Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

Associations of light exposure patterns with sleep among Dutch children: The ABCD cohort study.

Light exposure affects the circadian system and consequently can affect sleep quality. Only few studies examined this relationship in children. We evaluated associations between light exposure patterns and sleep metrics in children. We measured the sleep parameters of 247 Dutch children, aged between 11 and 13 years and recruited from the ABCD cohort, using actigraphy and sleep records for 7 consecutive nights. Personal light exposures were measured with a light meter during the whole day and night. We applied generalized mixed-effects regression models, adjusted for possible confounders, to evaluate the associations of light exposure patterns on sleep duration, sleep efficiency and sleep-onset delay. In the models mutually adjusted for potential confounders, we found the amount of hours between the first time of bright light in the morning and going to sleep and the duration of bright light to be significantly associated with decreased sleep duration (in min; ß: -2.02 [95% confidence interval: -3.84, -0.25], ß: -8.39 [95% confidence interval: -16.70, -0.07], respectively) and with shorter sleep-onset delay (odds ratio: 0.88 [95% confidence interval: 0.80, 0.97], odds ratio: 0.40 [95% confidence interval: 0.19, 0.87], respectively). Increased light intensities at night were associated with decreased sleep duration (T2 ß: -8.54 [95% confidence interval: -16.88, -0.20], T3 ß: -14.83 [95% confidence interval: -28.04, -1.62]), while increased light intensities before going to bed were associated with prolonged sleep onset (odds ratio: 4.02 [95% confidence interval: 2.09, 7.73]). These findings further suggest that children may be able to influence their sleep quality by influencing the light exposure patterns during day and night.

Parental infertility and offspring cardiometabolic trajectories: a pooled analysis of three European cohorts.

OBJECTIVE: To assess whether parental infertility is associated with differences in cardiometabolic trajectories in offspring. DESIGN: Pooled observational analysis in three prospective cohorts. SETTING: Three nationwide pregnancy cohorts. PATIENTS: A total of 14,609 singletons from the UK Avon Longitudinal Study of Parents and Children, the Portuguese Geraçao 21, and the Amsterdam Born Children and Their Development study. Each cohort contributed data up to ages 26, 12, and 13 years, respectively. INTERVENTION: Parental infertility is defined as time-to-pregnancy of ≥12 months (n = 1,392, 9.5%). MAIN OUTCOME MEASURES: Trajectories of body mass index (BMI), waist circumference, systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol (LDL-C) level, high-density lipoprotein cholesterol (HDL-C) level, triglycerides level, and glucose level were compared in the offspring of couples with and without infertility. Trajectories were modeled using mixed-effects models with natural cubic splines adjusting for cohort, sex of the offspring, and maternal factors (age, BMI, smoking, educational level, parity, and ethnicity). Predicted levels of cardiometabolic traits up to 25 years of age were compared with parental infertility. RESULTS: Offspring of couples with infertility had increasingly higher BMI (difference in mean predicted levels by age 25 years: 1.09 kg/m2, 95% confidence interval [0.68-1.50]) and suggestively higher diastolic blood pressure at age 25 years (1.21 mmHg [-0.003 to 2.43]). Their LDL-C tended to be higher, and their HDL-C values tended to be lower over time (age: 25 years, LDL-C: 4.07% [-0.79 to 8.93]; HDL-C: -2.78% [-6.99 to 1.43]). At age 17 years, offspring of couples with infertility had higher waist circumference (1.05 cm [0.11-1.99]) and systolic blood pressure (age: 17 years; 0.93 mmHg [0.044-1.81]), but these differences attenuated at later ages. No intergroup differences in triglyceride and glucose level trajectories were observed. Further adjustment for paternal age, BMI, smoking, and educational level, and both parents' histories of diabetes and hypertension in the cohort with this information available (Avon Longitudinal Study of Parents and Children) did not attenuate intergroup differences. CONCLUSION: Offspring of couples with infertility relative to those of fertile couples have increasingly higher BMI over the years, suggestively higher blood pressure levels, and tend to have greater values of LDL-C and lower values of HDL-C with age.

