Maternal PCOS status and metformin in pregnancy: Steroid hormones in 5–10 years old children from the PregMet randomized controlled study

Objective: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with potential effects on offspring both genetically and through altered intrauterine environment. Metformin, which ameliorate hormonal disturbances in non-pregnant women with PCOS is increasingly used in pregnancy. It passes the placenta, and the evidence on potential consequences for offspring endocrine development is scarce. We explore the potential effects of maternal PCOS status and intrauterine metformin exposure on offspring steroid hormone levels. Design: This is a follow-up study of 5–10 years old children from the PregMet-study–a randomized controlled trial comparing metformin (2000 mg/day) to placebo during PCOS pregnancies. Of the 255 children invited, 117 (46%) were included. Methods: There was no intervention in this follow-up study. Outcomes were serum levels of androstenedione, testosterone, SHBG, cortisol, 17-hydroxyprogesterone, 11-deoxycortisol and calculated free testosterone converted to gender-and age adjusted z-scores from a Norwegian reference population. These were compared in i) placebo-exposed children versus children from the reference population (z-score zero) by the deviation in z-score by one-sample t-tests and ii) metformin versus placebo-exposed children by two-sample t-tests. Holm-Bonferroni adjustments were performed to account for multiple endpoints. Results: Girls of mothers with PCOS (n = 30) had higher mean z-scores of androstenedione (0.73 (95% confidence interval (CI) 0.41 to 1.06), p<0.0001), testosterone (0.76 (0.51 to 1.00), p<0.0001), and free testosterone (0.99 (0.67 to 1.32), p<0.0001) than the reference population. Metformin-exposed boys (n = 31) tended to have higher 11-deoxycortisol z-score than placebo-exposed boys (n = 24) (mean difference 0.65 (95% CI 0.14–1.17), p = 0.014). Conclusion: Maternal PCOS status was associated with elevated androgens in 5- to 10-year-old daughters, which might indicate earlier maturation and increased risk of developing PCOS. An impact of metformin in pregnancy on steroidogenesis in children born to mothers with PCOS cannot be excluded. Our findings need confirmation in studies that include participants that have entered puberty.publishedVersio

Anthropometrics of neonates born to mothers with PCOS with metformin or placebo exposure in utero

Introduction: Fetal growth may be affected by both maternal polycystic ovary syndrome (PCOS) and metformin therapy. Here, we explore the effect of intrauterine metformin exposure on birth anthropometrics of infants born to women with PCOS. We also investigated whether the effect of metformin on birth anthropometrics is modified by maternal pre-pregnancy body mass index, PCOS hyperandrogenic phenotype, serum androgen levels, preconception use of metformin and offspring sex. Additionally, we assessed newborn anthropometrics in relation to a national reference population. Material and methods: Individual data from three randomized controlled triasl were pooled. The randomized controlled trials investigated the effects of metformin in pregnant women with PCOS. In all, 397 and 403 were randomized to the metformin and placebo groups, respectively. A Scandinavian growth reference was used to calculate sex and gestational age adjusted z-scores. Linear regression models were used to estimate the effect of metformin on offspring z-scores of head circumference, birth length, birthweight, placental weight, body mass index, ponderal index and birthweight:placental weight ratio. S-testosterone, s-androstenedione, and s-sex-hormone binding globulin from four timepoints in pregnancy were analyzed. Results: Compared with the PCOS-placebo group, newborns in the PCOS-metformin group had larger head circumference (head circumference z-score: mean difference = 0.25, 95% CI = 0.11– 0.40). This effect of metformin on head circumference z-score was particularly observed among offspring of overweight/obese mothers and mothers with hyperandrogenic PCOS-phenotype. We observed no difference in other anthropometric measures between the metformin and placebo groups or any clear interaction between maternal androgen levels and metformin. Newborns in the PCOS-placebo group were shorter than in the reference population (birth length z-score: mean = −0.04, 95% CI = –0.05 to −0.03), but head circumference and birthweight were similar. Conclusions: Larger head circumference was observed at birth in metformin-exposed offspring of mothers with PCOS. PCOS-offspring were also shorter, with a similar birthweight to the reference population, indirectly indicating higher weight-to-height ratio at birth.publishedVersio

Bygd med opplevelser: En studie av opplevelsestilbudenes betydning for stedet Tydal, med fokus på Tydalsfestivalen, Karolinerspelet og Storsylen Opp

The experience economy is viewed upon by many as a new dominating form of production in the western countries, and in the last decades it has flourished in rural districts. While rural Norway is characterized by depopulation, more and more people make their living from experience based production. Some social entrepreneurs meet the challenges that rural Norway faces by creating experiences. This paper is a case study of the importance of experience activities in the village of Tydal, focusing on Karolinerspelet, Tydalsfestivalen and Storsylen Opp, all of which are based on voluntary work. The theoretical framework is mainly based on place theory and social entrepreneurship. The empirical framework is based on qualitative methods, primarily nine interviews with people who in different ways are connected to experience activities. The analysis consists of two parts: the first part focuses on why the little village Tydal has three experience activities, which relies on roughly half of the inhabitants to exist. Part two discusses the importance the experience activities has for the place. The main findings show that Tydal has several social entrepreneurs who based on a desire to do something positive for the community, create experiences. The local authorities greatly support these experiences, partly due to a strong economy. The experiences create activities for a large part of the population. Furthermore, they contribute to reinforcing the identity of Tydal, through creating unity among the citizens, opening up the village for immigrants and visitors and focusing on the nature and the history of the place. This way they make Tydal a more attractive place to live and visit

