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Saadati S, Mason T, Godini R, Vanky E, Teede H, Mousa A. Metformin use in women with polycystic ovary syndrome (PCOS): Opportunities, benefits, and clinical challenges. Diabetes Obes Metab 2025; 27 Suppl 3:31-47. [PMID: 40329601 PMCID: PMC12094230 DOI: 10.1111/dom.16422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 04/04/2025] [Accepted: 04/14/2025] [Indexed: 05/08/2025]
Abstract
Metformin, a synthetic biguanide, is widely used to manage type 2 diabetes, and is commonly prescribed in polycystic ovary syndrome (PCOS) to address insulin resistance and associated metabolic and reproductive disturbances. PCOS is characterised by hormonal imbalances such as hyperandrogenism and anovulation, metabolic abnormalities including insulin resistance and increased cardiometabolic risk, and higher rates of pregnancy complications. However, the role of metformin in the multifaceted nature of PCOS remains debated. This review synthesises the mechanisms of action of metformin and its effects on metabolic, hormonal, reproductive, and pregnancy-related outcomes in PCOS. In non-pregnant women, metformin improves insulin resistance, menstrual regularity, and androgen levels, particularly in those with obesity or insulin resistance, and may enhance fertility when combined with other treatments. However, it is not effective as a first-line therapy for weight loss, ovulation induction, or treatment of clinical hyperandrogenic features, including hirsutism or acne. In pregnancy, metformin may reduce early pregnancy loss, miscarriage, and preterm birth, though findings for gestational diabetes and preeclampsia are inconsistent. Evidence is limited by study heterogeneity, varying diagnostic criteria, and the use of aggregate data in meta-analyses, all of which make interpretation challenging. Future research should prioritise well-powered clinical trials, individual patient data meta-analyses, and longer-term follow-up studies, particularly in pregnancy, to better define the populations most likely to benefit from metformin use across the PCOS spectrum. PLAIN LANGUAGE SUMMARY: Polycystic ovary syndrome (PCOS) is a common condition that affects up to 1 in 10 women of reproductive age. It is characterised by irregular or absent periods, signs of elevated male hormones (high androgens or excess hair growth), and/or polycystic ovaries seen on ultrasound. These features can lead to fertility problems, acne, psychological distress, and an increased risk of various disorders such as depression, type 2 diabetes and heart disease. Many women with PCOS also experience challenges during pregnancy, including a higher risk of miscarriage, preterm birth, and gestational diabetes. Metformin is a medication most often used to manage diabetes. In women with PCOS, it can help improve how the body responds to insulin, which may also reduce male hormone levels, improve menstrual cycles, and support fertility. This review examines the role of metformin in treating PCOS-both before and during pregnancy-by summarising key findings from the available evidence. In women who are not pregnant, metformin can help improve insulin resistance, hormone levels, and menstrual regularity, particularly among those who are overweight or have signs of insulin resistance. However, metformin alone is not a first-choice treatment for weight loss, ovulation problems, or symptoms such as acne and unwanted hair growth. When combined with other treatments, such as hormone therapy or fertility medications, it may offer additional benefits. During pregnancy, metformin is considered safe for use in women with PCOS and may lower the risk of early pregnancy loss and preterm birth. However, its effects on preventing gestational diabetes or high blood pressure are less clear, with mixed results across studies. Some research suggests that babies exposed to metformin in the womb may have slightly larger head sizes or a higher risk of being overweight in early childhood, but the long-term health effects remain unknown. Overall, metformin can be a helpful part of treatment for some women with PCOS, especially those with insulin resistance or certain pregnancy risks. Still, it is not a one-size-fits-all solution. More high-quality research is needed to better understand which women benefit most and to assess any long-term effects on children exposed to metformin during pregnancy.
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Affiliation(s)
- Saeede Saadati
- Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneVictoriaAustralia
| | - Taitum Mason
- Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneVictoriaAustralia
| | - Rasoul Godini
- Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneVictoriaAustralia
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental BiologyMonash UniversityMelbourneVictoriaAustralia
| | - Eszter Vanky
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health SciencesNorwegian University of Science and TechnologyTrondheimNorway
| | - Helena Teede
- Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneVictoriaAustralia
| | - Aya Mousa
- Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneVictoriaAustralia
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Mayadunne T, Saadati S, Asmelash D, Mason T, Vanky E, Teede H, Mousa A. Long-term effects of metformin on offspring health: A review of current evidence and future directions. Diabetes Obes Metab 2025; 27 Suppl 3:48-63. [PMID: 40326052 PMCID: PMC12094221 DOI: 10.1111/dom.16418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/31/2025] [Accepted: 04/11/2025] [Indexed: 05/07/2025]
Abstract
Metformin is widely prescribed for the management of type 2 diabetes mellitus, polycystic ovary syndrome, and gestational diabetes mellitus in pregnancy. Its use is driven by factors including oral administration, lower patient and health system burden and cost, and benefits including lower risk of excess gestational weight gain and hypoglycemia compared with insulin. Metformin use appears safe in pregnancy; however, there remain concerns regarding long-term effects of intrauterine metformin exposure on offspring health. Randomized controlled trial follow-up studies suggest that metformin-exposed offspring may have altered postnatal growth trajectories and increased adiposity in childhood, although data are limited. Whether this is a transient adaptation or a precursor to long-term metabolic dysfunction is unclear, as data on cardiometabolic and neurodevelopmental parameters, including glucose homeostasis, lipid metabolism, and cognitive function, are sparse and inconsistent. Methodological challenges include heterogeneous study