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.

Associations between parental and pre-adolescents' physical activity and diet quality: The role of parental child care involvement and child's sex.

BACKGROUND: Research has demonstrated the importance of the family environment in the eating and activity levels of offspring. We examined the cross-sectional associations between moderate-to-vigorous physical activity (MVPA) and diet quality of parents and the MVPA and diet quality of pre-adolescents. Interactions were tested to assess whether the child's sex and the parental level of involvement in daily child care moderated these associations. METHODS: Data from 2467 pre-adolescents (age 11.5 ± 0.2 years; collected in 2015-2016) and their parents or caregivers from a large-scale prospective birth cohort study in Amsterdam (ABCD-study) was used. Parents and pre-adolescents individually reported their diet quality and physical activity. Child care involvement was assessed using the Caregiver Child Interaction Scale. With hierarchical linear regression analyses, we assessed the independent contribution of fathers and mothers. RESULTS: An association between mother-child MVPA was found (ß = 0.013; 95 % CI: 0.006;0.021). The association between father-child MVPA was only significant for highly involved fathers (ß = 0.014; 95 % CI: 0.004;0.023). The child's sex did not change these MVPA associations. Regarding diet quality, associations were found between mother-child diet quality score (DQS) (ß = 0.254; 95 % CI: 0.192;0.316) and father-child DQS, with stronger associations between fathers and sons (ß = 0.234; 95 % CI: 0.169;0.298) than between fathers and daughters (ß = 0.114; 95 % CI: 0.047;0.181). Parental levels of involvement did not change these associations. CONCLUSION: These findings demonstrate that both parental behaviours represent an important factor in physical activity and diet quality in pre-adolescents in a sex-specific manner. As such, it is essential to include both parents in research to obtain the necessary insights for developing effective interventions to promote children's healthy eating and physical activity behaviours.

Differences in birth weight between immigrants' and natives' children in Europe and Australia: a LifeCycle comparative observational cohort study.

OBJECTIVE: Research on adults has identified an immigrant health advantage, known as the 'immigrant health paradox', by which migrants exhibit better health outcomes than natives. Is this health advantage transferred from parents to children in the form of higher birth weight relative to children of natives? SETTING: Western Europe and Australia. PARTICIPANTS: We use data from nine birth cohorts participating in the LifeCycle Project, including five studies with large samples of immigrants' children: Etude Longitudinale Française depuis l'Enfance-France (N=12 494), the Raine Study-Australia (N=2283), Born in Bradford-UK (N=4132), Amsterdam Born Children and their Development study-Netherlands (N=4030) and the Generation R study-Netherlands (N=4877). We include male and female babies born to immigrant and native parents. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is birth weight measured in grams. Different specifications were tested: birth weight as a continuous variable including all births (DV1), the same variable but excluding babies born with over 4500 g (DV2), low birth weight as a 0-1 binary variable (1=birth weight below 2500 g) (DV3). Results using these three measures were similar, only results using DV1 are presented. Parental migration status is measured in four categories: both parents natives, both born abroad, only mother born abroad and only father born abroad. RESULTS: Two patterns in children's birth weight by parental migration status emerged: higher birth weight among children of immigrants in France (+12 g, p<0.10) and Australia (+40 g, p<0.10) and lower birth weight among children of immigrants in the UK (-82 g, p<0.05) and the Netherlands (-80 g and -73 g, p<0.001) compared with natives' children. Smoking during pregnancy emerged as a mechanism explaining some of the birth weight gaps between children of immigrants and natives. CONCLUSION: The immigrant health advantage is not universally transferred to children in the form of higher birth weight in all host countries. Further research should investigate whether this cross-national variation is due to differences in immigrant communities, social and healthcare contexts across host countries.

Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis.

