High-Sensitivity Cardiac Troponin I Enhances Preeclampsia Prediction Beyond Maternal Factors and the sFlt-1/PlGF Ratio.

BACKGROUND: Preeclampsia shares numerous risk factors with cardiovascular diseases. Here, we aimed to assess the potential utility of high-sensitivity cardiac troponin I (hs-cTnI) values during pregnancy in predicting preeclampsia occurrence. METHODS: This study measured hs-cTnI levels in 3721 blood samples of 2245 pregnant women from 4 international, prospective cohorts. Three analytical approaches were used: (1) a cross-sectional analysis of all women using a single blood sample, (2) a longitudinal analysis of hs-cTnI trajectories in women with multiple samples, and (3) analyses of prediction models incorporating hs-cTnI, maternal factors, and the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio. RESULTS: Women with hs-cTnI levels in the upper quarter had higher odds ratios for preeclampsia occurrence compared with women with levels in the lower quarter. Associations were driven by preterm preeclampsia (odds ratio, 5.78 [95% CI, 2.73-12.26]) and remained significant when using hs-cTnI as a continuous variable adjusted for confounders. Between-trimester hs-cTnI trajectories were independent of subsequent preeclampsia occurrence. A prediction model incorporating a practical hs-cTnI level of detection cutoff (≥1.9 pg/mL) alongside maternal factors provided comparable performance with the sFlt-1/PlGF ratio. A comprehensive model including sFlt-1/PlGF, maternal factors, and hs-cTnI provided added value (cross-validated area under the receiver operator characteristic, 0.78 [95% CI, 0.73-0.82]) above the sFlt-1/PlGF ratio alone (cross-validated area under the receiver operator characteristic, 0.70 [95% CI, 0.65-0.76]; P=0.027). As assessed by likelihood ratio tests, the addition of hs-cTnI to each prediction model significantly improved the respective prediction model not incorporating hs-cTnI, particularly for preterm preeclampsia. Net reclassification improvement analyses indicated that incorporating hs-cTnI improved risk prediction predominantly by correctly reclassifying women with subsequent preeclampsia occurrence. CONCLUSIONS: These exploratory findings uncover a potential role for hs-cTnI as a complementary biomarker in the prediction of preeclampsia. After validation in prospective studies, hs-cTnI, alongside maternal factors, may either be considered as a substitute for angiogenic biomarkers in health care systems where they are sparce or unavailable, or as an enhancement to established prediction models using angiogenic markers.

Transgender healthcare: metabolic outcomes and cardiovascular risk.

Transgender identity is often associated with gender dysphoria and minority stress. Gender-affirming hormone treatment (GAHT) includes masculinising or feminising treatment and is expected to be lifelong in most cases. Sex and sex hormones have a differential effect on metabolism and CVD in cisgender people, and sex hormone replacement in hypogonadism is associated with higher vascular risk, especially in ageing individuals. Using narrative review methods, we present evidence regarding metabolic and cardiovascular outcomes during GAHT and propose recommendations for follow-up and monitoring of metabolic and cardiovascular risk markers during GAHT. Available data show no increased risk for type 2 diabetes in transgender cohorts, but masculinising GAHT increases lean body mass and feminising GAHT is associated with higher fat mass and insulin resistance. The risk of CVD is increased in transgender cohorts, especially during feminising GAHT. Masculinising GAHT is associated with a more adverse lipid profile, higher haematocrit and increased BP, while feminising GAHT is associated with pro-coagulant changes and lower HDL-cholesterol. Assigned male sex at birth, higher age at initiation of GAHT and use of cyproterone acetate are separate risk factors for adverse CVD markers. Metabolic and CVD outcomes may improve during gender-affirming care due to a reduction in minority stress, improved lifestyle and closer surveillance leading to optimised preventive medication (e.g. statins). GAHT should be individualised according to individual risk factors (i.e. drug, dose and form of administration); furthermore, doctors need to discuss lifestyle and preventive medications in order to modify metabolic and CVD risk during GAHT. Follow-up programmes must address the usual cardiovascular risk markers but should consider that biological age and sex may influence individual risk profiling including mental health, lifestyle and novel cardiovascular risk markers during GAHT.