designs, high attrition rates, and inadequate control for confounding variables. Given these uncertainties, further well-powered, long-term prospective studies and individual patient data meta-analyses, harmonizing data and adjusting for confounders, are needed to clarify risks and benefits of metformin use in pregnancy. Until such data are available, clinicians must weigh the benefits and advantages of metformin use in pregnancy against the unknowns regarding potential long-term impact on offspring health. PLAIN LANGUAGE SUMMARY: Metformin is a medicine often used during pregnancy to help manage conditions such as type 2 diabetes, gestational diabetes, and polycystic ovary syndrome (PCOS). It is commonly chosen because it is taken as a tablet rather than by injection, has a lower risk of causing low blood sugar, and is generally easier and less expensive to use than insulin. Research has shown that metformin is safe for use during pregnancy in the short term. However, there are still questions about whether it has any lasting effects on children who were exposed to it before birth. This review explores this topic in detail. Some studies have found that children exposed to metformin during pregnancy may have slightly different growth patterns, such as having more body fat or being heavier in early childhood. However, these results are inconsistent and most studies show no clear differences in overall health outcomes, including in heart health, metabolism, or brain development. The results are mixed, and many studies are small or have design limitations, which makes it difficult to draw strong conclusions. At this stage, there is no clear evidence that metformin causes harm to children in the long term. However, because some studies suggest there may be effects on childhood growth and development, researchers emphasize the need for further long-term research. These future studies should follow children into adolescence and adulthood to better understand any lasting impacts. Until more is known, doctors and patients will need to carefully consider the known benefits of metformin in pregnancy alongside the current uncertainties about long-term effects on child health.
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Affiliation(s)
| | - Saeede Saadati
- Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneVictoriaAustralia
| | - Daniel Asmelash
- Department of Medical Laboratory Science, College of Medicine and Health ScienceMizan Tepi UniversityMizan‐TeferiEthiopia
| | - Taitum Mason
- Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneVictoriaAustralia
| | - Eszter Vanky
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health SciencesNorwegian University of Science and TechnologyTrondheimNorway
| | - Helena Teede
- Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneVictoriaAustralia
| | - Aya Mousa
- Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneVictoriaAustralia
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Newman C, Dunne FP. Treatment of Diabetes in Pregnancy With Metformin. Obstet Gynecol 2024; 144:660-669. [PMID: 39208454 DOI: 10.1097/aog.0000000000005705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 06/06/2024] [Indexed: 09/04/2024]
Abstract
Metformin is a commonly used drug in the treatment of type 2 diabetes and has been used to treat gestational diabetes since the 1970s. In pregnancy, its proven benefits include reduced gestational weight gain and reduced fetal size; some studies have shown reduced risk of cesarean delivery and lower rates of hypertension. Metformin can reduce the need for insulin therapy but does not eliminate such need in many patients. Despite these benefits, metformin crosses the placenta and has been associated with increases in the risk of giving birth to small-for-gestational-age neonates in some studies of individuals with type 2 diabetes in pregnancy. In addition, higher body mass index (BMI) z-scores have been observed among exposed offspring in some of the long-term follow-up studies. Nevertheless, metformin's low cost, ease of administration, and global reach make it a reasonable intervention in a population affected by rising rates of obesity and diabetes in pregnancy. Further follow-up studies are required to monitor the long-term health of exposed offspring.
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Affiliation(s)
- Christine Newman
- Institute for Clinical Trials, the HRB-Clinical Research Facility, and the College of Medicine, Nursing and Health Sciences, University of Galway, and Galway University Hospital, Galway, Ireland
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Neola D, Angelino A, Sirico A, Murolo C, Bartolini G, Vigilante L, Raffone A, Carbone L, Sarno L, Saccone G, Guida M, Maruotti GM. Unveiling therapeutic potentials and exploring maternal-fetal health benefits of metformin in pregnancy: A scoping review. Int J Gynaecol Obstet 2024; 167:538-546. [PMID: 38887906 DOI: 10.1002/ijgo.15728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 05/20/2024] [Accepted: 06/01/2024] [Indexed: 06/20/2024]
Abstract
This scoping review synthesizes evidence on metformin's use during pregnancy, encompassing diverse conditions like gestational diabetes, type 1 and type 2 diabetes, polycystic ovary syndrome (PCOS), and obesity. Metformin demonstrates comparable efficacy to insulin in gestational diabetes, positive outcomes in type 2 diabetes pregnancies, and potential benefits in reducing complications. The review highlights nuances in its effects across conditions, indicating advantages such as reduced risk of macrosomia and cesarean section in gestational diabetes. However, its prophylactic role in preventing gestational diabetes and associated complications remains inconclusive. In obese pregnant women, mixed results are observed, with potential benefits in reducing pre-eclampsia risk. Metformin shows promise in preventing preterm birth and late miscarriage in PCOS pregnancies. Categorizing patient subgroups is crucial for identifying advantages, especially in gestational diabetes and type 2 diabetes. Challenges arise from study heterogeneity, necessitating standardized indications for dosage, timing, and postpartum follow ups. Efforts to identify patient characteristics influencing metformin efficacy are crucial for tailored therapy. Although metformin emerges as a viable option in complicated pregnancies, comprehensive research, standardized protocols, and subgroup identification efforts will enhance clinical utility, ensuring evidence-based therapies and optimal maternal and fetal outcomes. Bridging existing knowledge gaps remains imperative for advancing metformin's role in pregnancy management.