AIMS: To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. METHODS AND RESULTS: Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (-0.53 mmHg; 95% CI:-1.59 to 0.53), DBP (-0.24 mmHg; -0.83 to 0.35), or HR (0.02 beat/min; -0.91 to 0.94). Total cholesterol (2.59%; 0.10-5.07), HDL cholesterol (4.16%; 2.52-5.81), LDL cholesterol (4.95%; 0.47-9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. CONCLUSION: These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.

Parental Discontent with Infant Sleep During the First Two Years of Life.

BACKGROUND: Problematic sleep in infants can have a high impact on families. We examined parental discontent with infant sleep in the first six months of life and parent-perceived problematic sleep during the second year of life. METHODS: We used Sarphati Cohort data of 1471 children. During periodic youth health care visits in the first six months of life, professionals registered parental discontent with infant sleep. In the second year of life, parents filled out the Brief Infant Sleep Questionnaire (BISQ), from which we defined parent-perceived problematic sleep and BISQ-defined problematic sleep. We examined the association of parental discontent with infant sleep during the first six months with both BISQ-derived outcomes up to age two, using multivariable logistic regression analysis. RESULTS: 26% of parents were discontented with infant sleep during the first six months of life. During the second year of life, 27% of the parents perceived their child's sleep as problematic, and 9% of the infants had BISQ-defined problematic sleep. Early parental discontent with infant sleep was associated with parent-perceived problematic sleep [adjusted OR 2.50 (95% CI 1.91-3.28)], and BISQ-defined problematic sleep [adjusted OR 1.88 (1.11-3.17)]. CONCLUSIONS: Early registered parental discontent with infant sleep was a predictor of parent-perceived problematic sleep in early toddlerhood. Registering parental discontent during infancy might enable professionals to identify a group of infants at risk for later problematic sleep. We recommend screening and parental support for sleep difficulties in an early stage.

Early pregnancy triglycerides and not fructosamine are associated with birth weight (with foetal sexual dimorphism).

BACKGROUND: We evaluated whether maternal triglycerides (TGs) or fructosamine (measured in early pregnancy) predominantly contribute to birth weight (BW), in a foetal sexual dimorphism. METHODS: Analysis of data from the Amsterdam Born Children and their Development cohort study (total n = 3514). Maternal nonfasting TGs and fructosamine were determined in early gestation (median 13 weeks). Multivariable linear regression analysis was used to determine whether maternal TGs or fructosamine was associated with BW-small for gestational age (SGA)-large for gestational age (LGA) and whether it was sex-dependent. RESULTS: With each 1 mmol/L increase in TGs, BW increased significantly by 81.7 g. This increase was larger with boys (107.3 g; 95% CI 66-148) than girls (60.5 g; 95% CI 23.6-97.4). No association was found with fructosamine. When including different covariates (gestational age at blood sampling, total duration of pregnancy, maternal height, age, parity, ethnicity, educational level, smoking, alcohol, and pre-pregnancy BMI), 29% of the variance in BW can be explained. Adding fructosamine to this model gave no added value in predicting BW, in contrast to adding TGs (R2 raised from 0.292 to 0.299, p < .001). The odds of a newborn LGA with higher maternal TG were increased (OR 1.6, 95% CI 1.3-2.0), in contrast to fructosamine. CONCLUSIONS: Maternal TGs were more dominant (compared to fructosamine) in its association with BW (measured in early physiological pregnancy) and more prominently present when carrying a male foetus. These remarkable observations warrant more future research, especially in obese patients at risk for gestational diabetes.

Associations Between Maternal Lipid Blood Levels at the 13th Week of Pregnancy and Offspring's Adiposity at Age 11-12 Years.