Sex difference in patients with controlled acromegaly-A multicentre survey.

OBJECTIVE: Active acromegaly is subject to sex differences in growth hormone (GH) and Insulin like growth factor 1 (IGF-I) patterns as well as clinical features but whether this also pertains to controlled disease is unclear. DESIGN: In a cross-sectional, multi-centre study, 84 patients with acromegaly (F = 43, M = 41), who were considered controlled after surgery alone (n = 23) or during continued somatostatin receptor ligand (SRL) treatment (n = 61), were examined. METHODS: Serum concentrations of GH, insulin, glucose and free fatty acid (FFA) were measured during an oral glucose tolerance test (OGTT) together with baseline serum IGF-I and completion of two HR-Qol questionnaires (acromegaly quality of life questionnaire [AcroQol] and Patient-assessed Acromegaly Symptom Questionnaire [PASQ]). RESULTS: The mean age at the time of the study was 57 (±1.1) years and the majority of females (were postmenopausal. Females had significantly higher fasting GH but comparable IGF-I standard deviation scores (SDS). Using fasting GH < 1.0 µg/L as cut off, disease control was less prevalent in females (F: 56% vs. M: 83%, p = .007) whereas a comparable figure was observed using IGF-I SDS < 2 (F:79% vs. M:76%, p = .71). Compared with males, female patients showed impaired AcroQol physical score (p = .05), higher fasting FFA (p = .03) and insulin concentrations during the OGTT (p = .04). CONCLUSION: In patients with acromegaly considered controlled, postmenopausal females exhibited higher GH levels than males despite comparable IGF-I levels, which also translated into impaired metabolic health and well-being. Our findings point to the relevance of including GH measurements in the assessment of disease control and suggest that disease-specific sex differences prevail after treatment.

Higher free thyroxine associated with PFAS exposure in first trimester. The Odense Child Cohort.

BACKGROUND: Perfluoroalkyl substances (PFAS) are endocrine disrupting chemicals with elimination half-lives ranging from four to eight years. Experimental studies found PFAS able to interfere with thyroid hormone-binding proteins. During the first 20 weeks of gestation (GW), the fetus is reliant on placental transfer of maternal thyroid hormones, mainly free thyroxine (FT4). However, previous studies investigating associations between exposure to PFAS and thyroid hormone status mainly focused on blood samples from late pregnancy or umbilical cord with mixed findings. OBJECTIVES: To investigate associations between serum-PFAS concentrations and thyroid hormone status in early pregnancy as reflected by FT4 and thyroid-stimulating hormone (TSH). METHODS: In the Odense Child Cohort, a single-center study, we measured maternal pregnancy serum concentrations of five PFAS: perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA); and FT4 and TSH in 1048 pregnant women at median GW 12 (25th, 75th percentile: 10, 15). Multivariate linear regression models were performed to estimate associations between PFAS exposure and thyroid hormone status. RESULTS: A doubling in PFOS, PFOA, and PFNA concentrations was associated with an increment in FT4 concentration by 1.85% (95% CI: 0.66%, 3.05%), 1.29% (95% CI: 0.21%, 2.39%), and 1.70% (95% CI: 0.48%, 2.94%), respectively, in adjusted analyses. A statistically significant dose-response relationship was observed across exposure quartiles for PFOS, PFOA, and PFNA in the association with FT4. No association was found between concentrations of PFAS and TSH in adjusted analyses. CONCLUSION: Exposure to PFOS, PFOA, and PFNA was associated with higher FT4 concentrations in women during early pregnancy. The potential clinical implications of these findings remain to be clarified.

Maternal polycystic ovary syndrome and attention deficit hyperactivity disorder in offspring at 3 years of age: Odense Child Cohort.

