The quality and quantity of diabetes pregnancy publications continues to rise with .... early pregnancy. .... The controversy surrounding GDM diagnostic criteria.
DIABETES TECHNOLOGY & THERAPEUTICS Volume 19, Supplement 1, 2017 ª Mary Ann Liebert, Inc. DOI: 10.1089/dia.2017.2508
ORIGINAL ARTICLE
Technology and Pregnancy Eran Hadar1,2, Zoe A. Stewart 3, Moshe Hod1,2, and Helen R. Murphy 4
Introduction
T
he quality and quantity of diabetes pregnancy publications continues to rise with just under 3000 publications during the period from 01 July 2015 until 30 June 2016. We have selected 13 papers representing key clinical and scientific advances from the largest national audit of contemporary pregnancy in women with pregestational diabetes, to the latest advances in metabolomics for understanding the associations between maternal metabolism and infant adiposity and trying to predict which women are at greatest risk of type 2 diabetes mellitus (T2DM) following a gestational diabetes mellitus (GDM) pregnancy. While a variety of diet and lifestyle interventions have shown limited clinical improvement in large-scale randomized trials the meticulous long-term follow up of Gunderson and colleagues suggests lactation may be one of the most effective and accessible diabetes prevention interventions for women with GDM. The debate around the clinical and cost-effectiveness of the GDM diagnostic criteria continues to challenge clinicians and health-care providers with Farrar et al. highlighting important ethnic differences between white British and South Asian women. Sovio et al. challenge us to rethink how and when we screen for gestational diabetes, with prospective longitudinal data showing that diagnosis of gestational diabetes ‡ 28 weeks is already too late as excessive growth of the fetal abdominal circumference between 20 and 28 weeks precedes routine clinical diagnosis. The role of continuous glucose monitoring (CGM) in the management of diabetes pregnancy continues to expand with Law et al. demonstrating how new approaches to the analysis of CGM data can help us understand the relationship between temporal glycaemic profiles and pregnancy outcomes such as macrosomia. Important scientific advances with the first detailed metabolomics study in pregnancy are presented alongside novel data on placental adaptation to maternal GDM and obesity and a novel regulator of B-cell function; fatty acid metabolite 3-carboxy4-methyl-5-propyl-2-furanpropanoic acid (CMPF) are described. Aye et al. question whether adiponectin supplementation using the orally active receptor agonist (AdipoRon) may offer a novel and effective intervention strategy to prevent fetal overgrowth caused by maternal obesity. Finally, the clinical and research implications of three landmark clinical trials UK Pregnancies Better Eating and Activity Trial (UPBEAT), Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR), and Metformin in Obese Nondiabetic Pregnant Women (MOP) are considered.
1
Rabin Medical Center, Petah Tikva, Israel. Sackler Faculty of Medicine, Tel Aviv University, Israel. 3 Wellcome Trust Medical Research Council Institute of Metabolic Science, University of Cambridge, UK. 4 Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK. 2
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TECHNOLOGY AND PREGNANCY Key Articles Reviewed for the Article National pregnancy in Diabetes Audit Report, 2014. England, Wales and Northern Ireland Prepared in collaboration with the Health Quality Improvement Partnership (HQIP), the Health and Social Care Information Centre (HSCIC), Diabetes UK and Public Health England [Epub November 18, 2015] http://digital.nhs.uk/npid
Association between hyperglycaemia and adverse perinatal outcomes in south Asian and white British women: analysis of data from the Born in Bradford cohort Farrar D, Fairley L, Santorelli G, Tuffnell D, Sheldon TA, Wright J, van Overveld L, and Lawlor DA Lancet Diabetes Endocrinol 2015; 3: 795–804
Accelerated fetal growth prior to diagnosis of gestational diabetes mellitus: a prospective cohort study of nulliparous women Sovio U, Murphy HR, Smith GC Diabetes Care 2016; 39: 982–987
Analysis of continuous glucose monitoring in pregnant women with diabetes: distinct temporal patterns of glucose associated with large-for-gestational-age infants Law GR, Ellison GTH, Secher AL, Damm P, Mathiesen ER, Temple R, Murphy HR, Scott EM Diabetes Care 2015; 38: 1319–1325
Lactation and progression to type 2 diabetes mellitus after gestational diabetes mellitus Gunderson EP, Hurston SR, Ning X, Lo JC, Crites Y, Walton D, Dewey KG, Azevedo RA, Young S, Fox G, Elmasian CC, Salvador N, Lum M, Sternfeld B, Quesenberry CP, for the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy Investigators Ann Intern Med 2015; 163: 889–898
Metabolic networks and metabolites underlie associations between maternal glucose during pregnancy and newborn size at birth Scholtens DM, Bain JR, Reisetter AC, Muehlbauer MJ, Nodzenski M, Stevens RD, Ilkayeva O, Lowe LP, Metzger BE, Newgard CB, Lowe Jr WL; for the HAPO Study Cooperative Research Group Diabetes 2016; 65: 2039–2050
Quantification of the T2DM risk in women with GDM: systematic review and meta-analysis of 95,750 women Rayanagoudar G, Hashi AA, Zamora J, Khan SK, Hitman AG, Thangaratinam S Diabetologia 2016; 59: 1403–1411
Maternal body weight and gestational diabetes differentially influence placental and pregnancy outcomes Martino J, Sebert S, Segura MT, Garcı´a-Valde´s L, Florido J, Padilla MC, Marcos A, Rueda R, McArdle HJ, Budge H, Symonds ME, Campoy C Journal of Clinical Endocrinology and Metabolism 2016; 101: 59–68
Evaluation of circulating determinants of b-cell function in women with and without gestational diabetes Retnakaran R, Ye C, Kramer CK, Connelly PW, Hanley AJ, Sermer M, Zinman B Journal of Clinical Endocrinology and Metabolism 2016; 101: 2683–2691
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HADAR ET AL. Adiponectin supplementation in pregnant mice prevents adverse effects of maternal obesity on placental function and fetal growth Aye LMH, Rosario FJ, Powell TL, Jannson T Proceedings of the National Academy of Sciences of the USA 2015; 112: 12858–12863
Effect of a behavioural intervention in obese pregnant women (the UPBEAT study): a multicentre, randomised controlled trial Poston L, Bell R, Croker H, Flynn AC, Godfrey KM, Goff L, Hayes L, Khazaezadeh N, Nelson MS, Oteng-Ntim E, Pasupathy D, Patel N, Robson SC, Sandall J, Sanders TAB, Sattar N, Seed PT, Wardle J, Whitworth MK, Briley AL The Lancet Diabetes & Endocrinology 2015; 3: 767–777
Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial Chiswick C, Reynolds MR, Denison F, Drake AJ, Forbes S, Newby D, Walker RB, Quenby S, Wray S, Weeks A, Lashen H, Rodriguez A, Murray G, Whyte S, Norman EJ The Lancet Diabetes & Endocrinology 2015; 3: 778–786
Metformin versus placebo in obese pregnant women without diabetes mellitus (MOP trial) Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, Pastides A, Shehata H New England Journal of Medicine 2016; 374: 434–443
National pregnancy in Diabetes Audit Report, 2014 England, Wales and Northern Ireland
Standardized data collection forms are provided. All UK maternity units delivering women with diabetes are expected to participate (http://digital.nhs.uk/npid). Linkage with data collected in other systems (Hospital Episodes Statistics data, Patient Episode Database for Wales, National Maternity Data Set) means that only a limited number of data items need to be collected by local teams. Data is obtained only from women who provide informed consent.