CONTEXT: There is increasing evidence that intrauterine lipid metabolism influences the adiposity of the newborn and the first years thereafter. It remains unclear if these effects persist when these children grow older. OBJECTIVE: This study examined the associations between maternal lipid blood levels during the 13th week of pregnancy and an offspring's adiposity, measured at age 11-12, and if these associations were moderated by the child's sex. METHODS: Data were obtained from a community-based birth cohort, the Amsterdam Born Children and their Development (ABCD) study. At a median of 13 weeks' gestation, nonfasting blood samples of triglycerides (TGs), total cholesterol (TC), free fatty acids (FFAs), and apolipoprotein B/apolipoprotein A1 ratio (ApoB/ApoA1) were measured. An offspring's body mass index (BMI), subcutaneous fat (SCF), waist-to-height-ratio (WHtR), and fat percentage (fat%) were measured at age 11-12. Mothers with at-term born children were included (n = 1853). Multivariable linear regression analyses were performed to assess the associations between maternal lipids and each offspring's adiposity outcome separately. Sex differences were additionally evaluated. RESULTS: TGs, TC, ApoB/ApoA1, and FFAs were significantly positively associated with BMI, WHtR, and fat% (adjusted for gestational age at blood sampling, child's age, sex, and sexual maturation). After additional adjustments for potential confounders and covariates, only TGs remained significantly associated with WHtR (0.45, 95% CI -0.007; 0.91). There were no associations between maternal lipids and SCF and no clear sex-specific results were found. CONCLUSION: Overall, our results do not strongly support that maternal lipid profile during the 13th week of pregnancy has programming effects on adiposity in preadolescence.

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.

Association of Thyroid Peroxidase Antibodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy: An Individual Participant Data Meta-Analysis.

Objectives: Thyroid autoimmunity is common in pregnant women and associated with thyroid dysfunction and adverse obstetric outcomes. Most studies focus on thyroid peroxidase antibodies (TPOAbs) assessed by a negative-positive dichotomy and rarely take into account thyroglobulin antibodies (TgAbs). This study aimed at determining the association of TPOAbs and TgAbs, respectively, and interdependently, with maternal thyroid function. Methods: This was a meta-analysis of individual participant cross-sectional data from 20 cohorts in the Consortium on Thyroid and Pregnancy. Women with multiple pregnancy, pregnancy by assisted reproductive technology, history of thyroid disease, or use of thyroid interfering medication were excluded. Associations of (log2) TPOAbs and TgAbs (with/without mutual adjustment) with cohort-specific z-scores of (log2) thyrotropin (TSH), free triiodothyronine (fT3), total triiodothyronine (TT3), free thyroxine (fT4), total thyroxine (TT4), or triiodothyronine:thyroxine (T3:T4) ratio were evaluated in a linear mixed model. Results: In total, 51,138 women participated (51,094 had TPOAb-data and 27,874 had TgAb-data). Isolated TPOAb positivity was present in 4.1% [95% confidence interval, CI: 3.0 to 5.2], isolated TgAb positivity in 4.8% [CI: 2.9 to 6.6], and positivity for both antibodies in 4.7% [CI: 3.1 to 6.3]. Compared with antibody-negative women, TSH was higher in women with isolated TPOAb positivity (z-score increment 0.40, CI: 0.16 to 0.64) and TgAb positivity (0.21, CI: 0.10 to 0.32), but highest in those positive for both antibodies (0.54, CI: 0.36 to 0.71). There was a dose-response effect of higher TPOAb and TgAb concentrations with higher TSH (TSH z-score increment for TPOAbs 0.12, CI: 0.09 to 0.15, TgAbs 0.08, CI: 0.02 to 0.15). When adjusting analyses for the other antibody, only the association of TPOAbs remained statistically significant. A higher TPOAb concentration was associated with lower fT4 (p < 0.001) and higher T3:T4 ratio (0.09, CI: 0.03 to 0.14), however, the association with fT4 was not significant when adjusting for TgAbs (p = 0.16). Conclusions: This individual participant data meta-analysis demonstrated an increase in TSH with isolated TPOAb positivity and TgAb positivity, respectively, which was amplified for individuals positive for both antibodies. There was a dose-dependent association of TPOAbs, but not TgAbs, with TSH when adjusting for the other antibody. This supports current practice of using TPOAbs in initial laboratory testing of pregnant women suspected of autoimmune thyroid disease. However, studies on the differences between TPOAb- and TgAb-positive women are needed to fully understand the spectrum of phenotypes.

Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis.

BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT4 concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.

Mediating role of C-reactive protein in associations between pre-pregnancy BMI and adverse maternal and neonatal outcomes: the ABCD-study cohort.

OBJECTIVES: Increased body mass index (BMI) is associated with several adverse pregnancy outcomes, though the underlying mechanism of this association has not been fully elucidated. A mediating role of low-grade systemic inflammation in these associations is suspected but has been understudied. Our objective was to examine the effect of pre-pregnancy BMI (pBMI) on maternal and neonatal pregnancy outcomes and to explore potential mediation of these effects by C-reactive protein (CRP), a first trimester peripheral marker of inflammation. METHODS: Data from the prospective community-based ABCD-study cohort (n = 3547) was used to assess associations between self-reported continuous and categorized pBMI and outcome measures gestational hypertension (GH) and preeclampsia (PE), preterm birth (PTB) and small for gestational age (SGA) based on national perinatal registration linkage data. High-sensitivity CRP concentrations determined in serum were used to explore potential mediation of these associations by inflammation. RESULTS: Multivariable logistic regression analyses, adjusted for confounders, showed that pBMI was significantly related to gestational hypertensive disorders (odds ratio (OR) per standard deviation (SD) 1.66, 95% confidence interval (CI) 1.51-1.83) and PTB (OR 1.20, 95% CI 1.05-1.37). Dose-response relationships between categorical pBMI and gestational hypertensive disorders (overweight OR 2.37, 95% CI 1.85-3.03 and obese OR 4.45, 95% CI 2.93-6.72) and PTB (obese OR 2.12, 95% CI 1.16-3.87) were found as well. SGA was only significantly more prevalent in the underweight BMI category (OR 2.06, 95% CI 1.33-3.19). Mediation analyses revealed small but significant indirect effects of pBMI on overall PTB (0.037, bootstrapped 95% CI 0.005-0.065) and spontaneous PTB (0.038, bootstrapped 95% CI 0.002-0.069) through higher CRP. CRP was not a significant mediator of associations between BMI and gestational hypertensive disorders although larger mediation was found for GH than for PE. CONCLUSION: Our findings provide additional evidence that high(er) pBMI increases the risk of adverse maternal and neonatal outcomes and that systemic inflammation mediates some of these risks. Further research in large cohorts including (morbidly) obese women is warranted to identify pathways that may be incorporated in future interventions to reduce the risk of adverse pregnancy outcomes due to maternal obesity.

[Digital media use and sleep of adolescents: the effect of rules at home]. / Digitale-mediagebruik en slaap bij jongeren.

OBJECTIVE: To test whether parental rules regarding the amount of digital media use is associated with the sleep of Dutch adolescents, and whether this is indirectly due to lower digital media use. DESIGN: Cross-sectional study METHOD: Adolescents and their parents of the Amsterdam Born Children and their Development (ABCD) study completed questionnaires in 2019 at the age of 15-16 years (n=1369; 56% girls). Parents and adolescents reported whether there are rules regarding the amount of digital media use. The adolescents also reported their daily amount of digital media use, sleep duration, bedtime and sleep quality according to the Pittsburgh Sleep Quality Index (PSQI). We tested the association between rules and sleep duration, bedtime and sleep quality in adolescents using multivariate regression analysis. Using mediation analysis we tested whether rules were also indirectly associated with sleep outcome measures through the amount of digital media use. RESULTS: Setting rules regarding digital media use was related to sleep duration; 6.8 minutes (95%CI:0.1;13.5) longer with inconsistently experienced rules and 18.5 minutes (95%CI:9.2;27.8) longer with consistently existing rules. Setting rules was also related to bedtime; 10 minutes (95%CI: -17;-4) earlier with inconsistently experienced rules and 29 minutes (95%CI:-38;-2) earlier with consistently existing rules. Setting rules was not directly associated with sleep quality. Indirectly, rules were associated with longer sleep duration, earlier bedtime and better sleep quality due to lower digital media use per day. CONCLUSION: Parental rules regarding the amount of digital media use is associated with better sleep of adolescents. This is partly explained by lower digital media use.