INTRODUCTION: Previous data suggested a link between maternal polycystic ovary syndrome (PCOS) and offspring attention deficit hyperactivity disorder (ADHD), which could be mediated by higher prenatal androgen exposure. MATERIAL AND METHODS: The study was part of the prospective Odense Child Cohort and included 1776 pregnant women, 165 (9%) with PCOS and 1607 (91%) controls. ADHD symptoms at 3 years of age were defined using the parent-reported questionnaire Child Behavior Checklist/1.5-5 (scores >90th centile of Danish national standard). Maternal blood samples were collected in the third trimester measuring total testosterone by mass spectrometry, sex hormone-binding globulin, and calculated free testosterone. Offspring anogenital distance was measured at 3 months of age. Regression models were performed with presence of ADHD symptoms as the dependent variable and adjusted for maternal age, body mass index, parity, smoking status, educational level, and parental psychiatric diagnoses. RESULTS: ADHD symptoms were present in 105/937 (11%) boys and 72/839 (9%) girls. In boys, maternal PCOS was positively associated with ADHD symptoms (unadjusted odds ratio [OR] 1.91, 95% CI 1.07-3.43, p = 0.03, adjusted OR 2.20, 95% CI 1.20-4.02, p = 0.01), whereas maternal PCOS was not associated with ADHD symptoms in girls. Maternal total testosterone, free testosterone, and offspring anogenital distance were not associated with higher risk of ADHD symptoms in the offspring. CONCLUSIONS: Higher risk of ADHD in boys born of mothers with PCOS were not associated with maternal third-trimester testosterone levels or offspring anogenital distance.

Prenatal exposure to perfluorodecanoic acid is associated with lower circulating concentration of adrenal steroid metabolites during mini puberty in human female infants. The Odense Child Cohort.

BACKGROUND: Fetal programming of the endocrine system may be affected by exposure to perfluoroalkyl substances (PFAAs), as they easily cross the placental barrier. In vitro studies suggest that PFAAs may disrupt steroidogenesis. "Mini puberty" refers to a transient surge in circulating androgens, androgen precursors, and gonadotropins in infant girls and boys within the first postnatal months. We hypothesize that prenatal PFAA exposure may decrease the concentrations of androgens in mini puberty. OBJECTIVES: To investigate associations between maternal serum PFAA concentrations in early pregnancy and serum concentrations of androgens, their precursors, and gonadotropins during mini puberty in infancy. METHODS: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAAs: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured at median gestational week 12 (IQR: 10, 15) in 1628 women. Among these, offspring serum concentrations of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), androstenedione, 17-hydroxyprogesterone (17-OHP), testosterone, luteinizing (LH) and follicle stimulating hormones (FSH) were measured in 373 children (44% girls; 56% boys) at a mean age of 3.9 (±0.9 SD) months. Multivariate linear regression models were performed to estimate associations. RESULTS: A two-fold increase in maternal PFDA concentration was associated with a reduction in DHEA concentration by -19.6% (95% CI: -32.9%, -3.8%) in girls. In girls, also, the androstenedione and DHEAS concentrations were decreased, albeit non-significantly (p < 0.11), with a two-fold increase in maternal PFDA concentration. In boys, no significant association was found between PFAAs and concentrations of androgens, their precursors, and gonadotropins during mini puberty. CONCLUSION: Prenatal PFDA exposure was associated with significantly lower serum DHEA concentrations and possibly also with lower androstenedione and DHEAS concentrations in female infants at mini puberty. The clinical significance of these findings remains to be elucidated.

Vitamin D levels were significantly higher during and after lifestyle intervention in pregnancy: A randomized controlled trial.