achieved target HbA1c level (< 48 mmol/mol or 6.5%) in early pregnancy. Women with type 1 diabetes were better prepared for pregnancy; 51% took preconception folic acid (400 mcg or 5mg) compared to 33% type 2 diabetes. Ten percent women with type 2 diabetes were taking potentially harmful medications at conception (9% oral hypoglycemic agents, 11% statins/angiotensin receptor enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB)). After 24 weeks gestation more women with type 2 diabetes achieved target HbA1c (70% vs. 41% type 1 diabetes). Nine percent women with type 1 and 2% with type 2 diabetes were admitted with severe hypoglycemia. The average pregnancy duration was longer in type 2 diabetes (37.1 vs. 36.3 weeks) with low rates of spontaneous labor (13% type 1 diabetes, 14% type 2 diabetes). Rates of congenital anomaly, stillbirth, and neonatal death remain 2 to 3 times higher than the background maternity population (1 in 23, 78, and 132, respectively) with no statistically significant differences between type 1 and type 2 diabetes. The infants of women with type 1 diabetes have higher rates of perinatal morbidity with higher rates of LGA (46% vs. 23%) and preterm delivery (43% vs. 24%). Women with type 1 diabetes who achieved optimal HbA1c (< 48 mmol/mol or 6.5%) were still more likely to have an LGA infant than women with well controlled type 2 diabetes (36% vs. 14%).
Results
Conclusions
Data were collected on 1193 women with type 1 (52%) and 1069 women (47%) with type 2 diabetes. Women with type 2 diabetes were older (34 vs. 30 years) and more likely to have had two or more previous pregnancies (47% vs. 28%). Only 15% women with type 1 and 36% with type 2 diabetes
This large contemporary database of diabetes pregnancy reveals suboptimal pregnancy preparation (especially in type 2 diabetes), widespread suboptimal glycaemic control and persistently elevated neonatal morbidity especially in type 1 diabetes.
Prepared in collaboration with the Health Quality Improvement Partnership (HQIP), the Health and Social Care Information Centre (HSCIC), Diabetes UK and Public Health England [Epub November 18, 2015] http://digital.nhs.uk/npid
Aims To document maternal/fetal health outcomes as well as pregnancy preparation, treatment, and care given to women with type 1 and type 2 diabetes during pregnancy. Methods
TECHNOLOGY AND PREGNANCY Comment The UK has recognized the importance of making audit (‘‘how are we going to measure ourselves?’’) a mandatory component of diabetes pregnancy clinical practice. Over a decade after the previous confidential enquiry in maternal and child health (CEMACH) the National Pregnancy in Diabetes (NPID) audit has established a nationwide method to consistently measure maternal fetal health outcomes. The mandatory audit incorporates key clinical measures focusing on pregnancy preparation (preconception glucose control; folic acid supplementation and potentially harmful medications), screening for maternal renal and retinal complications and an agreed set of key obstetrical and neonatal outcomes. Despite concerns about limited resources and IT infrastructure 150 maternity units contributed data on 2537 pregnancies in women with diabetes who delivered during 2014. Regional reports demonstrate where diabetes pregnancy care is good and meets national guidelines and where improvements are needed. Association between hyperglycaemia and adverse perinatal outcomes in south Asian and white British women: analysis of data from the Born in Bradford cohort Farrar D 1,2, Fairley L1, Santorelli G 4, Tuffnell D 5, Sheldon TA 3, Wright J 1, van Overveld L 6, and Lawlor DA 7,8 1
Bradford Institute for Health Research, Bradford Teaching Hospitals, Bradford, UK; 2Department of Health Sciences, University of York, York, UK; 3Hull York Medical School, University of York, York, UK; 4Clinical Trials Research Unit, University of Leeds, Leeds, UK; 5Bradford Women’s and Newborn Unit, Bradford Teaching Hospitals, Bradford, UK; 6Radboud University, Nijmegen, Netherlands; 7MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; 8School of Social and Community Medicine, University of Bristol, Bristol, UK Lancet Diabetes Endocrinol 2015; 3: 795–804
Objectives To determine whether the same diagnostic criteria for GDM are applicable to South Asian and white British women. To study whether the relationship between maternal hyperglycemia and obstetric and neonatal health outcomes differed between these ethnic groups. To document the impact of ethnicity on GDM prevalence. The Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study had no South Asian sites and too few South Asian participants to address these questions. Methods Prospective observational study including data from 10,353 pregnancies with 75 g oral glucose tolerance test (OGTT) universally performed between 26 and 28 weeks gestation in all women. Women with GDM diagnosed as per World Health Organization (WHO) criteria (fasting ‡ 6.1 or 2 h ‡ 7.8) were excluded. Data on maternal fasting and 2 h post-