Associations Between Maternal Depression, Antidepressant Use During Pregnancy, and Adverse Pregnancy Outcomes: An Individual Participant Data Meta-analysis.

OBJECTIVE: To evaluate the associations of depressive symptoms and antidepressant use during pregnancy with the risks of preterm birth, low birth weight, small for gestational age (SGA), and low Apgar scores. DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov, and PsycINFO up to June 2016. METHODS OF STUDY SELECTION: Data were sought from studies examining associations of depression, depressive symptoms, or use of antidepressants during pregnancy with gestational age, birth weight, SGA, or Apgar scores. Authors shared the raw data of their studies for incorporation into this individual participant data meta-analysis. TABULATION, INTEGRATION, AND RESULTS: We performed one-stage random-effects meta-analyses to estimate odds ratios (ORs) with 95% CIs. The 215 eligible articles resulted in 402,375 women derived from 27 study databases. Increased risks were observed for preterm birth among women with a clinical diagnosis of depression during pregnancy irrespective of antidepressant use (OR 1.6, 95% CI 1.2-2.1) and among women with depression who did not use antidepressants (OR 2.2, 95% CI 1.7-3.0), as well as for low Apgar scores in the former (OR 1.5, 95% CI 1.3-1.7), but not the latter group. Selective serotonin reuptake inhibitor (SSRI) use was associated with preterm birth among women who used antidepressants with or without restriction to women with depressive symptoms or a diagnosis of depression (OR 1.6, 95% CI 1.0-2.5 and OR 1.9, 95% CI 1.2-2.8, respectively), as well as with low Apgar scores among women in the latter group (OR 1.7, 95% CI 1.1-2.8). CONCLUSION: Depressive symptoms or a clinical diagnosis of depression during pregnancy are associated with preterm birth and low Apgar scores, even without exposure to antidepressants. However, SSRIs may be independently associated with preterm birth and low Apgar scores. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42016035711.

Associations between autonomic nervous system activity and risk-taking and internalizing behavior in young adolescents.

Dysregulated autonomic nervous system (ANS) activity has been associated with adolescent risk-taking and internalizing behavior, but previous results in community samples have been mixed. We investigated whether ANS activity was associated with higher risk-taking and internalizing behavior in young adolescents (age 11/12; n = 875), and whether adolescents' gender, parents' parenting style or a combination of both moderated these associations. Adolescents and their parents were recruited as part of the population-based, longitudinal Amsterdam Born Children and their Development (ABCD) study. Risk-taking behavior was assessed with the Balloon Analogue Risk Task and the personality characteristics sensation seeking and impulsivity, measured with the Substance Use Risk Profile Scale (SURPS). Internalizing behavior was assessed via the SURPS subscales anxiety sensitivity and hopelessness. Authoritative (AUTH-SW) and authoritarian (AUTH-S) parenting styles were measured with the Parenting Styles and Dimensions Questionnaire. Resting ANS activity was assessed via heart rate and respiratory sinus arrhythmia (RSA). Hierarchical, multivariable regression analyses showed higher RSA, but not heart rate, being associated with higher risk-taking behavior and sensation seeking. The associations between ANS activity and risk-taking variables were not significantly moderated by gender, parenting, or interactions between gender and parenting. Our findings suggest that RSA activity may be a relevant factor in mild to moderate risk-taking behavior in adolescents from the general population, regardless of their gender or the type of parenting they experience.

Dysregulated functional brain connectivity in response to acute social-evaluative stress in adolescents with PTSD symptoms.