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Affiliation(s)
- Daniele Neola
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Antonio Angelino
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Angelo Sirico
- Obstetrics and Gynecology Unit, Sant'Anna e San Sebastiano Hospital, Caserta, Italy
| | - Chiara Murolo
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giorgia Bartolini
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Luigi Vigilante
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Antonio Raffone
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Luigi Carbone
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Laura Sarno
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Gabriele Saccone
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Maurizio Guida
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
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Gordon HG, Atkinson JA, Tong S, Mehdipour P, Cluver C, Walker SP, Lindquist AC, Hastie RM. Metformin in pregnancy and childhood neurodevelopmental outcomes: a systematic review and meta-analysis. Am J Obstet Gynecol 2024; 231:308-314.e6. [PMID: 38460832 DOI: 10.1016/j.ajog.2024.02.316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/22/2024] [Accepted: 02/28/2024] [Indexed: 03/11/2024]
Abstract
OBJECTIVE This study aimed to examine the impact of maternal metformin use during pregnancy on offspring neurodevelopmental outcomes. DATA SOURCES MEDLINE, Embase, and Web of Science (Core Collection) were searched from inception until July 1, 2023. STUDY ELIGIBILITY CRITERIA Studies of women who received treatment with metformin at any stage of pregnancy for any indication with neurodevelopmental data available for their offspring were included. Studies without a control group were excluded. Randomized controlled trials, case-control, cohort, and cross-sectional studies were included in the review. METHODS Studies were screened for inclusion and data were extracted independently by 2 reviewers. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale for nonrandomized studies, and the Risk of Bias 2 tool for randomized trials. RESULTS A total of 7 studies met the inclusion criteria, including a combined cohort of 14,042 children with 7641 children who were exposed and followed for up to 14 years of age. Metformin use during pregnancy was not associated with neurodevelopmental delay in infancy (relative risk, 1.09; 95% confidence interval, 0.54-2.17; 3 studies; 9668 children) or at ages 3 to 5 years (relative risk, 0.90; 95% confidence interval, 0.56-1.45; 2 studies; 6118 children). When compared with unexposed peers, metformin use during pregnancy was not associated with altered motor scores (mean difference, 0.30; 95% confidence interval, -1.15 to 1.74; 3 studies; 714 children) or cognitive scores (mean difference, -0.45; 95% confidence interval, -1.45 to 0.55; 4 studies; 734 children). Studies that were included were of high quality and deemed to be at low risk of bias. CONCLUSION In utero exposure to metformin does not seem to be associated with adverse neurodevelopmental outcomes in children up to the age of 14 years. These findings provide reassurance to clinicians and pregnant women considering metformin use during pregnancy.
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Affiliation(s)
- Hannah G Gordon
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
| | - Jessica A Atkinson
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Stephen Tong
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Parinaz Mehdipour
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Catherine Cluver
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia; Department of Obstetrics and Gynaecology, Stellenbosch University, Tygerberg Hospital, South Africa
| | - Susan P Walker
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Anthea C Lindquist
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Roxanne M Hastie
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
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Talmo MSA, Fløysand IS, Nilsen GØ, Løvvik TS, Ødegård R, Juliusson PB, Vanky E, Simpson MR. Growth Restriction in the Offspring of Mothers With Polycystic Ovary Syndrome. JAMA Netw Open 2024; 7:e2430543. [PMID: 39190302 PMCID: PMC11350484 DOI: 10.1001/jamanetworkopen.2024.30543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 07/03/2024] [Indexed: 08/28/2024] Open
Abstract
Importance Polycystic ovary syndrome (PCOS) is a common endocrine disorder, characterized by subfertility, increased risk of metabolic diseases, and pregnancy complications. Previous studies diverge regarding the association between maternal PCOS and newborn anthropometrics. Objective To explore the association between maternal PCOS and newborn anthropometrics and the modifying effects of maternal body mass index, PCOS phenotype, and gestational diabetes. Design, Setting, and Participants This cohort study followed up women from the first half of pregnancy to birth and combined data from 3 clinical trials of pregnant women with PCOS and a reference population consisting of participants in the Norwegian Mother, Father, and Child Cohort (MoBa) Study, with data from the Medical Birth Registry of Norway. The recruitment period for the clinical trials was between October 1, 2000, and August 31, 2017, and for MoBa, between July 1, 1999, and December 31, 2008. Participants included women with singleton pregnancies and live-born children. Data were analyzed from January 1 to June 15, 2023. Exposure Maternal PCOS status. Main Outcomes and Measures Newborn birth weight, birth length, and head circumference as continuous variables and z scores, and ponderal index (calculated as the birth weight in grams × 100 divided by the birth length in centimeters cubed), placenta weight, and ratio of birth weight to placenta weight (BWPW). Results The cohort included 390 pregnant women with PCOS (mean [SD] age, 29.6 [4.2] years) and 68 708 women in the reference group (mean [SD] age, 30.4 [4.5] years). Offspring in the PCOS group had lower birth weight, birth length, and head circumference than in the reference group offspring. The estimated mean differences in z scores were -0.26 (95% CI, -0.38 to -0.14) for birth weight, -0.19 (95% CI, -0.33 to -0.05) for birth length, and -0.13 (95% CI, -0.26 to -0.01) for head circumference. The PCOS group also had a lower ponderal index (-0.04 [95% CI, -0.07 to -0.004] g × 100/cm3) and placenta weight (-24 [95% CI, -43 to -5)] g), and higher BWPW ratio (0.4 [95% CI, 0.3 to 0.5]). The association between growth restriction and PCOS was more apparent when additionally adjusting for body mass index. Neither PCOS phenotype nor gestational diabetes diagnosis was associated with neonatal anthropometry in women with PCOS. Conclusions and Relevance In this cohort of mother-infant pairs, maternal PCOS status was associated with lower birth weight, shorter birth length, and smaller head circumference in the offspring. This growth restriction was more pronounced when adjusting for BMI, providing insight into the association between PCOS and body mass index. The study contributed to the understanding of how PCOS affects the offspring.