INTRODUCTION: Vitamin D deficiency is common in pregnancy, especially in obese women. Lifestyle intervention could potentially result in higher levels of vitamin D. We therefore aimed to study the effect of lifestyle intervention during pregnancy on serum levels of 25-hydroxyvitamin D (25(OH)D). MATERIAL AND METHODS: A total of 360 obese women were randomized before gestational age 14 weeks to lifestyle intervention (diet and exercise) or routine clinical follow up (controls). Clinical outcomes and levels of 25(OH)D were determined three times: At gestational age 12-15 weeks (baseline), gestational age 28-30 weeks and 6 months postpartum. RESULTS: A total of 304 (84%) women completed the intervention study and 238 (66%) attended postpartum follow up. Vitamin D levels were similar in the two groups at baseline. At gestational age 28-30 weeks and 6 months postpartum, 25(OH)D levels were significantly higher in the intervention group than in controls (75.6 vs 66.8 nmol/L, P = 0.009) and (54.8 vs 43.1 nmol/L, P = 0.013), respectively. Concurrently, vitamin D deficiency (25-hydroxyvitamin D <50 nmol/L) was less frequent in the intervention group than in controls: 15 vs 25% (P = 0.038) at gestational age 28-30 and 45 vs 63% (P = 0.011) 6 months postpartum, respectively. CONCLUSIONS: Lifestyle intervention during pregnancy was associated with significantly increased vitamin D levels in late pregnancy and postpartum compared with controls.

Effectiveness of One-Way Text Messaging on Attendance to Follow-Up Cervical Cancer Screening Among Human Papillomavirus-Positive Tanzanian Women (Connected2Care): Parallel-Group Randomized Controlled Trial.

BACKGROUND: Rapid human papillomavirus (HPV) DNA testing is an emerging cervical cancer screening strategy in resource-limited countries, yet it requires follow-up of women who test HPV positive. OBJECTIVE: This study aimed to determine if one-way text messages improved attendance to a 14-month follow-up cervical cancer screening among HPV-positive women. METHODS: This multicenter, parallel-group randomized controlled trial was conducted at 3 hospitals in Tanzania. Eligible participants were aged between 25 and 60 years, had tested positive to a rapid HPV test during a patient-initiated screening, had been informed of their HPV result, and had a private mobile phone with a valid number. Participants were randomly assigned in a 1:1 ratio to the intervention or control group through an incorporated algorithm in the text message system. The intervention group received one-way text messages, and the control group received no text messages. The primary outcome was attendance at a 14-month health provider-initiated follow-up screening. Participants were not blinded, but outcome assessors were. The analysis was based on intention to treat. RESULTS: Between August 2015 and July 2017, 4080 women were screened for cervical cancer, of which 705 were included in this trial-358 women were allocated to the intervention group, and 347 women were allocated to the control group. Moreover, 16 women were excluded before the analysis because they developed cervical cancer or died (8 from each group). In the intervention group, 24.0% (84/350) women attended their follow-up screening, and in the control group, 23.8% (80/335) women attended their follow-up screening (risk ratio 1.02, 95% CI 0.79-1.33). CONCLUSIONS: Attendance to a health provider-initiated follow-up cervical cancer screening among HPV-positive women was strikingly low, and one-way text messages did not improve the attendance rate. Implementation of rapid HPV testing as a primary screening method at the clinic level entails the challenge of ensuring a proper follow-up of women. TRIAL REGISTRATION: ClinicalTrials.gov NCT02509702; https://clinicaltrials.gov/ct2/show/NCT02509702. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/10.2196/15863.

Socioeconomic status in Danish women with polycystic ovary syndrome: A register-based cohort study.