S-85 OGTT glucose were related to three primary and five secondary outcomes. The primary neonatal outcomes were large for gestational age (LGA) (birth weight > 90th percentile), neonatal adiposity (sum of skinfolds > 90th percentile), and caesarean section (CS) delivery. Key secondary outcomes included preeclampsia, preterm delivery, shoulder dystocia, instrumental delivery, and neonatal intensive care unit admission. The fasting and 2 h post-OGTT glucose thresholds equating to an odds ratios (OR) of 1.75 for LGA and infant adiposity were calculated for white British and South Asian women. Results Of ten 353 eligible pregnancies, 844 women (18.5%) with GDM were excluded leaving 9509 for inclusion in the main analyses. Of these, 4821 women (41%) were white British, 5408 (51%) were South Asian, with 857 (8%) from other ethnicities providing data which are broadly representative of the local obstetric population. White British infants were three times more likely to be born LGA than their South Asian counterparts. For LGA, the adjusted odds ratio (OR) per 1 standard deviation (SD) increase in fasting glucose 1$22 (95% CI 1$08–1$38) in white British and 1$43 (1$23–1$67) in South Asian women. For neonatal adiposity they were 1$35 (1$23–1$49) and 1$35 (1$18–1$54), respectively. Associations were weaker for delivery by CS 1$06 (0$97–1$16) and 1$11 (1$02–1$20) and considerably weaker for the 2 h post-OGTT glucose than for fasting glucose level. Associations for secondary outcomes were comparable between the two groups. The fasting and 2 h post-OGTT glucose thresholds for identifying women with a 75% risk of LGA or neonatal adiposity were 5.4 and 7.5 mmol/L in white British women and 5.2 and 7.2 mmol/L in South Asian women. The GDM prevalence varied as per diagnostic criteria ranging from 1.2% to 8.7% in White British to between 4 to 24% in South Asian women. Use of the proposed Bradford ethnic specific diagnostic criteria (fasting < 5.2 and 2 h < 7.2) increased GDM prevalence from 17.4% to 24.2%. Conclusions The prevalence of GDM is almost three times higher in South Asian compared to white British women. Although the infants of white British women are almost three times more likely to be LGA than South Asians the associations between glucose and LGA are stronger in South Asian women. These data suggest that the current UK National Institute for Health Research (NIHR) criteria underestimate GDM prevalence and infant risk among South Asian women and support adoption of the more stringent International Association of Diabetes and Pregnancy Study Groups (IADPSG) diagnostic criteria in high risk women of South Asian ethnicity. Comment The controversy surrounding GDM diagnostic criteria continues to challenge patients, clinicians, and healthcare providers. This study provides compelling data on the racial differences between white British and South Asian women in terms of GDM prevalence (three times higher in South Asians women) and infant outcomes.
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The data are from a large and well-characterized cohort albeit with some missing data (mitigated by imputation). They suggest that South Asian women should have more stringent GDM diagnostic criteria (fasting glucose 5.2 and 2 h post-OGTT level of 7.2) compared to white British women. Because treatment for GDM is safe, effective, and cheap diagnosing and treating more South Asian women may help to reduce their offspring’s propensity to increased adiposity and cardio metabolic risk in later life. Accelerated fetal growth prior to diagnosis of gestational diabetes mellitus: a prospective cohort study of nulliparous women Sovio U 1,2, Murphy HR 3, Smith GC 1,2 1
Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK; 2National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre, Cambridge, UK; 3Norwich Medical School, University of East Anglia, Norwich, UK
Diabetes Care 2016; 39: 982–987
Aims The major complication of GDM is excessive fetal growth, which is associated with short- and long-term adverse outcome, and occurs despite screening and intervention. To determine at which gestational age excessive fetal growth occurs in women with a clinical diagnosis of GDM. Methods Prospective cohort study of 4003 nulliparous women with a singleton pregnancy. Fetal abdominal circumference (AC) and head circumference (HC), were measured by ultrasound at 20 and 28 weeks gestational age. Of these, 167 (4.2%) were diagnosed with GDM at ‡ 28 weeks. Results
HADAR ET AL. diagnosis of gestational diabetes. Earlier screening and intervention (before 28 weeks for gestational diabetes and before 20 weeks for obesity) may enhance the efficacy of interventions to prevent excessive fetal growth. Comment Excessive fetal growth begins even before at-risk women are screened for gestational diabetes, suggesting that current GDM screening programs are probably too late to improve offspring health. Interventions aimed at reducing the risk of LGA in the infants of obese women may need to be implemented even earlier, as fetal growth is already abnormal by 20 weeks among obese women. Analysis of continuous glucose monitoring in pregnant women with diabetes: distinct temporal patterns of glucose associated with large-for-gestational-age infants Law GR 1, Ellison GTH 1, Secher AL 2, Damm P 2, Mathiesen ER 2, Temple R 3, Murphy HR 4, Scott EM 1 1
Division of Epidemiology and Biostatistics, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK; 2Center for Pregnant Women With Diabetes, Departments of Endocrinology and Obstetrics, Rigshospitalet, Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 3Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK; 4Institute of Metabolic Science, University of Cambridge, Cambridge, UK Diabetes Care 2015; 38: 1319–1325
Aims/Objective Despite improvements in maternal glucose control macrosomia, defined as infant birth weight on or above the 90th percentile, remains the commonest complication of type 1 diabetes pregnancy.
At 20 weeks, there were no significant differences in any fetal biometric measurements in women with GDM. At 28 weeks, women with GDM had increased risk of AC > 90th percentile (2.05 [1.37 to 3.07]) and HC:AC ratio < 10th percentile (1.97 [1.30 to 2.99]). Maternal obesity was associated with a similar increase in the AC at 28 weeks. However, this was explained in part by increased AC at 20 weeks combined with a more modest increase in AC growth velocity than was observed with GDM. The combination of GDM and obesity was associated with an almost 5-fold risk of AC > 90th (4.52 [2.98 to 6.85]) and an almost 3-fold risk of HC:AC ratio < 10th percentile (2.80 [1.64 to 4.78]) at 28 weeks. Fetal AC > 90th percentile at 28 weeks was associated with 4-fold risk of macrosomia at birth.