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Affiliation(s)
- Maren Sophie Aaserud Talmo
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ingvild Skogedal Fløysand
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | | | - Tone S. Løvvik
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Obstetrics and Gynecology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Rønnaug Ødegård
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Centre for Obesity Research, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Petur Benedikt Juliusson
- Department of Health Registry Research and Development, National Institute of Public Health, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Paediatric and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway
| | - Eszter Vanky
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Obstetrics and Gynecology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Melanie Rae Simpson
- Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway
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Nilsen GØ, Simpson MR, Hanem LGE, Løvvik T, Ødegård R, Stokkeland LMT, Andersen M, Juliusson PB, Vanky E. Anthropometrics of neonates born to mothers with PCOS with metformin or placebo exposure in utero. Acta Obstet Gynecol Scand 2024; 103:176-187. [PMID: 37488743 PMCID: PMC10755130 DOI: 10.1111/aogs.14637] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/21/2023] [Accepted: 06/30/2023] [Indexed: 07/26/2023]
Abstract
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.
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Affiliation(s)
- Guro Ørndal Nilsen
- Faculty of Medicine and Health SciencesNorwegian University of Science and Technology (NTNU)TrondheimNorway
| | - Melanie Rae Simpson
- Department of Public Health and NursingNorwegian University of Science and TechnologyTrondheimNorway
| | - Liv Guro Engen Hanem
- Children's Clinic, St. Olav's HospitalTrondheim University HospitalTrondheimNorway
| | - Tone Shetelig Løvvik
- Department of Clinical and Molecular MedicineFaculty of Medicine and Health SciencesNorwegian University of Science and TechnologyTrondheimNorway
- Department of Obstetrics and Gynecology, St. Olav's HospitalTrondheim University HospitalTrondheimNorway
| | - Rønnaug Ødegård
- Department of Clinical and Molecular MedicineFaculty of Medicine and Health SciencesNorwegian University of Science and TechnologyTrondheimNorway
- Center for Obesity Research, St. Olav's HospitalTrondheim University HospitalTrondheimNorway
| | - Live Marie T. Stokkeland
- Department of Clinical and Molecular MedicineFaculty of Medicine and Health SciencesNorwegian University of Science and TechnologyTrondheimNorway
- Center of Molecular Inflammation Research (CEMIR)Norwegian University of Science and Technology (NTNU)TrondheimNorway
| | | | - Petur Benedikt Juliusson
- Department of Health Registry Research and DevelopmentNational Institute of Public HealthBergenNorway
- Department of Clinical ScienceUniversity of BergenBergenNorway
| | - Eszter Vanky
- Department of Clinical and Molecular MedicineFaculty of Medicine and Health SciencesNorwegian University of Science and TechnologyTrondheimNorway
- Department of Obstetrics and Gynecology, St. Olav's HospitalTrondheim University HospitalTrondheimNorway
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Paavilainen E, Nyman A, Niinikoski H, Nikkinen H, Veijola R, Vääräsmäki M, Tossavainen P, Rönnemaa T, Tertti K. Metformin Versus Insulin for Gestational Diabetes: Cognitive and Neuropsychological Profiles of Children Aged 9 years. J Dev Behav Pediatr 2023; 44:e642-e650. [PMID: 38019468 PMCID: PMC10686276 DOI: 10.1097/dbp.0000000000001233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 09/18/2023] [Indexed: 11/30/2023]
Abstract
OBJECTIVE We compared cognitive profile and neuropsychological performance in 9-year-old offspring of mothers who were treated with metformin or insulin for gestational diabetes mellitus (GDM). METHODS A total of 172 children whose mothers were randomly assigned to receive either metformin or insulin for GDM were studied at the age of 9 years. Of these children, 127 were from Turku, Finland (63 metformin and 64 insulin), and 45 from Oulu, Finland (19 metformin and 26 insulin). Clinical and demographic background characteristics were obtained at enrolment, birth, and 9-year follow-up. Cognitive profiles were examined at age 9 years with the Wechsler Intelligence Scale for Children. Neuropsychological functions were examined with 2 subtests of the Developmental Neuropsychological Assessment test battery assessing comprehension of instructions and narrative memory, Trail Making Test assessing attention and with Behavioral Rating Inventory of Executive Functioning, including parent-rated and teacher-rated evaluations. Academic functioning was studied with reading fluency subtest of the Screening test for reading, writing, and calculus for first to sixth grades and information about educational support received at school reported by parents. RESULTS The cognitive profiles, including indexes of verbal comprehension, perceptual reasoning, working memory, and processing speed, did not differ significantly between metformin-treated and insulin-treated groups. Significant differences were not found between the treatment groups in assessed neuropsychological functions, reading fluency, or received level of support at school. CONCLUSION Cognitive and neuropsychological outcomes were similar in 9-year-old children whose mothers had either metformin or insulin treatment of GDM.