INTRODUCTION: Low socioeconomic status (SES) may be associated with increased risk of polycystic ovary syndrome (PCOS) and vice versa. Possible associations between SES, obesity and ethnicity in PCOS are undetermined. MATERIAL AND METHODS: National register-based study including women with PCOS aged 25 years or above (PCOS Denmark and an embedded cohort; PCOS Odense University Hospital [OUH]) and one control population. PCOS Denmark (n = 13 891) included women with PCOS in the Danish National Patient Register. Women in PCOS OUH underwent clinical examination (n = 814). Three age-matched controls were included per patient (n = 41 584). The main outcome measure was SES (personal income, occupational status and education). RESULTS: The median (Q1; Q3) age of women in PCOS Denmark and controls was 33 (29; 39) years. Women with personal income in the lower tertile had a higher probability of a PCOS diagnosis than women in the high-income tertile (adjusted odds ratio [aOR] 1.5, 95% confidence interval [CI] 1.4-1.6). Women who were unemployed or on welfare payment (aOR 1.5, 95% CI 1.4-1.6), or who retired early (OR 1.8, 95% CI 1.7-2.0) had a higher probability of a PCOS diagnosis than women affiliated to the labor market. Women originating from the Middle East more often had PCOS (aOR 3.2, 95% CI 2.8-3.7) compared with women originating from Europe. In PCOS OUH, SES was lower in obese than in normal weight women. CONCLUSIONS: A diagnosis of PCOS was associated with lower SES. In PCOS, women of foreign origin and women with obesity more often had low SES.

Hair cortisol in the perinatal period mediates associations between maternal adversity and disrupted maternal interaction in early infancy.

Existing literature points to the possibility that cortisol could be one link between maternal adversity and poorer parenting quality, but most studies have examined salivary cortisol concentrations rather than hair cortisol concentrations. The current study examined hair cortisol concentration (HCC) during the third trimester of pregnancy as a mediator between maternal adversity indicators (childhood abuse, severe mental illness, symptomatic functioning) and maternal caregiving behavior at 4 months postpartum. Forty-four women participated in the study: 30 with severe mental disorders, and 14 nonclinical controls. HCC was assessed during the third trimester of pregnancy (HCC-P) and at 4 months postpartum (HCC-4M). Sexual, physical, and emotional abuse were assessed by the Adverse Childhood Experiences Study Questionnaire. Maternal disrupted interaction was reliably coded from mother-infant video interactions during a Still-Face Procedure. Mediation models indicated that maternal HCC-P and HCC-4M mediated associations between maternal psychopathology (severe mental illness, symptomatic functioning) and maternal disrupted interaction at 4 months. Maternal HCC at 4 months also mediated associations between experienced childhood abuse and overall disrupted interaction. Our findings indicate that HCC may be a potential early biomarker for future caregiving challenges among mothers with severe mental illness and histories of childhood abuse.

Anogenital distance as a phenotypic signature through infancy.

BackgroundAnogenital distance (AGD) has been suggested to represent a phenotypic signature reflecting in utero androgen action. However, it is not known whether an individual's AGD at birth correlates to the AGD later in life. We investigate correlations of AGD between 3 and 18 months of age and assess reproducibility of measurements.MethodsWe measured AGD from anus to scrotum (AGDas) and to penis (AGDap) in 407 boys, and to posterior fourchette (AGDaf) and clitoris (AGDac) in 282 girls. Each measure was repeated three times at 3 and 18 months of age, and some children were, furthermore, examined by two different examiners. We assessed age-related changes and reproducibility of measurements.ResultsAGD increased between the two examinations and correlated within the child. A large proportion of the observed variation in AGD was due to true differences between the children (AGDas: 62%, AGDap: 40%, AGDaf: 30%, AGDac: 21%), and measurement error due to between- and within-examiner variation was low.ConclusionsOur study showed that measures of AGD within a child correlated during infancy, especially in boys and particularly for AGD measured as the distance between anus and scrotum. A planned cohort follow-up through childhood and puberty will reveal whether AGD represents a phenotypic signature throughout life.

Thyroid autoimmunity in euthyroid pregnant women is associated with slower productive language acquisition: the Odense child cohort study.