Methods
Conclusion
Results
The babies of obese women who develop gestational diabetes are five times as likely to be excessively large by six months gestation. Excessive growth of the fetal abdominal circumference between 20 and 28 weeks precedes clinical
Among the infants, 54 (46%) were born macrocosmic > 90th percentile. Using conventional CGM metrics, macrosomia was associated with higher time spent hyperglycemic during the second trimester. Functional data analyses
Continuous glucose monitoring (CGM) data from 117 women with pregestational type 1 (n = 89) and type 2 (n = 28) diabetes who participated in two previous randomized controlled trials (Secher AL et al. Denmark, Murphy HR et al. UK). Conventional CGM metrics (standard deviation (SD); percentage time above target; area under the curve (AUC); and glucose variability) and novel functional data analysis was performed on the 759 CGM profiles. Sequential glucose measurements were modeled as trajectories by calculating continuous mathematical functions of glucose measurements. These trajectories were modeled using the technique of fitting B-splines to the repeated CGM glucose measures.
TECHNOLOGY AND PREGNANCY demonstrated that during the first trimester mothers of macrosomic infants had lower midmorning (09:00 to 11:00 h) and early evening (19:00 to 21:30 h) glucose levels, with higher overnight (03:30 to 6:30 h) and midday (11:30 to 17:00 h) glucose levels in the second trimester and higher late evening levels (20:30 to 23:30 h) during the third trimester. Macrosomia was also associated with lower glucose variability during trimester 1 and higher variability during trimester 3 (both P < 0.01). Conclusions This study provides new insight into how temporal glucose control might contribute to macrosomia and illustrates the role of functional data analysis of CGM alongside conventional summary statistics. Comment This study identified statistically significant differences in 12 out of 18 summary measures of CGM data among women with or without LGA infants. The functional data analyses (FDA) are appropriate for the vast time-series data produced by CGM. FDA may increase understanding of how CGM measures can be used for more precise targeting of glycaemic control at specific times of the day and night and for specific gestational ages.
S-87 Results Of the participants, 11.8% of women developed incident diabetes mellitus representing an incident rate of 5.64 cases per 1000 person months. Incident diabetes was inversely associated with lactation intensity at baseline with adjusted hazard ratios of 0.64, 0.54, and 0.46 for mostly formula or mixed/ inconsistent, mostly lactation, and exclusive lactation versus exclusive formula feeding respectively (P trend = 0.016). Timedependent lactation duration was also inversely associated with incident diabetes. Adjusted hazard ratios were 0.55, 0.50, and 0.43 for greater than 2 to 5 months, greater than 5 to 10 months, and greater than 10 months respectively versus 0 to 2 months (P trend = 0.007). Weight change slightly attenuated hazard ratios but the associations remained significant. Conclusion Longer duration and higher intensity of breastfeeding were associated with significant reductions in incidence of type 2 diabetes after GDM pregnancy. Comment Women with gestational diabetes have a 50% to 70% chance of developing type 2 diabetes within the first 5 to 10 years after delivery. Prevention of type 2 diabetes in these women is significant public health challenge and a range of strategies including lifestyle modification programs and pharmacotherapies have been proposed and studied as possible interventions. Lactation is known to improve metabolic parameters including glucose and lipid metabolism and insulin sensitivity. However, until now, the small number of studies assessing the role of lactation in development of type 2 diabetes after GDM has been inconclusive. This well-conducted study suggests that breastfeeding is protective against development of diabetes, at least in the first two years after GDM pregnancy. As a modifiable behavior, it suggests that breastfeeding education and support should form a part of clinical advice about preventing type 2 diabetes following GDM pregnancy.
Lactation and progression to type 2 diabetes mellitus after gestational diabetes mellitus Gunderson EP 1, Hurston SR 1, Ning X 1, Lo JC 1, Crites Y1, Walton D 1, Dewey KG 1, Azevedo RA 1, Young S1, Fox G 1, Elmasian CC 1, Salvador N 1, Lum M 1, Sternfeld B 1, Quesenberry CP 1, for the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy Investigators 1
Kaiser Permanente Northern California and the Permanente Medical Group, Oakland, and University of California Davis, Davis, CA
Ann Intern Med 2015; 163: 889–898
Aims Type 2 diabetes is common after pregnancies complicated by gestational diabetes (GDM). Breastfeeding improves glucose metabolism and may be able to prevent or delay development of type 2 diabetes in these women. We aim to evaluate lactation and the 2 year incidence of diabetes mellitus after GDM pregnancy. Methods In this prospective, observational cohort study, 1035 women with GDM who were enrolled in the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy and delivered singletons at or after 35 weeks gestation were enrolled. Anthropometric measurement, 75 g oral glucose tolerance tests and interviews were done at three time points: six to nine weeks after delivery, and then annually for 2 years. Lactation intensity and duration were assessed prospectively by trained staff, using feeding diaries, telephone calls, and monthly mailed questionnaires.
Metabolic networks and metabolites underlie associations between maternal glucose during pregnancy and newborn size at birth Scholtens DM 1, Bain JR 2,3,4, Reisetter AC1, Muehlbauer MJ 2,3,4, Nodzenski M 1, Stevens RD 2,3,4, Ilkayeva O 2,3,4, Lowe LP 1, Metzger BE 1, Newgard CB 2,3,4, Lowe Jr WL1; for the HAPO Study Cooperative Research Group 1
Feinberg School of Medicine, Northwestern University, Chicago, IL,; 2Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC; 3 Duke Molecular Physiology Institute, Durham, NC; 4Duke University School of Medicine, Durham, NC Diabetes 2016; 65: 2039–2050
Aim Offspring of women with hyperglycemia or diabetes in pregnancy are at high risk of being large-for-gestational
S-88 weight and having higher adiposity. While maternal glucose and offspring birthweight and fatness are linearly related, the mechanisms and metabolic networks underlying these associations are poorly understood. Methods
HADAR ET AL. Epidemiologia y Salud Publica, Madrid, Spain; 4Multidisciplinary Evidence Synthesis Hub, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK Diabetologia 2016; 59: 1403–1411
Targeted and nontargeted gas-chromatography/massspectrometry metabolomics were performed on serum collected at fasting and 1 hour postglucose load during a 76 g oral glucose tolerance test from 400 caucasian women at approximately 28 weeks gestation during the Hyperglycemia and Adverse Pregnancy Outcome Study (HAPO).
