Inflammatory markers in pregnancy - surprisingly stable. Mapping trajectories and drivers in four large cohorts.

Adaptations of the immune system throughout gestation have been proposed as important mechanisms regulating successful pregnancy. Dysregulation of the maternal immune system has been associated with adverse maternal and fetal outcomes. To translate findings from mechanistic preclinical studies to human pregnancies, studies of serum immune markers are the mainstay. The design and interpretation of human biomarker studies require additional insights in the trajectories and drivers of peripheral immune markers. The current study mapped maternal inflammatory markers (C-reactive protein (CRP), interleukin (IL)-1ß, IL-6, IL-17A, IL-23, interferon- γ ) during pregnancy and investigated the impact of demographic, environmental and genetic drivers on maternal inflammatory marker levels in four multi-ethnic and socio-economically diverse population-based cohorts with more than 12,000 pregnant participants. Additionally, pregnancy inflammatory markers were compared to pre-pregnancy levels. Cytokines showed a high correlation with each other, but not with CRP. Inflammatory marker levels showed high variability between individuals, yet high concordance within an individual over time during and pre-pregnancy. Pre-pregnancy body mass index (BMI) explained more than 9.6% of the variance in CRP, but less than 1% of the variance in cytokines. The polygenic score of CRP was the best predictor of variance in CRP (>14.1%). Gestational age and previously identified inflammation drivers, including tobacco use and parity, explained less than 1% of variance in both cytokines and CRP. Our findings corroborate differential underlying regulatory mechanisms of CRP and cytokines and are suggestive of an individual inflammatory marker baseline which is, in part, genetically driven. While prior research has mainly focused on immune marker changes throughout pregnancy, our study suggests that this field could benefit from a focus on intra-individual factors, including metabolic and genetic components.

High first trimester ferritin levels differ according to parity and are independently related to preterm birth: A prospective cohort study.

INTRODUCTION: A considerable amount of neonatal morbidity and mortality worldwide is caused by preterm birth. To date, the underlying etiology of preterm birth has not been fully clarified. Previous studies demonstrate that inflammation is one of the pathological factors that might cause preterm birth, and that there is a difference between primiparous and multiparous women in immune response to pregnancy. The objective of this prospective cohort study was to investigate the role of two inflammatory markers, ferritin and C-reactive protein (CRP) and preterm birth, in first trimester women, stratified for parity. In addition, a possible association between high ferritin and CRP, and a possible association between high ferritin and CRP and preterm birth were assessed. MATERIAL AND METHODS: A total of 2044 healthy, low-risk pregnant women from primary obstetric care in the Netherlands participated in this study. Their ferritin and CRP levels were evaluated at 12 weeks' gestation. Levels above the parity specific 95th percentile were defined as high. The main outcome of this study was to assess the presence of a possible association between parity specific high ferritin and CRP, and preterm birth. The secondary outcomes were the ferritin and CRP levels of women, stratified for parity, and the possible association between high ferritin and CRP levels. Logistic regression analysis was performed with preterm birth as a dependent variable and parity specific high ferritin and CRP as an independent variable, adjusting for age and history of preterm birth. RESULTS: Ferritin levels decreased with increasing parity. Ferritin and CRP levels at 12 weeks' gestation were significantly higher in women with preterm birth. In primiparous women, high ferritin levels (OR: 2.5, CI: 1.14-5.38) and high CRP levels (OR: 5.0, CI: 2.61-9.94) were independently associated with preterm birth. In multiparous women, high ferritin levels (OR: 6.0, CI: 2.28-16.67) were independently associated with preterm birth while high CRP levels were not. CONCLUSIONS: First trimester parity specific ferritin and CRP levels could play a part in predictive models for preterm birth, and further research for their additive role in preterm birth is needed.

A longitudinal study on the association between trait mindfulness and maternal bonding across the perinatal period.