The rural area in the experience economy : A study of the experience economies impact on the place Tydal, with a focus on Tydalsfestivalen, Karolinerspelet and Storsylen Opp

The experience economy is viewed upon by many as a new dominating form of production in the western countries, and in the last decades it has flourished in rural districts. While rural Norway is characterized by depopulation, more and more people make their living from experience based production. Some social entrepreneurs meet the challenges that rural Norway faces by creating experiences. This paper is a case study of the importance of experience activities in the village of Tydal, focusing on Karolinerspelet, Tydalsfestivalen and Storsylen Opp, all of which are based on voluntary work. The theoretical framework is mainly based on place theory and social entrepreneurship. The empirical framework is based on qualitative methods, primarily nine interviews with people who in different ways are connected to experience activities. The analysis consists of two parts: the first part focuses on why the little village Tydal has three experience activities, which relies on roughly half of the inhabitants to exist. Part two discusses the importance the experience activities has for the place. The main findings show that Tydal has several social entrepreneurs who based on a desire to do something positive for the community, create experiences. The local authorities greatly support these experiences, partly due to a strong economy. The experiences create activities for a large part of the population. Furthermore, they contribute to reinforcing the identity of Tydal, through creating unity among the citizens, opening up the village for immigrants and visitors and focusing on the nature and the history of the place. This way they make Tydal a more attractive place to live and visit.Opplevelsesøkonomien blir av flere sett på som en ny dominerende produksjonsform i de vestlige landene og har de siste tiårene blomstret opp i bygdene. Samtidig som distrikts-Norge preges av fraflytting, er det stadig flere som livnærer seg av produksjon som spiller på opplevelser. Noen samfunnsentreprenører møter de utfordringene som distrikts-Norge står overfor med å skape opplevelsestilbud. Denne oppgaven er et case-studie av opplevelsestilbudenes betydning for bygda Tydal, med fokus på Karolinerspelet, Tydalsfestivalen og Storsylen Opp, som alle er basert på frivillig arbeid. Teorigrunnlaget baseres i stor grad på stedsteori og samfunnsentreprenørskap. Det empiriske grunnlaget baseres på kvalitative metoder, først og fremst ni intervju med mennesker som på forskjellige måter har tilknytning til opplevelsestilbudene. Oppgavens analyse består av to deler: den første delen har fokus på hvorfor ei lita bygd som Tydal har tre opplevelsestilbud, som alle er avhengig av rundt halvparten av stedets befolkning for å eksistere. Del to diskuterer opplevelsestilbudenes betydning for stedet. Hovedfunnene viser at Tydal har flere samfunnsentreprenører som skaper opplevelsestilbud på bakgrunn av et ønske om å gjøre noe positivt for bygda. Kommunen støtter godt opp om opplevelsestilbudene, blant annet som en følge av god økonomi. Opplevelsestilbudene skaper aktiviteter til en stor del av innbyggerne. Videre bidrar de til å forsterke Tydals identitet, blant annet gjennom å skape samhold blant innbyggerne, åpne bygda for innflyttere og mennesker utenfra og sette fokus på naturen og stedets historie. Slik skaper de bolyst og gjør stedet mer attraktivt

Children born to women with polycystic ovary syndrome - short- and long-term impacts on health and development

Maternal PCOS status may negatively influence offspring infant and childhood growth, cardiometabolic health, reproductive health, and neurodevelopment. Current findings across studies are divergent, often because of small numbers of subjects, as well as heterogeneous selection criteria, ethnicities, and definitions of control groups. Coexisting maternal obesity, pregnancy complications, and comorbidity make it difficult to identify the contribution of maternal PCOS. Large, prospective, international, multiethnic studies with standardized investigation protocols and questionnaires on PCOS offspring health and development are needed

Cognitive function in metformin exposed children, born to mothers with PCOS – follow-up of an RCT