Introduction
Results
Meta-analysis and systematic search of major electronic databases, to extract dichotomous and continuous data for risk factors in women with GDM and T2DM.
Amino acids, fatty acids, acylcarnitines, and products of lipid metabolism decreased and triglycerides increased following glucose ingestion. Associations between fasting glucose and metabolites were limited. At 1 hour postglucose load, more associations were significant including amino acids, fatty acids, carbohydrates, lipids, and markers of oxidative stress and insulin resistance. Individual maternal metabolites were not significantly associated with newborn outcomes after adjustment for false discovery rate. However, there were positive association trends between maternal fasting and 1 h triglycerides, 1 h fructose, gluconic acid, and hexitols. Network analyses modeling metabolite correlations elucidated collective associations of multiple classes of metabolic fuels with newborn size and adiposity, including acylcarnitines, fatty acids, carbohydrates, and organic acids. Conclusions Broad-scale association of fuel metabolites with maternal glucose is evident during pregnancy. Newborn birthweight and adiposity are potentially influenced by maternal metabolites. Comment Pregnancy necessitates significant maternal metabolic adaptations. This is the largest study to characterize the metabolome of the pregnant woman, and the first to examine maternal metabolites pre- and postglucose load. The results of the study suggest that metabolites other than glucose are likely to contribute to fetal growth and adiposity. Further targeted assays and characterization of the metabolomes of different groups of pregnant women are warranted in order to improve our understanding of the contribution of specific metabolites or metabolite networks to maternal and infant phenotypes. Quantification of the T2DM risk in women with GDM: systematic review and meta-analysis of 95,750 women Rayanagoudar G 1, Hashi AA 1, Zamora J 1,2,3, Khan SK 1,4, Hitman AG 1, Thangaratinam S1,4 1
Women’s Health Research Unit, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK; 2Clinical Biostatistics Unit, Hospital Ramon y Cajal, Madrid, Spain; 3CIBER
The current meta-analysis aimed to quantify the risk of progression to T2DM among women with previous GDM, focusing on maternal and pregnancy-related risk factors. Design
Results From 5966 citations, 178 studies were evaluated and 39 (22 prospective and 17 retrospective cohort) studies among 95,750 women included for analysis. The duration of follow-up varied from 6 weeks to 20 years after birth. High body mass index (BMI) doubled the overall risk (relative risk (RR) = 1.95; 1.60–2.31), according to BMI: overweight (BMI > 25 Kg/m2; relative risk RR = 3.18, 1.96–5.16), obese (BMI > 27 kg/m2; RR = 2.52, 1.69–3.74), and morbid obese (BMI > 30 kg/m2; RR = 2.85, 2.21–3.69). Additional maternal risk factors included: familial diabetes (RR = 1.70, 1.47– 1.97), nonwhite ethnicity (RR = 1.49, 1.14–1.94), and older age (RR = 1.20, 1.09–1.34). Increased levels of fasting (RR = 3.57; 2.98–4.04), 1 h (RR = 3.05, 2.40–3.63), 2 h (RR = 3.46, 2.60–4.10), and 3 h (RR = 3.2, 2.54–3.75) glucose levels after OGTT and high HbA1c (RR = 2.56, 2.00–3.17) were also associated with an increased risk of future diabetes. Women who required insulin were more likely to develop T2DM (RR = 3.66, 2.78–4.82) compared with those without insulin. Multiparity compared with nulliparity (RR = 1.23, 1.01–1.50) and pregnancy complications such as hypertensive disorders (RR = 1.38, 1.32–1.45) and preterm delivery (RR = 1.81, 1.35–2.43) were associated with a higher risk for future T2DM. Gestational weight gain, birthweight, macrosomia, and breastfeeding were not found as significant risk factors for future T2DM in this study. Conclusion Current prediction models for T2DM should be updated and validated by including the factors identified in this metaanalysis. Comment Factors specific to pregnancy such as glycemic control and gestational age at GDM onset were associated with future onset of type 2 diabetes in addition to the conventional risk factors of maternal BMI, ethnicity, and family history. The authors propose two previously unreported risk factors – gestational hypertensive disorders and preterm delivery. There was no added risk for T2DM among women with high weight gain during pregnancy.
TECHNOLOGY AND PREGNANCY
Interestingly, many studies, including that of Gunderson et al., have shown a reduced T2DM risk among women who breastfed, but this was not demonstrated here. It should be noted that Gunderson’s data were not included in this review. Maternal body weight and gestational diabetes differentially influence placental and pregnancy outcomes Martino J 1,2, Sebert S1,7, Segura MT 2, Garcı´a-Valde´s L 2, Florido J 3, Padilla MC 3, Marcos A 4, Rueda R 5, McArdle HJ 6, Budge H 1, Symonds ME 1, Campoy C 2 1
Early Life Research Unit, Division of Child Health and Obstetrics & Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK; 2EURISTIKOS Excellence Centre for Paediatric Research, University of Granada, Granada, Spain; 3Department of Obstetrics and Gynaecology, University of Granada, Granada, Spain; 4Immunonutrition Research Group, Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition, Spanish National Research Council, Madrid, Spain; 5Abbott Nutrition, Granada, Spain; 6The Rowett Institute of Nutrition and Health, University of Bucksburn, Aberdeen, UK; 7Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland
S-89 energy sensing and oxidative stress, were primarily affected by maternal obesity as mammalian target of rapamycin (mTOR) was reduced, whereas markers of oxidative stress (SIRT-1 and UCP2) were upregulated. In placenta from obese women with GDM, gene expression for adenosine monophosphate activated protein kinase (AMPK) was also reduced, whereas the downstream regulator of mTOR, p70S6KB1 was raised. Conclusion Placental gene expression is sensitive to both maternal BMI and GDM, which affects placental triglyceride content, energy sensing factors, and oxidative stress levels. Overall, maternal obesity, but not GDM, contributed to greater placental weight, whereas placental adaptation was demonstrated in markers of energy sensing for both groups. Comment These findings indicate an adaptive placental response to increased BMI, in line with the physiological role of mitochondria in regulating cellular adenosine triphosphate (ATP) and adenosine monophosphate (AMP) concentrations. Although the placenta is a source of plasma leptin, which can be stimulated by obesity and GDM – the investigators did not demonstrate differences in leptin gene expression, suggesting that adipocytes, rather than the placenta, are the main origin of differences in plasma leptin. Plasma leptin concentrations were raised in cord blood of infants born to obese and obese GDM mothers. This could reflect increased transplacental substrate supply from raised maternal plasma glucose acting through fetal insulin to promote fetal fat deposition. Further studies are exploring potential long-term implications of obesity and diabetes in offspring neurodevelopment through functional measurements.