AIMS/BACKGROUND: The mother-to-infant is important for healthy child development. The current study focused on the association between maternal trait mindfulness and the course of maternal bonding from pregnancy to one year postpartum. DESIGN/METHODS: Women participating in a prospective perinatal cohort study (n = 1003) completed online questionnaires on maternal bonding (Pre- and Post-natal Bonding Scale) at 28 weeks of pregnancy, and at 8 weeks, 6 months and 12 months postpartum. At 20 weeks of pregnancy, women completed the Three Facet Mindfulness Questionnaire - Short Form. Multilevel analyses were used to analyse 1) changes in maternal bonding over time and 2) the relationship of these changes with different facets of trait mindfulness measured once during pregnancy. Demographics, obstetrics, and depressive symptoms were controlled for. RESULTS: Results showed that maternal bonding first increased from pregnancy to 8 weeks postpartum and then remained relatively stable throughout the first-year postpartum. On average, women with high scores on acting with awareness and non-judging also scored higher on maternal bonding, but demonstrated a smaller increase in maternal bonding scores over time when compared to women with medium and low scores on these mindfulness facets. Furthermore, non-reacting was also positively associated with the level of maternal bonding but was not related to the course of bonding over time. The main effects of non-reacting and non-judging were not significant after adjusting for covariates. Depressive symptoms and a high educational level were negatively associated with bonding. CONCLUSION: Mindfulness-based interventions may be helpful in supporting expectant mothers who are at risk for suboptimal bonding.

Hypothyroxinaemia during gestation is associated with low ferritin and increased levels of inflammatory markers.

Objective: Pregnancy is a state of physiological inflammation facilitating implantation. Early isolated hypothyroxinaemia (IH) and increased inflammation (including obesity) have been associated with severe obstetric complications. The current study evaluated the association between IH, low ferritin and inflammation parameters (interleukin 6 (IL-6), C-reactive protein (CRP), human chorionic gonadotrophin (hCG) and obesity. Moreover, the course of these parameters throughout pregnancy was evaluated in relation to IH. Methods: In the cross-sectional study (A) at 12 weeks, 2759 women participated and 2433 participated in the longitudinal study (B) with assessments at 12, 20 and 28 weeks gestation. At the first trimester, 122 (4.4%) IH women (free thyroxine (FT4) <5th percentile, normal TSH levels) were compared with 2114 (76.6%) reference women (FT4 between tenth and 90th percentiles, normal thyrotrophin (TSH) levels), in study B these figures were 99 (4.1%) and 1847 (75.9%), respectively. Results: Cross-sectionally, compared to reference women, IH was independently associated with low ferritin (<5th percentile, OR: 2.6, 95% CI: 1.4-4.9), high CRP (>95th percentile: OR: 1.9, 95% CI: 1.04-3.7), low hCG ( 30, OR: 1.7, 95% CI: 1.12.9) and higher age (OR: 1.1, 95% CI: 1.04-1.15). Longitudinally, compared to reference women, women with IH at 12 weeks gestation showed persistently and significantly lower ferritin and hCG levels, and persistently higher CRP and IL-6 levels throughout gestation. Conclusion: Gestational IH could be viewed as a condition of increased inflammation, as reported in non-thyroidal illness syndrome. Less favourable inflammation parameters and low iron status during early gestation in IH women seem to persist throughout gestation.

Prediction of cardiovascular events in older patients with hypertension in primary care: a cohort study.