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Affiliation(s)
- Elisa Paavilainen
- Department of Pediatrics and Adolescent Medicine, University of Turku and Turku University Hospital, Turku, Finland
| | - Anna Nyman
- Department of Psychology and Speech-Language Pathology, University of Turku, Turku, Finland
| | - Harri Niinikoski
- Department of Pediatrics and Adolescent Medicine, University of Turku and Turku University Hospital, Turku, Finland
| | - Hilkka Nikkinen
- Department of Obstetrics and Gynecology, Research Unit of Clinical Medicine, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Riitta Veijola
- Department of Pediatrics, Research Unit of Clinical Medicine, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Marja Vääräsmäki
- Department of Obstetrics and Gynecology, Research Unit of Clinical Medicine, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Päivi Tossavainen
- Department of Pediatrics, Research Unit of Clinical Medicine, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Tapani Rönnemaa
- Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland; and
| | - Kristiina Tertti
- Department of Obstetrics and Gynecology, University of Turku and Turku University Hospital, Turku, Finland
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9
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S J, S N, S SK, Haripriya G, Sheriff D, S JC, Mohammad H, K P. Anthropometric Measurements in Newborns: A Comparative Study of Infants Born to Mothers With and Without Polycystic Ovary Syndrome. Cureus 2023; 15:e48012. [PMID: 38034170 PMCID: PMC10687346 DOI: 10.7759/cureus.48012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2023] [Indexed: 12/02/2023] Open
Abstract
Objective Fetal growth can be affected by maternal PCOS and may have an impact on offspring and childhood growth. The current findings across studies are divergent and controversial. This study aims to determine whether maternal PCOS can affect the physical measurements of newborns and to establish the differences in birth weight, length, head, and chest circumference between newborns of mothers with polycystic ovarian syndrome and those of mothers without polycystic ovarian syndrome. Methods In this study, we examined the gestational age, birth weight, length, head circumference, chest circumference, and ponderal index of 75 infants born to mothers with polycystic ovary syndrome (PCOS) and compared them to those of 94 infants born to mothers without PCOS. Result Compared with the other groups, the PCOS group does not show significant differences in anthropometric indices compared to the control group. Infants born to normal and PCOS mothers birth weight were categorized as SGA (small for gestational age) if birth weight was less than the 5th percentile. LGA is large for gestational age if birth weight is greater than the 90th percentile. Other appropriate for gestational age if infant birth weight is between> 5th and < 90th percentile. Significant differences in anthropometric indices like birth weight, head circumference, and Ponderal index were observed in SGA and LGA newborns of normal and PCOS mothers. Conclusion The study findings indicate that neonates born to mothers with PCOS have higher rates of SGA and LGA newborns, and differences in anthropometric indices (birth weight, head circumference, and Ponderal index) were observed between SGA and LGA newborns of PCOS mothers.
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Affiliation(s)
- Jayakumari S
- Anatomy, Sree Balaji Medical College and Hospital, Chennai, IND
| | - Nirupa S
- Obstetrics and Gynaecology, Sree Balaji Medical College and Hospital, Chennai, IND
| | - Shivaranjani K S
- Obstetrics and Gynecology, Sri Lalithambigai Medical College & Hospital, Chennai, IND
| | - Geetha Haripriya
- Obstetrics and Gynecology, Prashanth Fertility Research Centre, Chennai, IND
| | | | - Janaki C S
- Anatomy, Bharath Medical College and Hospital, Chennai, IND
| | | | - Prabhu K
- Anatomy, Sree Balaji Medical College and Hospital, Chennai, IND
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10
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Newman C, Rabbitt L, Ero A, Dunne FP. Focus on Metformin: Its Role and Safety in Pregnancy and Beyond. Drugs 2023:10.1007/s40265-023-01899-0. [PMID: 37354354 PMCID: PMC10322786 DOI: 10.1007/s40265-023-01899-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2023] [Indexed: 06/26/2023]
Abstract
Metformin is used worldwide in the treatment of type 2 diabetes and has been used in the treatment of diabetes in pregnancy since the 1970s. It is highly acceptable to patients due to its ease of administration, cost and adverse effect profile. It is effective in reducing macrosomia, large-for-gestational-age infants and reduces maternal weight gain. Despite its many advantages, metformin has been associated with reductions in foetal size and has been associated with an increase in infants born small-for-gestational-age in certain cohorts. In this article, we review its efficacy, adverse effects and long-term follow-up before, during and after pregnancy for both mother and infant. We also evaluate the other forms of treatment for gestational diabetes, including oral therapies, insulin therapy and emerging treatments.
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Affiliation(s)
- Christine Newman
- Centre for Diabetes, Endocrinology and Metabolism, Galway University Hospital, Galway, Ireland.