Journal of Clinical Endocrinology and Metabolism 2016; 101: 59–68
Introduction The aim of this study was to determine whether maternal BMI and/or GDM influence the placental homeostasis, metabolic function, and energy balance, by which, pregnancy outcomes can be modified. Design Overall, 135 of the 331 women from the Spanish longitudinal study of Maternal Nutrition and Genetics on the Fetal Adiposity Programming (PREOBE) participated in the current study. Women were classified according to their selfreported prepregnancy BMI as: normal weight (BMI = 18.5– 25 kg/m2, n = 59), overweight (BMI = 25–30 kg/m2, n = 29), and obese (BMI ‡ 30 kg/m2, n = 22) as well as additional 25 women with GDM, also classified as either normal weight GDM (n = 14) or obese GDM (n = 11). The study population underwent maternal, placental, and cord blood molecular analysis as well as anthropometric maternal and neonatal measurements. Results Obese women gained less weight up to 34 weeks compared to those of normal weight and glucose tolerance. Obese women with GDM gained significantly less weight than the Institute of Medicine (IOM) recommendations, in concordance with their lower total energy and carbohydrate intake. Obese women with GDM had higher estimated fetal weight at 34 weeks, but actual birthweight was unaffected by either BMI or GDM. Gene expression for markers of placental
Evaluation of circulating determinants of b-cell function in women with and without gestational diabetes Retnakaran R 1,2,3, Ye C 1, Kramer CK1,2, Connelly PW 2,4, Hanley AJ1,2,5, Sermer M 6, Zinman B 1,2,3 1
Leadership Sinai Centre for Diabetes, Mt Sinai Hospital, Toronto, Ontario, Canada; 2Division of Endocrinology, University of Toronto, Toronto, Ontario, Canada; 3LunenfeldTanenbaum Research Institute, Mt Sinai Hospital, Toronto, Canada; 4Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Canada; 5Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada; 6Division of Obstetrics and Gynecology, Mt Sinai Hospital, Toronto, Canada Journal of Clinical Endocrinology and Metabolism 2016; 101: 2683–2691
Background GDM arises in women in whom there is insufficient b-cell compensation for the gestational insulin resistance, during late pregnancy. The physiology and pathophysiology
S-90 underlying normal and gestational b-cell adaptation are not well understood. Recently, the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) has emerged as a potential negative regulator of b-cell function. The authors aimed to evaluate the role of human placental lactogen (HPL), prolactin, and CMPF in relation to glucose homeostasis and b-cell function. Methods Participating women underwent a 100 g 3 h oral glucose tolerance test (OGTT) in late pregnancy, enabling assessment of glycemic status (OGTT-AUC), b-cell function (Insulin Secretion-Sensitivity Index-2, insulinogenic index/homeostatic model assessment of insulin resistance [HOMA-IR]), insulin sensitivity/resistance (Matsuda index, HOMA-IR), as well as circulating levels HPL, prolactin, and CMPF. Results Overall, data from 395 women were analyzed, with (n = 105) and without (n = 290) GDM. Women with GDM had higher prepregnancy BMI, reduced gestational weight gain, higher glycemia (fasting glucose and OGTT-AUC), lower whole-body insulin sensitivity with greater insulin resistance and poorer b-cell function. Measured hormonal concentrations were similar between women in both groups, even after adjustments for maternal age, ethnicity, familial diabetes, BMI, gestational age, and gestational weight gain (HPL: 2.4 vs. 2.2 mg/L, P = 0.17; prolactin: 99.1 vs. 98.8 ng/mL, P = 0.94; CMPF: 79.8 vs. 79.9 ng/mL, P = 0.98). CMPF was a significant predictor of OGTT-AUC in women with GDM (t = 4.75, P < 0.0001) vs. those without GDM. Moreover, CMPF independently predicts lower Insulin secretion-sensitivity index (t = - 2.28, P = 0.02) and lower insulinogenic index/HOMA-IR (t = - 2.22, P = 0.03) in women with GDM. Conclusion CMPF is a potential determinant of b-cell dysfunction and hyperglycemia in women with GDM. In the future, dietary regulation of CMPF or pharmacological intervention on its receptor may aid in treatment or prevention of GDM. Comment Circulating concentrations of HPL, prolactin, and CMPF do not differ between women with and without GDM. However, CMPF exhibited differential relationships depending on maternal GDM status and is independently associated with poorer b-cell function and higher glycemia in women with GDM. The study does not support the previous observations that serum CMPF levels are different among women with and without GDM, rather that despite similar serum levels, it is associated with adverse effects on b-cell function and glycemia, specifically among women with GDM. The reason for this differential effect depending on GDM status is unclear, but suggests that additional susceptibility factors are required. One possibility is that a genetic tendency to GDM is required for manifestation of the adverse glucoregulatory effects of CMPF.