Objective: Maternal thyroid autoimmunity and thyroid function in early pregnancy may impact fetal neurodevelopment. We aimed to investigate how thyroid autoimmunity and thyroid function in early pregnancy were associated with language acquisition in offspring at 12-36 months of age. Methods: This study was embedded in the prospective Odense child cohort. Mother-child dyads were excluded in case of maternal intake of thyroid medication during pregnancy. The parents completed MacArthur-Bates Communicative Development Inventories (MB-CDI) every third month to assess their offspring's productive vocabulary. All completed reports for each child were included in the analyses. Logistic growth curve models evaluated associations between MB-CDI scores and levels of maternal thyroid peroxidase antibodies (TPOAb), free thyroxine (FT4), and thyrotropin, respectively, measured in early pregnancy (median gestational week 12). All models were stratified by offspring sex and adjusted for maternal age, education, pre-pregnancy body mass index, parity, breastfeeding, and offspring age. Results: The study included 735 mother-child dyads. Children born to mothers with TPOAb ≥11 kIU/L, opposed to TPOAb <11 kIU/L, had a lower probability of producing words at age 18-36 months for girls (OR = 0.78, P < 0.001) and 33-36 months for boys (OR = 0.83, P < 0.001). The probability of producing words was higher in girls at 30-36 months of age with low-normal maternal FT4 vs high-normal FT4 (OR = 0.60, P < 0.001), and a similar trend was seen in boys. Results were ambiguous for thyrotropin. Conclusion: In women without known thyroid disease, TPOAb positivity in early pregnancy was negatively associated with productive vocabulary acquisition in girls and boys. This association was not mediated by a decreased thyroid function, as low-normal maternal FT4, unexpectedly, indicated better vocabulary acquisition. Our results support that maternal thyroid autoimmunity per se may affect fetal neurodevelopment.

GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

CONTEXT: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. OBJECTIVE: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. DESIGN, PATIENTS, SETTING, INTERVENTIONS: 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. MAIN OUTCOME MEASURE: The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. RESULTS: In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. CONCLUSIONS: Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Effects of exercise and group counselling on body composition and VO2max in overweight women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is often associated with an increased waist circumference and with lower cardio-respiratory fitness as a consequence of obesity, which may be improved by physical activity. OBJECTIVE: To investigate the effect of high-intensity aerobic training combined with group counselling sessions on anthropometry and cardio-respiratory fitness in women with PCOS. DESIGN: Seventeen sedentary, overweight women with PCOS were randomized in a cross-over design to 16 weeks of intervention: eight weeks high-intensity aerobic exercise was followed by eight weeks of group counselling (n = 8) or vice versa (n = 9). Fourteen of the women completed the tests. MAIN OUTCOME MEASURES: Waist circumference, body mass index and maximal aerobic capacity (VO(2max) ) were measured at baseline, cross-over and post-intervention. RESULTS: There was a decrease in waist circumference (119.9 vs. 106.5 cm) and body mass index (34.9 vs. 34.4 kg/m(2) ) and an increase in VO(2max) (2554.9 vs. 2807.9 mL/min) during the intervention period (t = 16 weeks, n = 14), all p < 0.05. Weight loss tended to be highest in the group which started with group counselling (2.9 vs. 0.6 kg, t = 16 weeks, n = 14, p = 0.055). CONCLUSION: Exercise in groups followed by counselling or vice versa had beneficial effects on waist circumference, weight, and VO(2max) in women with PCOS. Future studies should examine possible beneficial effects of combined group counselling and exercise on weight loss and adherence to exercise protocols among women with PCOS.

Higher Maternal Cortisol Associated With Lower Blood Pressure in Offspring From 3 Months to 5 Years of Age in the Odense Child Cohort.