BACKGROUND: Accurate risk stratification identifying patients with hypertension at risk of future cardiovascular disease in primary care would be desirable. AIM: To investigate the association between elevated brain natriuretic peptide (BNP), left ventricular hypertrophy (LVH) on an electrocardiogram (ECG), and LVH on an echocardiogram and the development of cardiovascular events (CVEs), especially heart failure and all-cause mortality (ACM), in a primary care population with hypertension without symptoms of heart failure. DESIGN AND SETTING: A prospective cohort study in five Dutch general practices between 2010-2012 and 2020. METHOD: In total, 530 patients (aged 60-85 years) underwent laboratory testing, ECGs, and echocardiograms at baseline. The incidence of new CVEs and ACM at up to 9 years' follow-up was recorded by data extraction from the digital information systems. RESULTS: Among the 530 participants, 31 (5.8%) developed a coronary event, 44 (8.3%) a cerebrovascular accident, 53 (10.0%) atrial fibrillation, 23 (4.3%) heart failure, and 66 (12.5%) died. Cox regression analyses, adjusting for relevant Framingham covariates, showed that elevated BNP increased the risk of ACM, CVEs, and specifically heart failure independently by 44% (hazard ratio [HR] 1.44, 95% confidence interval [CI] = 1.07 to 1.94, P = -0.017), 45% (HR 1.45, 95% CI = 1.15 to 1.82, P = 0.002), and 288% (HR 3.88, 95% CI = 2.13 to 7.10, P<0.001), respectively. LVH on ECG increased the risk of ACM independently by 108% (HR 2.08, 95% CI = 1.14 to 3.81, P = 0.017). LVH either on an ECG and/or echocardiogram increased the risk of heart failure independently by 309% (HR 4.09, 95% CI = 1.34 to 12.49, P = 0.014). CONCLUSION: In primary care patients with hypertension, BNP seems to be an important marker predicting future CVEs, especially heart failure, as well as all-cause mortality.

Browsing throughout pregnancy: The longitudinal course of social media use during pregnancy.

BACKGROUND: The number of people using social media has substantially increased over the past years. Previous studies have shown associations between social media overuse and mental health problems during pregnancy. The current study evaluates changes in social media use during pregnancy. METHODS: Pregnant women were recruited at their first antenatal appointment between January 2020 and July 2022 (N = 1135). The time spent on social media, frequency of social media use and problematic social media use, using the Bergen Social Media Addiction Scale (BSMAS), were assessed at 12, 20 and 28 weeks of pregnancy. Pearson r correlations and repeated measures ANOVAs were performed to assess possible changes in social media use over the course of pregnancy. Lastly, we stratified social media use throughout pregnancy for parity. RESULTS: There was a significant change in social media use over time, for the time spent on social media, frequency of social media use and problematic social media use. Mean social media scores were the lowest at 12 weeks of pregnancy and increased significantly at 20 weeks of pregnancy, after which they remained stable at 28 weeks. Compared to multiparous women, primiparous women spent more time on social media at 20 weeks of pregnancy, but not at 12 or 28 weeks. CONCLUSION: Because overuse of social media has been associated with poor mental health, healthcare professionals should be aware of the intensity of social media use throughout pregnancy.

TSH and FT4 Reference Interval Recommendations and Prevalence of Gestational Thyroid Dysfunction: Quantification of Current Diagnostic Approaches.

CONTEXT: Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. METHODS: We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. RESULTS: The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. CONCLUSION: Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.

Paternal bonding in pregnancy and early parenthood: a qualitative study in first-time fathers.

The birth of an infant marks a period of profound change in first-time parents. Parental love and warmth, however, already begin to develop during pregnancy. Also for fathers, the development of bonding to the infant may be a unique process. The current qualitative study aimed to explore views and experiences of first-time fathers on the origins and development of paternal bonding during pregnancy and early childhood. In total, 30 in-depth semi-structured interviews were conducted with expectant fathers (second or third trimester of pregnancy; n = 10) and fathers of infants (0-6 months postpartum; n = 11) and toddlers (2-3 years of age; n = 9). Two major themes were uncovered from the data: feelings of bonding and facilitators of bonding. The first theme was supported with three subthemes: 1) from abstract to concrete, 2) positive emotions, and 3) uncertainties and worries. The second theme, facilitators of bonding, was supported with four subthemes: 1) experiencing the foetus, 2) meeting the child, 3) interaction, and 4) communication. Similar to previous studies, our results suggested that, in most fathers, paternal bonding originates in pregnancy and that it evolves over time. Seeing or feeling the child, both during pregnancy and postpartum, as well as interacting or communicating with the child, appears to facilitate fathers' feelings of bonding. Involving fathers in pregnancy, childbirth, and parenting may be essential for their bonding process.

Maternal-infant bonding and partner support during pregnancy and postpartum: Associations with early child social-emotional development.