HADAR ET AL. Adiponectin supplementation in pregnant mice prevents adverse effects of maternal obesity on placental function and fetal growth Aye LMH1, Rosario FJ 1, Powell TL 1,2, Jannson T1,3 1
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO; 2Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO; 3Center for Pregnancy & Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX
Proceedings of the National Academy of Sciences of the USA 2015; 112: 12858–12863
Introduction Obesity in pregnant women is associated with activation of placental insulin and mechanistic target of rapamycin complex 1 (mTORC1) signaling, up-regulation of specific placental amino acid transporters, and fetal overgrowth. Adiponectin (ADN), in contrast to its wellknown insulin-sensitizing effects in skeletal muscle and liver, inhibits insulin and mTORC1 signaling and amino acid transport in human trophoblasts and in pregnant mice. Thus, low circulating ADN in maternal obesity may be causally linked to changes in placental function and increased fetal growth. An orally active ADN receptor agonist (AdipoRon) facilitates exploring the possibility that maternal ADN supplementation may prevent adverse fetal outcomes. Design A mouse model was used to test the hypothesis that ADN supplementation in obese pregnant dams improves maternal insulin sensitivity, restores normal placental insulin signaling and nutrient transport, and prevents fetal overgrowth. After mating, three groups of pregnant animals were studied: lean mice on a control diet infused with placebo (C/PBS), obese mice infused with placebo (OB/PBS), and obese mice with ADN infusion (OB/ADN). To target placental function during the period of rapid fetal growth rather than placental development, all infusions were performed for the last four days of pregnancy, a period that accounts for 70% of murine fetal growth. Results The fetuses of obese dams were 29% heavier than the fetuses of control mice, and this effect was completely reversed by maternal ADN infusion. The increase in fasting leptin, insulin, and C-peptide in obese compared with normal dams was normalized by ADN infusion. Supplementation of ADN in obese mice (over four days) modestly reduced food intake but did not reduce maternal body weight or fat mass. Despite no significant changes in totalADN with maternal obesity, high molecular weight (HMW)-adiponectin (ADN) was markedly reduced in obese dams, while supplementation with ADN increased both total and HMW-ADN. Consequently, the HMW-to-total ADN
TECHNOLOGY AND PREGNANCY ratio was reduced in OB/PBS mice compared with C/PBS mice, and ADN infusion in obese mice normalized this ratio to control levels. Maternal ADN infusion normalized maternal insulin sensitivity, placental insulin/mTORC1 and PPARa signaling and nutrient transport. Conclusion ADN functions as an endocrine link between maternal adipose tissue and fetal growth by regulating placental function. Maternal ADN supplementation reversed the adverse effects of maternal obesity on placental function and fetal growth. Comment The placentas of obese dams exhibit activation of insulin and mTORC1 signaling and greater nutrient transport capacity, in agreement with obese women giving birth to large babies. This study provides novel evidence, that maternal ADN supplementation prevents fetal overgrowth caused by maternal obesity. These findings suggest that interventions aimed at increasing low maternal ADN may improve the fetal metabolic phenotype associated with maternal obesity and/or GDM. Furthermore, the use of synthetic ADN receptor agonists may increase ADN function in maternal and placental tissues to alleviate the adverse metabolic effects of maternal obesity and GDM.
Effect of a behavioural intervention in obese pregnant women (the UPBEAT study): a multicentre, randomised controlled trial Poston L1, Bell R 2, Croker H 3, Flynn AC 4, Godfrey KM 5, Goff L 4, Hayes L 2, Khazaezadeh N 6, Nelson MS 7, Oteng-Ntim E 6, Pasupathy D 1, Patel N 1, Robson SC 8, Sandall J 1, Sanders TAB 4, Sattar N 9, Seed PT1, Wardle J 3, Whitworth MK 10, Briley AL1 1
Division of Women’s Health, King’s College London, St Thomas’ Hospital, London, UK; 2Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK; 3 Health Behaviour Research Centre, Institute of Epidemiology and Health, University College London, London, UK; 4Division of Diabetes and Nutritional Sciences, King’s College London, London, UK; 5MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK; 6Guys and St Thomas’ NHS Foundation Trust, London, UK; 7School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK; 8Institute of Cellular Medicine, Uterine Cell Signalling Group, The Medical School, Newcastle University, Newcastle upon Tyne, UK; 9Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK; 10Maternity Services, Central Manchester University Hospitals NHS Foundation Trust, St Mary’s Hospital, Manchester, UK The Lancet Diabetes & Endocrinology 2015; 3: 767–777
S-91 Introduction Obese women are at risk for complications, including large-for-gestational-age (LGA) infants and offspring’s long term risk of metabolic disease. The aim of this study was to investigate whether a lifestyle intervention addressing nutrition and physical activity could reduce the incidence of GDM and LGA infants. Design UPBEAT (UK Pregnancies Better Eating and Activity Trial) was a randomized controlled trial conducted at eight UK hospitals. Pregnant women older than 16 years, carrying a single fetus, from 15 to 18 + 6 weeks, who were obese (BMI ‡ 30 kg/m2), without chronic disease or concurrent metformin treatment, were randomly assigned to behavioral intervention or standard antenatal care. The intervention was delivered once a week through eight health trainer-led sessions, focusing on dietary modification and physical activity. Primary outcomes were the occurrence of GDM (diagnosed by IADPSG criteria) and incidence of LGA infants ( ‡ 90th customized birthweight centile). Results For the study, 1555 women were recruited, 772 assigned to standard care and 783 to behavioral intervention, ultimately 651 and 629, respectively, completed the OGTT for GDM diagnosis. The primary outcomes did not differ between groups. GDM was reported in 26% of women in the standard care group compared with 25% in the intervention group (RR = 0.96, 0.79– 1.16). LGA was detected in 8% of the standard care and 9% of the intervention group (RR = 1.15, 0.83–1.59). Some improvements were found in secondary outcomes, including: reduced glycemic load, gestational weight gain, maternal sumof-skinfold thicknesses, and increased physical activity. Conclusion Behavioral intervention by nutrition and physical activity in obese pregnant women is not adequate to prevent maternal GDM or infant LGA. Comment Two issues arise on such intervention programs - firstly, large numbers of women had to be approached to meet recruitment target, and secondly a relatively high dropout rate, suggests compliance is a major limitation. The self-reported physical activity falls well below the suggested targets to prevent GDM. The 0.55 kg lower gestational weight gain in the intervention group adds to growing evidence from other studies that a substantial reduction in gestational weight gain is unlikely to be achievable during pregnancy in women with obesity. The recorded incidence of 9% and 12% incidence of LGA was lower than the 15%–20% expected. The IADPSG criteria, increases the proportion of women diagnosed with GDM to approximately 25% (compared to 9% by WHO criteria), but reduces by half the rate of LGA due to follow up and treatment. More effort is needed to prevent obesity in women of reproductive age, prior to conception.
S-92 Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial
HADAR ET AL. Conclusion Metformin does not have a role in reducing the birthweight of offspring’s of obese, nondiabetic, pregnant women.