Background: Posttraumatic stress disorder (PTSD) is associated with dysregulated neural, cortisol, and cardiac stress reactivity and recovery. This understanding is predominantly based on studies in adults applying emotional-cognitive and trauma-related stimuli inducing negative emotions or perceived threat. Despite large numbers of adolescents with PTSD, few studies are available on neurobiological stress reactivity in this population. Moreover, no previous studies investigated neural reactivity to social-evaluative stress. Objective: To investigate functional brain connectivity, cortisol and cardiac reactivity to acute social-evaluative stress, and additional cortisol measures in trauma-exposed adolescents with and without high PTSD symptoms. Method: A speech preparation task to induce acute social-evaluative stress elicited by anticipatory threat, was used in a subsample of the Amsterdam Born Child and their Development (ABCD) birth cohort, consisting of trauma-exposed adolescents with (n = 20) and without (n = 29) high PTSD symptoms. Psychophysiological interaction analyses were performed to assess group differences in functional connectivity of the hippocampus, mPFC and amygdala during social-evaluative stress and recovery, measured by fMRI. Additionally, perceived stress, heart rate and cortisol stress reactivity and recovery, cortisol awakening response and day curve were compared. Results: The stressor evoked significant changes in heart rate and perceived stress, but not cortisol. The PTSD symptom and control groups differed in functional connectivity between the hippocampus and cerebellum, middle and inferior frontal gyrus, and the mPFC and inferior frontal gyrus during social-evaluative stress versus baseline. Mostly, the same patterns were found during recovery versus baseline. We observed no significant group differences in amygdala connectivity, and cortisol and cardiac measures. Conclusions: Our findings suggest threat processing in response to social-evaluative stress is disrupted in adolescents with PTSD symptoms. Our findings are mainly but not entirely in line with findings in adults with PTSD, which denotes the importance to investigate adolescents with PTSD as a separate population.

Antecedentes: El trastorno de estrés postraumático (TEPT) está asociado con la recuperación. Esta comprensión se basa predominantemente en estudios con adultos, que aplican estímulos emocional-cognitivos y relacionados con el trauma que inducen emociones negativas, o percepción de amenaza. A pesar del gran número de adolescentes con TEPT, hay pocos estudios disponibles sobre la reactividad neurobiológica al estrés en esta población. Además, ningún estudio previo ha investigado la reactividad neuronal al estrés socio-evaluativo.Objetivos: Investigar la conectividad cerebral funcional, el cortisol y la reactividad cardíaca al estrés socio-evaluativo, y medidas adicionales de cortisol en adolescentes expuestos a trauma con y sin síntomas elevados de TEPT.Método: Se utilizó una tarea de preparación de discurso para inducir un estrés socio-evaluativo agudo, provocado por la amenaza anticipatoria, en una submuestra del cohorte de nacimiento del Niño nacido en Amsterdam y su Desarrollo (Amsterdam Born Child and their Development, ABCD), que consta de adolescentes expuestos a traumas con (n = 20) y sin (n = 29) síntomas elevados de TEPT. Se realizaron análisis de interacción psicofisiológica para evaluar las diferencias de grupo en la conectividad funcional del hipocampo, mPFC y amígdala durante el estrés socio-evaluativo y la recuperación, medido por fMRI. Además, se compararon el estrés percibido, la frecuencia cardíaca y la reactividad y recuperación del estrés por cortisol, la respuesta del cortisol al despertar, y la curva diurna.Resultados: El estresor provocó cambios significativos en la frecuencia cardíaca y el estrés percibido, pero no del cortisol. Los grupos con síntomas de TEPT y control difirieron en la conectividad funcional entre el hipocampo y el cerebelo, la circunvolución frontal media e inferior, y la mPFC y la circunvolución frontal inferior durante el estrés socio-evaluativo frente al valor inicial. En su mayoría, se encontraron los mismos patrones durante la recuperación frente a la línea de base. No observamos diferencias significativas entre grupos respecto de la conectividad de la amígdala, ni en las medidas de cortisol y cardíacas.Conclusiones: Nuestros hallazgos sugieren que el procesamiento de amenazas en respuesta al estrés socio-evaluativo se encuentra alterado en adolescentes con síntomas de TEPT. Nuestros hallazgos están principalmente, pero no completamente, en línea con los hallazgos en adultos con TEPT, lo que denota la importancia de investigar a adolescentes con TEPT como una población aparte.