The first 1000 days after conception are considered critical for healthy development and well-being throughout life. Fundamental to health practices during pregnancy and positive parenting after birth is the development of maternal-infant bonding. Previous research has demonstrated the importance of having an involved partner during pregnancy and in parenting for optimal maternal-infant bonding. The current study examined maternal-infant bonding and partner support during pregnancy and the postpartum period, and their associations with early child social-emotional development. A total of 227 women completed the Pre- and Postnatal Bonding Scale (PPBS) and Tilburg Pregnancy Distress Scale (TPDS) during pregnancy (32 weeks of gestation) and at 8 months postpartum, assessing maternal-infant bonding and partner support. Additionally, a questionnaire on social-emotional behavior of the Bayley Scales of Infant and Toddler Development was administered to mothers to measure child development at 2 years of age. Path analyses revealed an indirect positive effect of prenatal maternal-infant bonding on child social-emotional development through postnatal maternal-infant bonding, as well as mediating effects of pre- and postnatal maternal-infant bonding on the association between pre- and postnatal partner support and child social-emotional development. Our findings support the notion that an emotional connection from mother to child originates in pregnancy and that experiencing positive feelings towards the fetus promotes positive maternal-infant bonding after birth and social-emotional capacities of the child. Additionally, having a supportive partner during pregnancy and postpartum, might be essential for the development of optimal maternal-infant bonding.

Breastfeeding continuation is associated with trait mindfulness but not with trajectories of postpartum depressive symptoms.

OBJECTIVE: The WHO recommends breastfeeding for at least six months as breastfeeding has many benefits for both infant and mother. The association of breastfeeding continuation with trait mindfulness during pregnancy and trajectories of postpartum depressive symptoms has not been examined yet. The current study aimed to assess this association using cox regression analysis. DESIGN, SETTING AND PARTICIPANTS: The current research is part of a large longitudinal prospective cohort study following women from 12 weeks of pregnancy onwards in the South-East part of the Netherlands. MEASUREMENTS: A total of 698 participants filled out the Three Facet Mindfulness Questionnaire-Short Form (TFMQ-SF) at 22 weeks of pregnancy and completed both the Edinburgh Postnatal Depression Scale (EPDS) and questions on breastfeeding continuation one week, six weeks, four months, and eight months postpartum. Breastfeeding continuation was defined as exclusive breastfeeding or both breastfeeding and formula. The assessment eight months postpartum was used as a proxy for the WHO recommendation to continue breastfeeding for at least six months. FINDINGS: Two trajectories (classes) of EPDS scores were determined using growth mixture modeling: 1) low stable (N = 631, 90.4%), and 2) increasing (N = 67, 9.6%). Cox regression analysis showed that the trait mindfulness facet non-reacting was significantly and inversely associated with the risk of breastfeeding discontinuation (HR = 0.96, 95% CI [0.94, 0.99], p = .002), while no significant association was found for belonging to the increasing EPDS class versus belonging to the low stable class (p = .735), adjusted for confounders. KEY CONCLUSIONS: This study is the first to show that higher trait mindfulness non-reacting scores, but not persistently low levels of postpartum depressive symptoms, increase the likelihood of breastfeeding continuation. IMPLICATIONS FOR PRACTICE: Improving non-reacting in perinatal women by meditation practice as part of a mindfulness-based intervention may lead to better breastfeeding continuation outcomes. Several mindfulness-based programs may be suitable.

Social media use as a risk factor for depressive symptoms during pregnancy.