Background Metformin is widely used in pregnancy to treat gestational diabetes mellitus and polycystic ovary syndrome (PCOS). Association between PCOS and developmental delay in offspring, and larger head circumference of metformin-exposed newborns has been reported. The objective of this study was to explore whether metformin exposure in utero had any effect on offspring cognitive function. Method The current study is a follow-up of two randomized, placebo-controlled studies which were conducted at 11 public hospitals in Norway In the baseline studies (conducted in 2000–2003, and 2005–2009), participants were randomized to metformin 1700 and 2000 mg/d or placebo from first trimester to delivery. There was no intervention in the current study. We invited parents of 292 children to give permission for their children to participate; 93 children were included (mean age 7.7 years). The follow-up study was conducted in 2014–2016. The Wechsler Preschool and Primary Scale of Intelligence version III and the Wechsler Intelligence Scale for Children version IV were applied for cognitive assessment. Androstenedione and testosterone were measured in maternal blood samples at four time-points in pregnancy. Results We found no difference in mean, full scale IQ in metformin (100.0 (SD 13.2)) vs. placebo-exposed (100.9 (SD 10.1)) children. There was an association between metformin exposure in utero and borderline intellectual function of children (full scale IQ between 70 and 85). Free testosterone index in gestational week 19, and androstenedione in gestational week 36 correlated positively to full scale IQ. Conclusions We found no evidence of long-term effect of metformin on average child cognitive function. The increase of borderline intellectual functioning in metformin-exposed children must be interpreted with caution due to small sample size

Fetal growth and birth anthropometrics in metformin exposed offspring born to mothers with PCOS

Context Metformin is used in an attempt to reduce pregnancy complications associated with polycystic ovary syndrome (PCOS). Little is known about the effect of metformin on fetal development and growth. Objectives To compare the effect of metformin versus placebo on fetal growth and birth anthropometrics in PCOS offspring compared with a reference population in relation to maternal body mass index (BMI). Design Post hoc analysis of a randomized controlled trial. Setting Double-blind, placebo-controlled, multicenter study. Patients 258 offspring born to mothers with PCOS. Intervention 2000 mg metformin (n = 131) or placebo (n = 121) from first trimester to delivery. Main Outcome Measures Mean abdominal diameter and biparietal diameter (BPD) at gestational weeks 19 and 32. Head circumference (HC), birth length, and weight related to a reference population of healthy offspring, expressed as gestational age– and sex-adjusted z-scores. Results Metformin- versus placebo-exposed offspring had larger heads at gestational week 32 (BPD, 86.1 mm versus 85.2 mm; P = 0.03) and at birth (HC, 35.6 cm versus 35.1 cm; P < 0.01). Analyses stratified by maternal prepregnancy BMI, larger heads were observed only among offspring of overweight/obese mothers. Among normal-weight mothers, the effect of metformin compared with placebo was reduced length (z-score = −0.96 versus -0.42, P = 0.04) and weight (z-score = −0.44 versus 0.02; P = 0.03). Compared with the reference population, offspring born to PCOS mothers (placebo group) had reduced length (z-score = −0.40; 95% confidence interval, −0.60 to −0.40), but similar birth weight and HC. Conclusions Metformin exposure resulted in larger head size in offspring of overweight mothers, traceable already in utero. Maternal prepregnancy BMI modified the effect of metformin on offspring anthropometrics. Anthropometrics of offspring born to PCOS mothers differed from those of the reference population

Maternal PCOS status and metformin in pregnancy: Steroid hormones in 5–10 years old children from the PregMet randomized controlled study

Objective: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with potential effects on offspring both genetically and through altered intrauterine environment. Metformin, which ameliorate hormonal disturbances in non-pregnant women with PCOS is increasingly used in pregnancy. It passes the placenta, and the evidence on potential consequences for offspring endocrine development is scarce. We explore the potential effects of maternal PCOS status and intrauterine metformin exposure on offspring steroid hormone levels. Design: This is a follow-up study of 5–10 years old children from the PregMet-study–a randomized controlled trial comparing metformin (2000 mg/day) to placebo during PCOS pregnancies. Of the 255 children invited, 117 (46%) were included. Methods: There was no intervention in this follow-up study. Outcomes were serum levels of androstenedione, testosterone, SHBG, cortisol, 17-hydroxyprogesterone, 11-deoxycortisol and calculated free testosterone converted to gender-and age adjusted z-scores from a Norwegian reference population. These were compared in i) placebo-exposed children versus children from the reference population (z-score zero) by the deviation in z-score by one-sample t-tests and ii) metformin versus placebo-exposed children by two-sample t-tests. Holm-Bonferroni adjustments were performed to account for multiple endpoints. Results: Girls of mothers with PCOS (n = 30) had higher mean z-scores of androstenedione (0.73 (95% confidence interval (CI) 0.41 to 1.06), p<0.0001), testosterone (0.76 (0.51 to 1.00), p<0.0001), and free testosterone (0.99 (0.67 to 1.32), p<0.0001) than the reference population. Metformin-exposed boys (n = 31) tended to have higher 11-deoxycortisol z-score than placebo-exposed boys (n = 24) (mean difference 0.65 (95% CI 0.14–1.17), p = 0.014). Conclusion: Maternal PCOS status was associated with elevated androgens in 5- to 10-year-old daughters, which might indicate earlier maturation and increased risk of developing PCOS. An impact of metformin in pregnancy on steroidogenesis in children born to mothers with PCOS cannot be excluded. Our findings need confirmation in studies that include participants that have entered puberty