- Diabetes Collaborative Clinical Trial Network, Clinical Research Facility, University of Galway, Galway, Ireland.
| | - Louise Rabbitt
- Department of Clinical Pharmacology and Therapeutics, Galway University Hospital, Galway, Ireland
- Discipline of Pharmacology and Therapeutics, School of Medicine, University of Galway, Galway, Ireland
| | - Adesuwa Ero
- Centre for Diabetes, Endocrinology and Metabolism, Galway University Hospital, Galway, Ireland
| | - Fidelma P Dunne
- Centre for Diabetes, Endocrinology and Metabolism, Galway University Hospital, Galway, Ireland
- Diabetes Collaborative Clinical Trial Network, Clinical Research Facility, University of Galway, Galway, Ireland
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11
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Tosti G, Barberio A, Tartaglione L, Rizzi A, Di Leo M, Viti L, Sirico A, De Carolis S, Pontecorvi A, Lanzone A, Pitocco D. Lights and shadows on the use of metformin in pregnancy: from the preconception phase to breastfeeding and beyond. Front Endocrinol (Lausanne) 2023; 14:1176623. [PMID: 37409227 PMCID: PMC10319127 DOI: 10.3389/fendo.2023.1176623] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/17/2023] [Indexed: 07/07/2023] Open
Abstract
During pregnancy, the complex hormonal changes lead to a progressive decrease of insulin sensitivity that can drive the onset of gestational diabetes (GDM) or worsen an already-known condition of insulin resistance like type 2 diabetes, polycystic ovarian syndrome (PCOS), and obesity, with complications for the mother and the fetus. Metformin during pregnancy is proving to be safe in a growing number of studies, although it freely crosses the placenta, leading to a fetal level similar to maternal concentration. The aim of this literature review is to analyze the main available evidence on the use of metformin during, throughout, and beyond pregnancy, including fertilization, lactation, and medium-term effects on offspring. Analyzed studies support the safety and efficacy of metformin during pregnancy. In pregnant women with GDM and type 2 diabetes, metformin improves obstetric and perinatal outcomes. There is no evidence that it prevents GDM in women with pregestational insulin resistance or improves lipid profile and risk of GDM in pregnant women with PCOS or obesity. Metformin could have a role in reducing the risk of preeclampsia in pregnant women with severe obesity, the risk of late miscarriages and preterm delivery in women with PCOS, and the risk of ovarian hyperstimulation syndrome, increasing the clinical pregnancy rate in women with PCOS undergoing in vitro fertilization (IVF/FIVET). Offspring of mothers with GDM exposed to metformin have no significant differences in body composition compared with insulin treatment, while it appears to be protective for metabolic and cardiovascular risk.
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Affiliation(s)
- Giulia Tosti
- Diabetes Care Unit, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Catholic University School of Medicine, Rome, Italy
| | - Annarita Barberio
- Diabetes Care Unit, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Catholic University School of Medicine, Rome, Italy
| | - Linda Tartaglione
- Diabetes Care Unit, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Catholic University School of Medicine, Rome, Italy
| | - Alessandro Rizzi
- Diabetes Care Unit, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Catholic University School of Medicine, Rome, Italy
| | - Mauro Di Leo
- Diabetes Care Unit, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Catholic University School of Medicine, Rome, Italy
| | - Luca Viti
- Diabetes Care Unit, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Catholic University School of Medicine, Rome, Italy
| | - Angelo Sirico
- Catholic University School of Medicine, Rome, Italy
- Department of Woman and Child Health, Woman Health Area Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Sara De Carolis
- Catholic University School of Medicine, Rome, Italy
- Department of Woman and Child Health, Woman Health Area Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Alfredo Pontecorvi
- Catholic University School of Medicine, Rome, Italy
- Department of Endocrinology, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Antonio Lanzone
- Catholic University School of Medicine, Rome, Italy
- Department of Woman and Child Health, Woman Health Area Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Dario Pitocco
- Diabetes Care Unit, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Catholic University School of Medicine, Rome, Italy
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12
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Polycystic Ovary Syndrome: Challenges and Possible Solutions. J Clin Med 2023; 12:jcm12041500. [PMID: 36836035 PMCID: PMC9967025 DOI: 10.3390/jcm12041500] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 02/05/2023] [Accepted: 02/07/2023] [Indexed: 02/16/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. This syndrome not only impairs female fertility but also increases the risk of obesity, diabetes, dyslipidemia, cardiovascular diseases, psychological diseases, and other health problems. Additionality, because of the high clinical heterogeneity, the current pathogenesis of PCOS is still unclear. There is still a large gap in precise diagnosis and individualized treatment. We summarize the present findings concerning the genetics, epigenetics, gut microbiota, corticolimbic brain responses, and metabolomics of the PCOS pathogenesis mechanism, highlight the remaining challenges in PCOS phenotyping and potential treatment approaches, and explain the vicious circle of intergenerational transmission of PCOS, which might provide more thoughts for better PCOS management in the future.