BACKGROUND: Accumulating research has shown associations between excessive social media use (SMU) with depressive symptoms. Depression is common during pregnancy, but it is not known whether SMU plays a role in the etiology and clinical course of depressive symptoms during pregnancy. METHODS: The current study is a prospective cohort study with Dutch-speaking pregnant women recruited at the first antenatal appointment (N = 697). Depressive symptoms were measured at each trimester of pregnancy using the Edinburgh Depression Scale. Growth mixture modeling was used to determine classes of women based on longitudinal trajectories of depressive symptoms. SMU was assessed at 12 weeks of pregnancy, specifically, intensity (time and frequency) and problematic SMU (Bergen Social Media Addiction Scale). Multinomial logistic regression analyses were used to examine the associations between SMU and trajectories of depressive symptoms. RESULTS: Three trajectories of depressive symptoms during pregnancy were identified: a low stable (N = 489, 70.2 %), intermediate stable (N = 183, 26.3 %), and high stable (N = 25, 3.6 %) class. SMU Time and Frequency were significantly associated with belonging to the high stable class. Problematic SMU was significantly associated with belonging to the intermediate or high stable class. LIMITATIONS: The study does not allow to draw conclusions about causality. The group sizes of the three trajectories differed considerably. Data were collected during the COVID-19 pandemic which may have influenced the results. SMU was measured by self-report. CONCLUSIONS: These results indicate that both higher intensity of SMU (time and frequency) and problematic SMU may be a risk factor for higher levels of prenatal depressive symptoms during pregnancy.

Online mindfulness-based intervention for women with pregnancy distress: A randomized controlled trial.

BACKGROUND: Pregnancy distress among childbearing women is common and can negatively affect both mother and infant. Mindfulness-based interventions (MBIs) may have a positive effect on pregnancy distress but randomized controlled trials with sufficient power are lacking. The current study examined the effectiveness of an online self-guided MBI in pregnant women with pregnancy distress. METHODS: Pregnant women with elevated pregnancy distress levels at 12 weeks of pregnancy, measured with the Edinburgh Depression Scale (EDS) and Tilburg Pregnancy Distress Scale negative affect (TPDS-NA), were randomized into an intervention group (online MBI, N = 109) or control group (care as usual, N = 110). The primary outcome was the change in pregnancy distress post-intervention and at eight-weeks-follow-up. Secondary outcomes were mindfulness skills (Three Facet Mindfulness Questionnaire-Short Form), rumination (Rumination-Reflection Questionnaire), and self-compassion (Self-Compassion Scale-Short Form) at post-intervention and follow-up in the intervention group. RESULTS: Significant improvements were found in pregnancy distress scores, but no significant differences between intervention and control group appeared. The MBI group showed improvements in mindfulness skills, rumination, and self-compassion. LIMITATIONS: Low adherence to the intervention and assessment of secondary outcome measures in the intervention group only. CONCLUSIONS: An intervention trial with one of the largest samples (N = 219) provided no evidence of a significant effect of an online self-guided MBI in distressed pregnant women. An online MBI may be associated with an improvement in mindfulness skills, rumination, and self-compassion. Future research should address the effectiveness of MBI's with different formats (online and group-based combined) and examine a possible delayed effect. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03917745, registered on 4 March 2019.

The first trimester plasma copper-zinc ratio is independently related to pregnancy-specific psychological distress symptoms throughout pregnancy.

OBJECTIVES: High plasma copper (Cu) and low zinc (Zn) levels have been associated with depression. However, most studies used low sample sizes and a cross-sectional design, and perinatal data are scarce. We investigated the possible association between pregnancy-specific psychological distress and the plasma CuZn ratio using a prospective design. METHODS: Pregnancy-specific distress symptoms were assessed at each trimester by means of the Tilburg Pregnancy Distress Scale, negative affect subscale, in 2036 pregnant women. Cu and Zn were assessed at 12 wk of gestation in plasma samples by inductively coupled plasma mass spectrometry. Growth mixture modeling determined trajectories of women's pregnancy-specific negative affect (P-NA) symptoms, which were entered in a multiple logistic regression analysis as dependent variable and the CuZn ratio as independent variable. RESULTS: Two P-NA symptom classes were found: 1) persistently low (n = 1820) and 2) persistently high (n = 216). A higher CuZn ratio was independently associated with persistently high P-NA symptom scores (odds ratio = 1.52; 95% confidence interval, 1.13-2.04) after adjustment for confounders. A sensitivity analysis was performed excluding all women with high P-NA scores at 12 wk of gestation (>1 SD above the mean P-NA score). In the 1719 remaining women, a higher CuZn ratio significantly predicted the development of increasing P-NA symptom scores after adjustment for confounders (odds ratio = 1.40; 95% confidence interval, 1.04-1.95). CONCLUSIONS: A higher CuZn plasma ratio is an independent determinant of developing pregnancy-specific distress symptoms throughout pregnancy, suggesting that micronutrients could be used as novel biomarkers for psychological distress research of perinatal mood disorders.