BACKGROUND: Synthetic glucocorticoid exposure in late pregnancy may be associated with higher blood pressure in offspring. We hypothesized that endogenous cortisol in pregnancy relates to offspring blood pressure (OBP). OBJECTIVE: To investigate associations between maternal cortisol status in third trimester pregnancy and OBP. METHODS: We included 1317 mother-child pairs from Odense Child Cohort, an observational prospective cohort. Serum (s-) cortisol and 24-hour urine (u-) cortisol and cortisone were assessed in gestational week 28. Offspring systolic blood pressure and diastolic blood pressure were measured at age 3, 18 months, and 3 and 5 years. Associations between maternal cortisol and OBP were examined by mixed effects linear models. RESULTS: All significant associations between maternal cortisol and OBP were negative. In boys in pooled analyses, 1 nmol/L increase in maternal s-cortisol was associated with average decrease in systolic blood pressure (ß=-0.003 mmHg [95% CI, -0.005 to -0.0003]) and diastolic blood pressure (ß=-0.002 mmHg [95% CI, -0.004 to -0.0004]) after adjusting for confounders. At 3 months of age, higher maternal s-cortisol was significantly associated with lower systolic blood pressure (ß=-0.01 mmHg [95% CI, -0.01 to -0.004]) and diastolic blood pressure (ß=-0.010 mmHg [95% CI, -0.012 to -0.011]) in boys after adjusting for confounders, which remained significant after adjusting for potential intermediate factors. CONCLUSIONS: We found temporal sex dimorphic negative associations between maternal s-cortisol levels and OBP, with significant findings in boys. We conclude that physiological maternal cortisol is not a risk factor for higher blood pressure in offspring up to 5 years of age.

Prenatal Androgen Exposure and Traits of Autism Spectrum Disorder in the Offspring: Odense Child Cohort.

Fetal androgen exposure may be associated with autism spectrum disorder (ASD). We studied 1777 mother-child pairs in the prospective Odense Child Cohort. Prenatal androgen exposure was assessed by maternal 3rd trimester testosterone concentrations, maternal polycystic ovary syndrome (PCOS), and 3 months offspring anogenital distance. ASD traits were assessed at age 3 years with the ASD-symptom scale of the Child Behavior Checklist for ages 1½-5 years. Maternal testosterone was positively associated with traits of ASD in boys (p < 0.05). Maternal PCOS was associated with increased offspring ASD traits (p = 0.046), but became non-significant after excluding parental psychiatric diagnosis. Offspring anogenital distance was not linked to ASD traits. Higher prevalence of ASD in boys could be linked to higher susceptibility to fetal androgen exposure.

SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO. DISCUSSION: The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention. TRIAL REGISTRATION: EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .

Myoinositol vs. Metformin in Women with Polycystic Ovary Syndrome: A Randomized Controlled Clinical Trial.

Polycystic ovary syndrome (PCOS) is associated with insulin resistance. Few randomized controlled trials (RCT) compared myoinositol (MI) with metformin (MET) regarding insulin resistance in PCOS. This was an open-label six-month RCT in women with PCOS (n = 45) with interventions MI 4 g/day or MET 2 g/day. Primary outcome was the homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were fasting glucose, weight, cycle length, lipids, testosterone, adverse effects, quality of life, and depression scores. Median age was 26 years. Body mass was index was 34.4 kg/m2. HOMA-IR was unchanged during MI (p = 0.31) and MET (p = 0.11) (MI vs. MET, p = 0.09). Median fasting glucose changed +0.2 mmol/L during MI (p < 0.001) and −0.1 mmol/L during MET (p = 0.04) (MI vs. MET p < 0.001). Median weight changed −2.3 kg during MI (p = 0.98) and −6.1 kg during MET (p < 0.001) (MI vs. MET, p = 0.02). Median cycle length decreased nine days during MI (p = 0.03) and 13 days during MET (p = 0.03) (MI vs. MET, p = 0.93). High-density lipoprotein (HDL) changed +0.1 mmol/L during MET (p = 0.04) (MI vs. MET, p = 0.07). All other blood parameters and scores of quality of life and depression remained unchanged during MI and MET (all p > 0.06) (MI vs. MET, all p > 0.27). Adverse effects appeared in four women during MI and 16 women during MET (MI vs. MET, p = 0.001). In conclusion, there was no effect on the metabolic outcomes during MI, but positive effects on fasting blood glucose, weight, and HDL during MET. The effect on cycle length was comparable during MI and MET. Adverse effects were less frequent during MI.

