Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5–10 year follow-up of the PregMet randomised controlled trial

Hanem, Liv Guro Engen; Salvesen, Øyvind; Júlíusson, Pétur Benedikt; Carlsen, Sven Magnus; Nossum, Marit Cecilie Fonn; Vaage, Marte Øye; Ødegård, Rønnaug; Vanky, Eszter

doi:10.1016/s2352-4642(18)30385-7

Cited by 80 publications

(80 citation statements)

References 30 publications

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“…Gestational T excess induction of metabolically compromised gestation may thus provide the developmental origins necessary for metabolic pathophysiology accompanying PCOS. Pre-conception lifestyle and therapeutic approaches to maternal weight reduction and improved glucoregulation can ameliorate the metabolic environment of subsequent PCOS pregnancies [179], but gestation-based therapies, including maternal metformin administration, risk increased weight gain and accelerated glucoregulatory dysfunction among offspring beyond that achieved by PCOS alone [180].…”

Section: Gestational and Placental Contributions To Transgenerationalmentioning

confidence: 99%

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

et al. 2019

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Indian rhesus macaque nonhuman primate models for polycystic ovary syndrome (PCOS) implicate both female hyperandrogenism and developmental molecular origins as core components of PCOS etiopathogenesis. Establishing and exploiting macaque models for translational impact into the clinic, however, has required multi-year, integrated basic-clinical science collaborations. Paradigm shifting insight has accrued from such concerted investment, leading to novel mechanistic understanding of PCOS, including hyperandrogenic fetal and peripubertal origins, epigenetic programming, altered neural function, defective oocytes and embryos, adipogenic constraint enhancing progression to insulin resistance, pancreatic decompensation and type 2 diabetes, together with placental compromise, all contributing to transgenerational transmission of traits likely to manifest in adult PCOS phenotypes. Our recent demonstration of PCOS-related traits in naturally hyperandrogenic (High T) female macaques additionally creates opportunities to employ whole genome sequencing to enable exploration of gene variants within human PCOS candidate genes contributing to PCOS-related traits in macaque models. This review will therefore consider Indian macaque model contributions to various aspects of PCOS-related pathophysiology, as well as the benefits of using macaque models with compellingly close homologies to the human genome, phenotype, development and aging.

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Section: Gestational and Placental Contributions To Transgenerationalmentioning

confidence: 99%

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

et al. 2019

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“…Interestingly, in all three studies, metformin exposed offspring had a larger head, both at gestational age 32 weeks and at birth [13]. Follow-up of the children from the PregMet study also showed that metformin-exposed children at 4 and 8 years og age, had higher BMI, waist circumference, waist-to-height ratio and prevalence of obesity than those exposed to placebo [14,15].…”

Section: Introductionmentioning

confidence: 87%

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

2020

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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.

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“…In two RCTs of metformin use in pregnancy for polycystic ovary syndrome, follow-up of 4-year-old offspring demonstrated higher BMI and increased obesity in the offspring exposed to metformin (69,70). A follow-up study at 5-10 years showed that the offspring had higher BMI, weight-toheight ratios, waist circumferences, and a borderline increase in fat mass (70,71 [73]), but long-term offspring data will not be available for some time. A recent meta-analysis concluded that metformin exposure resulted in smaller neonates with acceleration of postnatal growth resulting in higher BMI in childhood (68,69).…”

Section: Metforminmentioning

confidence: 99%

14. Management of Diabetes in Pregnancy:Standards of Medical Care in Diabetes—2020

2019

Diabetes Care

284

148

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The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidencegrading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. DIABETES IN PREGNANCY The prevalence of diabetes in pregnancy has been increasing in the U.S. in parallel with the worldwide epidemic of obesity. Not only is the prevalence of type 1 diabetes and type 2 diabetes increasing in women of reproductive age, but there is also a dramatic increase in the reported rates of gestational diabetes mellitus. Diabetes confers significantly greater maternal and fetal risk largely related to the degree of hyperglycemia but also related to chronic complications and comorbidities of diabetes. In general, specific risks of diabetes in pregnancy include spontaneous abortion, fetal anomalies, preeclampsia, fetal demise, macrosomia, neonatal hypoglycemia, hyperbilirubinemia, and neonatal respiratory distress syndrome, among others. In addition, diabetes in pregnancy may increase the risk of obesity, hypertension, and type 2 diabetes in offspring later in life (1,2). PRECONCEPTION COUNSELING Recommendations 14.1 Starting at puberty and continuing in all women with diabetes and reproductive potential, preconception counseling should be incorporated into routine diabetes care. A 14.2 Family planning should be discussed, and effective contraception (with consideration of long-acting, reversible contraception) should be prescribed and used until a woman's treatment regimen and A1C are optimized for pregnancy. A 14.3 Preconception counseling should address the importance of achieving glucose levels as close to normal as is safely possible, ideally A1C ,6.5% (48 mmol/mol), to reduce the risk of congenital anomalies, preeclampsia, macrosomia, and other complications. B All women of childbearing age with diabetes should be informed about the importance of achieving and maintaining as near euglycemia as safely possible prior Suggested citation: American Diabetes Association. 14. Management of diabetes in pregnancy:

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Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5–10 year follow-up of the PregMet randomised controlled trial

Cited by 80 publications

References 30 publications

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

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

14. Management of Diabetes in Pregnancy:Standards of Medical Care in Diabetes—2020

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