Association between high levels of comorbid anxiety and depressive symptoms and decreased likelihood of birth without intervention: A longitudinal prospective cohort study.

OBJECTIVE: To assess the association between trajectories of comorbid anxiety and depressive (CAD) symptoms assessed in each pregnancy trimester and physiological birth. DESIGN: Large longitudinal prospective cohort study with recruitment between January 2013 and September 2014. SETTING: Primary care, in the Netherlands. POPULATION: Dutch-speaking pregnant women with gestational age at birth ≥37 weeks, and without multiple pregnancy, severe psychiatric disorder or chronic disease history. METHODS: Pregnancy-specific anxiety and depressive symptoms were measured prospectively in each trimester of pregnancy using the negative affect subscale of the Tilburg Pregnancy Distress Scale and Edinburgh (Postnatal) Depression Scale. Data on physiological birth were obtained from obstetric records. Multivariate growth mixture modelling was performed in MPLUS to determine longitudinal trajectories of CAD symptoms. Multiple logistic regression analysis was used to examine the association between trajectories and physiological birth. MAIN OUTCOME MEASURES: Trajectories of CAD symptoms and physiological birth. RESULTS: Seven trajectories (classes) of CAD symptoms were identified in 1682 women and subsequently merged into three groups: group 1-persistently low levels of symptoms (reference class 1; 79.0%), group 2-intermittently high levels of symptoms (classes 3, 6 and 7; 11.2%), and group 3-persistently high levels of symptoms (classes 2, 4 and 5; 9.8%). Persistently high levels of CAD symptoms (group 3) were associated with a lower likelihood of physiological birth (odds ratio 0.67, 95% confidence interval 0.47-0.95, P = 0.027) compared with the reference group (persistently low levels of symptoms), after adjusting for confounders. CONCLUSIONS: This study is the first showing evidence that persistently high CAD levels, assessed in each pregnancy trimester, are associated with a lower likelihood of physiological birth.

The Tilburg Pregnancy Distress Scale revised (TPDS-R): Psychometric aspects in a longitudinal cohort study.

Pregnant women may be specifically prone to experience pregnancy-specific distress, which has been associated with adverse maternal, pregnancy and child outcomes. Accurately identifying pregnancy-specific distress is thus crucial. The Tilburg Pregnancy Distress Scale (TPDS) - translated into many different languages - was previously developed to measure pregnancy-specific distress, resulting in a 16-item screening scale with a partner involvement dimension (PI) and a negative affect dimension (NA). A critical evaluation of the psychometric properties of the TPDS-NA items and feedback from pregnant women over the last decade has led to the need to revise the TPDS. Therefore, in the current study, we describe the procedure for revision and evaluate the psychometric properties of the revised TPDS (TPDS-R). More specifically, we describe the revision of the TPDS-R-PI (4 items) and the TPDS-R-NA (10 items: five-item pregnancy and five-item childbirth subcomponent). A sample of 1081 pregnant women participating in the Brabant Study completed the TPDS-R at 12, 20 and 28 weeks of pregnancy. An exploratory factor analysis and confirmatory factor analysis, descriptive statistics and repeated measures ANOVA demonstrated good test-retest reliability, concurrent validity, internal consistency, and construct validity of the TPDS-R. The TPDS-R provides a robust screening tool to accurately identify pregnant women at risk of pregnancy-specific distress.

Hypothyroid Symptoms Throughout Pregnancy Are Predominantly Associated with Thyroxine and Not with Thyrotropin Concentrations.