Psychosocial and peripartum determinants of postpartum depression: Findings from a prospective population-based cohort. The ABCD study.

BACKGROUND: Postpartum depression is prevalent and concerns a serious health problem for women and their families. The current large-scale birth cohort study investigated: (1) the associations of various potential determinants of postpartum depression using a multidimensional approach, and (2) the individual contribution of obstetric and perinatal determinants and pregnancy-specific anxiety to the risk of postpartum depression. METHODS: This study was based on a large-scale birth cohort study in Amsterdam, the Netherlands (ABCD-study). In 5109 women depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (cut-off ≥16 indicating high risk of postpartum depression). Determinants were assessed using self-report or perinatal registries. RESULTS: In the final multivariable model, other-Western and non-Western ethnic background, increased antepartum depressive symptoms, increased antepartum anxiety, increased pregnancy-specific anxiety, being unemployed, poor sleep quality, unwanted pregnancy, abuse, multiparity, and congenital abnormality were all independently related to an increased risk of postpartum depression. The strongest risk factors for postpartum depression were antepartum depressive symptoms (adjusted odds ratio (AOR) = 3.86, 95% confidence interval (CI) 3.02-4.92), having a baby with a congenital abnormality (AOR = 2.33, 95% CI 1.46-3.73), and abuse (AOR = 1.95, 95% CI 1.02-3.73). The final model accounted for 24.5% of the variance. LIMITATIONS: Our dataset did not provide information on social support or maternal and family history of depression. Next to these determinants, future research should include biological factors. CONCLUSIONS: The determinants identified provide opportunities for the development of multidimensional early screening and early intervention strategies for women with an increased risk of postpartum depression.

Ideal cardiovascular health at age 5-6 years and cardiometabolic outcomes in preadolescence.

BACKGROUND: The American Heart Association (AHA) developed a definition of ideal cardiovascular health (ICH) based on the presence of both ideal health behaviours (diet, physical activity, weight status and smoking) and ideal health factors (glucose, total cholesterol and blood pressure levels). However, research of ICH in the paediatric population is scarce. We aimed to study ICH at age 5-6 years by extending the original ICH score with the health behaviours: sleep duration, screen time and prenatal smoke exposure, and to evaluate its association with cardiometabolic outcomes at age 11-12. METHODS: A total of 1666 children aged 5-6 years were selected from the database of the ABCD-study, a prospective cohort study on the health and development of children born in Amsterdam, the Netherlands. Of these, 846 (50.8%) were boys and 1460 (87.6%) had a healthy weight. Data on self-reported health behaviours and health factors were used to calculate the ICH scores (original and extended) by adding the frequency of scoring 'healthy' on each indicator, based on international cut-offs. The children were followed up for 6 years and cardiometabolic outcomes (carotid intima-media thickness (CIMT), blood pressure, glucose and lipids) were measured. Associations between ICH (both original and extended) and cardiometabolic outcomes were examined using multivariable regression models. RESULTS: At age 5-6 years, 11% scored poor (score 1-5), 56% intermediate (score 6-7) and 33% good (score 8-9) on extended ICH. Healthy diet and normal total cholesterol concentrations were the least prevalent. Neither the original nor the extended ICH scores were associated with CIMT at age 11-12. A higher score on the extended ICH was associated with lower total cholesterol (p for trend < 0.001), lower systolic (p for trend = 0.012) and diastolic blood pressure (p for trend = 0.011), and lower body mass index (BMI) (p < 0.001) at age 11-12. The original ICH score was associated with lower total cholesterol (p < 0.001) and BMI (p < 0.001) only. CONCLUSION: Our findings suggest that extending the ICH score in young children with additional health behaviours improves prediction of some cardiometabolic outcomes, but not CIMT in preadolescence, compared to the original ICH score. We would recommend other researchers to incorporate objective measures of health behaviours and longer follow-up to find out whether associations persist into adulthood.