Elevated blood pressure in pregnant women with gestational diabetes according to the WHO criteria: importance of overweight.

OBJECTIVE: Hypertension before and during early pregnancy has been associated with an increased risk of gestational diabetes mellitus (GDM) in retrospective analyses. We aimed to investigate the prospective blood pressure trackings in a population-based cohort of pregnant women, who were stratified according to their metabolic status in early third trimester. METHODS: We recorded blood pressure longitudinally during pregnancy in 1230 women from the Odense Child Cohort, Denmark. Fasting glucose and insulin were measured at gestational weeks 28-30. Metabolic status was evaluated according to the WHO 2013 threshold for GDM (GDM-WHO: fasting plasma glucose ≥5.1 mmol/l), insulin and homeostatic model assessment of insulin resistance (HOMA-IR). Relationships between metabolic status in third trimester and blood pressure trajectories were evaluated with adjusted linear mixed models. Trajectory was defined as blood pressure records in pregnancy per 4 weeks interval. RESULTS: Prevalence of GDM-WHO was 40% (498/1230). GDM-WHO was associated with 1.46 (0.22-2.70) mmHg higher SBP and 1.04 (0.07-2.01) mmHg higher DBP trajectories in the overall cohort. The associations were driven by differences in the overweight group, with 3.14 (1.05-5.25) mmHg higher SBP and 1.94 (0.42-3.47) mmHg higher DBP per 4 weeks in women with GDM-WHO compared with women without GDM-WHO. GDM-WHO was not associated with blood pressure in women with normal weight. Blood pressure trajectories were elevated across quartiles of insulin resistance. CONCLUSION: GDM-WHO is associated with higher blood pressure in pregnancy, and there appears to be a stronger effect in overweight women.

Prenatal paraben exposure and anogenital distance and reproductive hormones during mini-puberty: A study from the Odense Child Cohort.

BACKGROUND: Parabens are added to personal care products as antimicrobial preservatives. They have been suggested to have endocrine disrupting abilities. Prenatal exposure to parabens has been associated with reproductive endpoints including reduced male anogenital distance (AGD, distance from anus to genitals), which is sensitive to prenatal anti-androgenic exposure. OBJECTIVES: To study the associations between maternal paraben concentrations in second trimester urine and AGD and reproductive hormone concentrations at 3 months of age in offspring. METHODS: Pregnant women from Odense, Denmark were included in early pregnancy from 2010 to 12, and their children are being followed up. Fasting spot urine samples from 536 pregnant women were analyzed for methylparaben (MeP), ethyl-paraben (EtP), iso-propylparaben (i-PrP), n-propylparaben (n-PrP), n-butylparaben (n-BuP) and benzylparaben (BzP) by liquid chromatography tandem mass spectrometry and thereafter osmolarity adjusted. Three months after expected date of birth, AGD was measured in 452 children, and serum concentrations of follicle stimulating hormone (FSH), luteinizing (LH), testosterone, dehydroepiandrosterone-sulphate (DHEAS), androstenedione and 17-hydroxyprogesterone (17-OHP) were measured in 198 children. Maternal paraben exposure was categorized into tertiles or below and above level of detection, and sex-stratified multiple linear regression analyses were performed with AGD or reproductive hormones as outcomes. RESULTS: Most pregnant women had low concentrations of parabens in urine, but 10% exceeded the threshold for adverse estrogenic effects. Higher maternal paraben exposure was associated with shorter AGD in male offspring and longer AGD in girls, although only significant for MeP in boys. In addition, FSH, LH, DHEAS, 17-OHP concentrations were lower in girls with high prenatal paraben exposure, whereas no consistent pattern was found in boys. DISCUSSION: The endocrine disrupting abilities of parabens may affect humans at vulnerable time periods during development, which may have long term impact on reproductive function. This is the first study to find these associations in girls and our findings need confirmation.