Background: It is unclear whether levels of hypothyroid symptoms in pregnant women with (sub)clinical thyroid dysfunction differ from euthyroid controls and whether free thyroxine (fT4)/thyrotropin (TSH) changes throughout pregnancy affect hypothyroid symptom levels. The objective was twofold: (1) To compare hypothyroid symptom levels between thyroid dysfunction subgroups and a carefully defined reference group; (2) to assess the association between fT4/TSH changes throughout pregnancy and hypothyroid symptom levels adjusted for depressive symptoms. Methods: The current study was a longitudinal prospective cohort study in 1800 healthy pregnant women. At each trimester of pregnancy, hypothyroid symptoms were assessed with a 12-item symptom hypothyroidism checklist and depressive symptoms with the Edinburgh Depression Scale. Thyroid dysfunction was defined using the 2.5-97.5th fT4/TSH percentile of thyroid peroxidase antibodies-negative women. Euthyroid controls consisted of women with appropriate fT4 levels within the 10-90th percentile and with a normal TSH level. Hypothyroid symptom mean scores were compared between controls and several thyroid dysfunction subgroups. Growth mixture modeling was performed to evaluate possible longitudinal trajectories of hypothyroid and depressive symptoms. The association between hypothyroid symptom trajectories (adjusted for depression) and fT4/TSH changes was assessed with multivariate logistic regression analysis. Results: Women with overt hypothyroidism (fT4 < 2.5th, TSH >97.5th) and hypothyroxinemia (fT4 < 2.5th, TSH: 2.5-97.5th) showed higher hypothyroid symptom levels compared with the euthyroid controls and women with subclinical hypothyroidism (SCH, fT4: 2.5-97.5th, TSH >97.5th), because 82% of these SCH women had fT4 levels in the euthyroid range. Two groups of hypothyroid and depressive symptoms were defined: a persistently low and persistently high symptom group. fT4 decreased in 98% of the women from the first to third trimester and per unit pmol/L fT4 decrease (not TSH increase), the likelihood to present persistently high hypothyroid symptoms increased with 46%, adjusted for depression. Conclusions: A properly defined euthyroid control group distinguishes women with hypothyroid symptoms. An fT4 decrease toward end term is associated with persistently high hypothyroid symptom levels. Clinicians should be aware of the importance of fT4 stratification in SCH women.

TSH and FT4 Reference Intervals in Pregnancy: A Systematic Review and Individual Participant Data Meta-Analysis.

CONTEXT: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. OBJECTIVE: (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. METHODS: (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. RESULTS: (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody-positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from -10.8% to -21.8% for TSH and -1.2% to -13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. CONCLUSION: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.

Psychological distress is independently related to new coronary events at 8 years' follow-up in elderly primary care patients with hypertension.

OBJECTIVE: Occurrence of psychological distress in hypertensive patients could have a negative synergistic effect on future cardiovascular events (CVEs). The aim of this study was to determine the association between anxiety or depressive symptoms in elderly hypertensive primary care patients and the development of new CVEs and all-cause mortality. METHODS: A prospective cohort study was conducted in five Dutch general practices between June 2010 and January 2012. Patients with primary care managed hypertension, aged 60-85 years, were included and completed the GAD-7 and PHQ-9, measuring anxiety and depressive symptoms respectively. The incidence of new CVEs (coronary event, cerebrovascular disease, atrial fibrillation and heart failure) and all-cause mortality at 8 years' follow-up was recorded by data extraction of the digital information systems. RESULTS: Among the 555 included participants (mean age 70 ± 6.6 years; 56% female), 29 (5.2%) had a new coronary event, 42 (7.6%) a cerebrovascular disease, 57 (10.3%) atrial fibrillation, 22 (4%) heart failure and 68 (12.3%) died. Elevated anxiety and depression scores increased the risk of a coronary event independently and significantly by 12% (HR 1.12; 95% CI [1.04-1.22], p = 0.005) and 18% (HR 1.18; 95% CI [1.08-1.28], p < 0.0001), respectively, adjusted for relevant (Framingham) baseline covariates. No associations were found with regard to other CVEs and all-cause mortality. CONCLUSION: In a random sample of elderly primary care hypertension patients there was a significant association between psychological distress and the occurrence of new coronary events after 8 years' follow-up but not with other CVEs and all-cause mortality.