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13
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Mohammadi A, Higazy R, Gauda EB. PGC-1α activity and mitochondrial dysfunction in preterm infants. Front Physiol 2022; 13:997619. [PMID: 36225305 PMCID: PMC9548560 DOI: 10.3389/fphys.2022.997619] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/09/2022] [Indexed: 11/26/2022] Open
Abstract
Extremely low gestational age neonates (ELGANs) are born in a relatively hyperoxic environment with weak antioxidant defenses, placing them at high risk for mitochondrial dysfunction affecting multiple organ systems including the nervous, respiratory, ocular, and gastrointestinal systems. The brain and lungs are highly affected by mitochondrial dysfunction and dysregulation in the neonate, causing white matter injury (WMI) and bronchopulmonary dysplasia (BPD), respectively. Adequate mitochondrial function is important in providing sufficient energy for organ development as it relates to alveolarization and axonal myelination and decreasing oxidative stress via reactive oxygen species (ROS) and reactive nitrogen species (RNS) detoxification. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a master regulator of mitochondrial biogenesis and function. Since mitochondrial dysfunction is at the root of WMI and BPD pathobiology, exploring therapies that can regulate PGC-1α activity may be beneficial. This review article describes several promising therapeutic agents that can mitigate mitochondrial dysfunction through direct and indirect activation and upregulation of the PGC-1α pathway. Metformin, resveratrol, omega 3 fatty acids, montelukast, L-citrulline, and adiponectin are promising candidates that require further pre-clinical and clinical studies to understand their efficacy in decreasing the burden of disease from WMI and BPD in preterm infants.
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Affiliation(s)
- Atefeh Mohammadi
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Randa Higazy
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
| | - Estelle B. Gauda
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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14
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Tabatabaei Malazy O, Bandarian F, Qorbani M, Mohseni S, Mirsadeghi S, Peimani M, Larijani B. The effect of metformin on cognitive function: A systematic review and meta-analysis. J Psychopharmacol 2022; 36:666-679. [PMID: 35297284 DOI: 10.1177/02698811211057304] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Most people are familiar with metformin as a diabetic treatment option. Different positive benefits have been found for it, in addition to its anti-diabetes properties. Cognitive function enhancement is the most recent characteristic that has been studied. This study aimed to look at the evidence on the effects of metformin on cognitive performance. Web of Science, PubMed, Scopus, the Cochrane Library, EMBASE, and PsycINFO databases were searched systematically. After eliminating duplicates and irrelevant documents, the findings were screened. The documents that remained were scanned and data were extracted. Nineteen studies were qualified for meta-analysis after evaluating 3827 identified records. There was no significant relationship between metformin therapy and cognitive performance in none of the studies including cross-sectionals, cohorts, and clinical trials (p > 0.05). Results show that metformin has no significant effect on improving cognitive function or protecting against any dementia including vascular dementia and Alzheimer's disease, and cognitive impairment as well.
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Affiliation(s)
- Ozra Tabatabaei Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Bandarian
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Qorbani
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Shahrzad Mohseni
- Evidence Based Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Mirsadeghi
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Peimani
- Metabolomics and Genomics Research Center Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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15
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Newman C, Dunne FP. Metformin for pregnancy and beyond: the pros and cons. Diabet Med 2022; 39:e14700. [PMID: 34569082 DOI: 10.1111/dme.14700] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/26/2021] [Accepted: 09/21/2021] [Indexed: 12/16/2022]
Abstract
CONTEXT AND AIM Metformin has been used in pregnancy since the 1970s. It is cheap, widely available and is acceptable to women. Despite its increasing use, controversy remains surrounding its benefits and risks. Metformin effectively reduces hyperglycaemia for the mother during pregnancy and it reduces rates of macrosomia and neonatal hypoglycaemia. However, concern exists surrounding an increase in the rate of SGA births and obesity in childhood. We aim to review the evidence and expert opinion behind metformin in pregnancy through to the post-partum period. METHODS We performed a literature review of relevant studies from online databases using a combination of keywords. We also searched the references of retrieved articles for pertinent studies. RESULTS There is strong evidence that metformin is safe in early pregnancy with no risk of congenital malformations. If used throughout pregnancy, it is likely to lead to reduced maternal weight gain and reduced insulin dose in women with type 2 diabetes. In infants, metformin reduces hypoglycaemia and macrosomia but may increase the rate of infants born SGA. There is some evidence of an increased risk of obesity and altered fat distribution in offspring. Metformin appears well tolerated in pregnancy and is more acceptable to women than insulin therapy. CONCLUSION Due to increasing rates of maternal obesity, GDM and type 2 diabetes, metformin use in pregnancy is increasing. Overall, it appears safe and effective but further research is needed to examine mechanisms linking metformin to obesity reported during childhood in some follow-up studies.
