish Medical Birth Registry. We used multiple logistic regression analyses to assess the association and to adjust for potential confounders. MAIN OUTCOME MEASURES: The outcome of interest, preeclampsia, included the preeclampsia subtypes eclampsia and HELLP (Haemolysis, Elevated Liver enzymes, and Low Platelets) syndrome. RESULTS: In total 12,954 women (85%) reported multivitamin use. A diagnosis of preeclampsia was found in 397 women (2.6%). We found a similar risk of preeclampsia in multivitamin user and non-users, adjusted odds ratio (AOR) for periconceptional multivitamin use = 0.97 (95% CI: 0.70 to 1.36) and AOR for early pregnancy multivitamin use = 0.97 (95% CI: 0.71 to 1.32). Subgroup analyses stratified on body mass index showed that among women with overweight, both periconceptional and early pregnancy multivitamin use were associated with a statistically significant lower risk of preeclampsia (AOR = 0.49, 95% CI: 0.24 to 0.99 and AOR = 0.35, 95% CI: 0.18 to 0.69, respectively). CONCLUSION: Periconceptional- and early pregnancy multivitamin use was found to be associated with a similar risk of preeclampsia compared to non-users.