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Affiliation(s)
- Christine Newman
- College of Medicine, Nursing and Health Science, National University of Ireland, Galway, Republic of Ireland
| | - Fidelma P Dunne
- College of Medicine, Nursing and Health Science, National University of Ireland, Galway, Republic of Ireland
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16
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Roy A, Sahoo J. Long-term effects of metformin use in gestational diabetes mellitus on offspring health. World J Diabetes 2021; 12:1812-1817. [PMID: 34888009 PMCID: PMC8613655 DOI: 10.4239/wjd.v12.i11.1812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 10/03/2021] [Indexed: 02/06/2023] Open
Abstract
Metformin is the first-line drug for the treatment of type 2 diabetes mellitus, but its role in gestational diabetes mellitus (GDM) management is not clear. Recent evidence suggests a certain beneficial effect of metformin in the treatment of GDM, but a high treatment failure rate leads to the initiation of additional medications, such as insulin. Moreover, since metformin crosses the placental barrier and reaches a significant level in the fetus, it is likely to influence the fetal metabolic milieu. The evidence indicates the long-term safety in children exposed to metformin in utero except for mild adverse anthropometric profiles. Diligent follow-up of metformin-exposed offspring is warranted from the clinician's point of view.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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17
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Yu DQ, Xu GX, Teng XY, Xu JW, Tang LF, Feng C, Rao JP, Jin M, Wang LQ. Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis. BMC Endocr Disord 2021; 21:199. [PMID: 34641848 PMCID: PMC8513183 DOI: 10.1186/s12902-021-00865-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 09/24/2021] [Indexed: 02/06/2023] Open
Abstract
AIMS We aimed to assess the comparative efficiency and safety of the use of glyburide, metformin, and insulin in gestational diabetes mellitus (GDM). METHODS We searched for randomized controlled trials that compared glyburide, metformin, and insulin in GDM. Data regarding glycemic control and neonatal safety were collected and analyzed in pairwise and network meta-analyses. RESULTS A total of 4533 individuals from 23 trials were included. Compared with glyburide, metformin reduced 2-h postprandial blood glucose (2HPG) to a greater extent (standard mean difference (SMD) 0.18; 95% credible interval (CI) 0.01, 0.34). There were significantly lower prevalence of neonatal hypoglycemia (risk difference (RD) - 0.07; 95%CI - 0.11, - 0.02) and preeclampsia (RD - 0.03; 95%CI - 0.06, 0) in the metformin group than in the insulin group. The metformin group had significantly lower birth weight (SMD - 0.17; 95%CI - 0.25, - 0.08) and maternal weight gain (SMD - 0.61; 95%CI - 0.86,- 0.35) compared with the insulin group. Network meta-analysis suggested that metformin had the highest probability of successfully controlling glycemia and preventing neonatal complications. CONCLUSIONS The present meta-analysis suggests that metformin may be as effective as insulin for glycemic control and is the most promising drug for the prevention of neonatal and maternal complications.
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Affiliation(s)
- Dan-Qing Yu
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Rd, Zhejiang, 310009, Hangzhou, China
| | - Guan-Xin Xu
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Rd, Zhejiang, 310009, Hangzhou, China
| | - Xin-Yuan Teng
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Rd, Zhejiang, 310009, Hangzhou, China
| | - Jing-Wei Xu
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Rd, Zhejiang, 310009, Hangzhou, China
| | - Liang-Fang Tang
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Rd, Zhejiang, 310009, Hangzhou, China
| | - Chun Feng
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Rd, Zhejiang, 310009, Hangzhou, China
| | - Jin-Peng Rao
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Rd, Zhejiang, 310009, Hangzhou, China
| | - Min Jin
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Rd, Zhejiang, 310009, Hangzhou, China
| | - Li-Quan Wang
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Rd, Zhejiang, 310009, Hangzhou, China.
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18
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Raperport C, Chronopoulou E, Homburg R. Effects of metformin treatment on pregnancy outcomes in patients with polycystic ovary syndrome. Expert Rev Endocrinol Metab 2021; 16:37-47. [PMID: 33634727 DOI: 10.1080/17446651.2021.1889366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 02/09/2021] [Indexed: 01/28/2023]
Abstract
INTRODUCTION This review covers the current evidence regarding the use of metformin as a therapeutic intervention for optimizing pregnancy outcomes in women with polycystic ovary syndrome (PCOS). AREAS COVERED After searching Medline, Embase and CINAHL, all important large clinical trials and observational studies plus systematic reviews, meta-analyses and Cochrane reviews have been summarized here. The results have been compared to culminate in a thorough review and discussion on the use of metformin in relation to reproductive outcomes for women with PCOS. The role of metformin in PCOS is explored both in terms of achieving conception and during pregnancy. The existing evidence around metformin use is summarized both during the preconceptual period and during pregnancy, in relation to reproductive outcomes. EXPERT OPINION Metformin is a widely used medication, often prescribed to improve reproductive outcomes for women with PCOS. However, the evidence remains equivocal regarding its efficacy both in optimizing fertility and pregnancy outcomes. More research is required with special emphasis on metformin use within different populations, including ethnic groups and women with varying BMI ranges.
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Affiliation(s)
- Claudia Raperport
- Fertility Unit, Homerton University Hospital, London, UK
- Blizard Institute, Queen Mary University of London, London, UK
| | | | - Roy Homburg
- Fertility Unit, Homerton University Hospital, London, UK
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19
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Valent AM, Barbour LA. Management of Women with Polycystic Ovary Syndrome During Pregnancy. Endocrinol Metab Clin North Am 2021; 50:57-69. [PMID: 33518186 DOI: 10.1016/j.ecl.2020.10.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women and is associated with subfertility and adverse perinatal outcomes, which may include early pregnancy loss, gestational diabetes mellitus, hypertensive spectrum disorder, preterm birth, fetal growth disorders, and cesarean deliveries. The phenotypic heterogeneity, different diagnostic criteria, and PCOS-related conditions that women enter pregnancy with have limited evidenced-based studies and guidelines to reduce pregnancy complications among this high-risk population. This review summarizes the available evidence on the approach and management of women with PCOS preconception, prenatal, and postpartum.
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Affiliation(s)
- Amy M Valent
- Department of Obstetrics and Gynecology, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Mail Location L-458, Portland, OR 97239, USA.
| | - Linda A Barbour
- Department of Medicine, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, RC1 South Room 7103, Aurora, CO 80045, USA; Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, RC1 South Room 7103, Aurora, CO 80045, USA
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