Chiswick C 1, Reynolds MR 2, Denison F 1, Drake AJ 2, Forbes S 2, Newby D 3, Walker RB 2, Quenby S 4, Wray S 5, Weeks A 5, Lashen H 6, Rodriguez A 7, Murray G 7, Whyte S,1 Norman EJ 1
Comment Metformin given at a median dose of 2000 mg/d to obese and severely obese pregnant women without diabetes, from 12 to 16 weeks until delivery, had no effect on birthweight or neonatal/maternal anthropometry, or any adverse pregnancy outcomes. The lack of efficacy of metformin in reducing birthweight, despite lowering maternal glucose and insulin in midpregnancy, challenge the Pedersen hypothesis that maternal hyperglycemia drives fetal hyperinsulinemia and fetal overgrowth. Maternal lipids might be as, or even more important than glucose, particularly in the presence of maternal obesity. In animals, prenatal metformin improved glucose tolerance, reduced bodyweight and fat mass, despite having only marginal effects on birthweight. Additionally, in the metformin in gestational diabetes study, children of women in the metformin group had lower visceral body fat at two years compared to children of women randomized to insulin, despite similar birthweight. Further follow-up will be essential to provide important long term outcomes on offspring of obese women given metformin during pregnancy.
1
Tommy’s Centre for Maternal and Fetal Health, Medical Research Council Centre for Reproductive Health, Queen’s Medical Research Institute, Edinburgh, UK; 2British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh, UK; 3Chancellor’s Building, Royal Infirmary of Edinburgh, Edinburgh, UK; 4 Division of Reproductive Health, Warwick Medical School, University of Warwick, Coventry, UK; 5Faculty of Health and Life Sciences, First Floor, Liverpool Women’s Hospital, Liverpool, UK; 6Academic Unit of Reproductive and Developmental Medicine, The Jessop Wing, Sheffield, UK; 7 Centre for Population Health Sciences, Teviot Place, Edinburgh, UK The Lancet Diabetes & Endocrinology 2015; 3: 778–786
Introduction Maternal obesity incurs on the child a predisposition for obesity, with high birthweight as a marker for future risk. A body of evidence implicates insulin resistance and hyperglycemia as the mechanism by which maternal obesity causes excessive neonatal birthweight. The aim was to test the hypothesis that the insulin sensitizing drug metformin would reduce birthweight when given to obese women during pregnancy.
Metformin versus placebo in obese pregnant women without diabetes mellitus (MOP trial) Syngelaki A 1,4, Nicolaides KH 1, Balani J 2, Hyer S 2,3, Akolekar R 1, Kotecha R 1, Pastides A 1, Shehata H 3 1
Design This was a randomized, double-blind, placebo-controlled trial at 15 UK hospitals. Eligible women were nondiabetic, aged ‡ 16 years, with BMI ‡ 30 kg/m2, between 12 and 16 weeks with no pregnancy complications, chronic disease, or medical therapy. Participants were randomized to either metformin (in escalating doses of 500 mg, from 1 to 5 times a day) versus placebo. The primary outcome was Z-score corresponding to the gestational age, parity, sex-standardized birthweight percentile of live born infants. Results The 449 participants were randomized to either placebo (n = 223) or metformin (n = 226), with 434 (97%) included in the intention-to-treat analysis. Baseline demographics, medical history, and maternal anthropometry were similar between groups, with mean BMI of 37.7 kg/m 2. Mean birthweight at delivery was 3463 – 660 g in the placebo group and 3462 – 548 g in the metformin group, with similar proportions of Z-score for birthweight percentile and LGA infants (17% and 14%) between the groups. However, fasting glucose and insulin resistance was lower in women in the metformin group at 28 weeks, but with no differences at 36 weeks and no effect on anthropometric variables, maternal weight gain or development or onset of GDM.
Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK; 2Departments of Endocrinology, Epsom and St. Helier University Hospitals NHS Trust, London, UK; 3Maternal Medicine, Epsom and St. Helier University Hospitals NHS Trust, London, UK; 4 Department of Fetal Medicine, Medway Maritime Hospital, Gillingham, Kent, UK New England Journal of Medicine 2016; 374: 434–443
Introduction The Metformin in Obese Nondiabetic Pregnant Women (MOP) trial was designed to test the hypothesis that metformin, as compared with placebo, would be associated with a lower birth weight when administered to obese pregnant women without diabetes. Design Investigators randomly assigned women without diabetes, with a BMI > 35 kg/m2 at 12 to 18 weeks of gestation with a singleton fetus to receive either metformin or placebo. All the women received standardized personal advice on healthy eating, with an emphasis on low-glycemic-index foods, and were encouraged to exercise for 30 min/d. The primary outcome measure was the median neonatal birth-weight Z-score (difference between observed and expected birth weight, at or beyond 24 weeks, with adjustment for gestational age, divided by the fitted standard deviation).
TECHNOLOGY AND PREGNANCY Results A total of 1071 women were assessed for eligibility, 227 were excluded and 450 (53.3%) consented for participation. After randomization, 50 women (23 women in the metformin group and 27 in the placebo group) withdrew consent. Maternal age was higher in the metformin group than in the placebo group. There were no significant differences between the metformin group and the placebo group in the median neonatal birth-weight Z-score, the incidence of LGA neonates or the incidence of adverse fetal or neonatal outcomes. However, maternal gestational weight gain and incidence of preeclampsia were lower in the metformin group. Women in the metformin group had higher rates of side effects (nausea, vomiting, diarrhea, and headache), due to which 17.6% stopped metformin and 41.8% reduced the dose. Regardless of side effects, adherence to the study regimen (more than half of tablets consumed) was good in nearly 80% of the women. Conclusion In pregnant obese women without diabetes, prophylactic daily therapy with 3 g of metformin from 12 to 18 weeks of gestation until delivery was associated with reduced maternal gestational weight gain, but not with a lower neonatal birth weight.
S-93 Comment Daily administration of metformin, from 12 to 18 weeks until delivery, does not reduce birthweight or LGA among obese non-diabetic women. However, it was associated with less maternal gestational weight gain and a lower incidence of preeclampsia. To date, most metformin interventions focused on women with polycystic ovaries, with four randomized trials describing no effect on birthweight, but less gestational weight gain and conflicting results on preeclampsia. The EMPOWaR trial, discussed above showed no effect of metformin on birthweight, nor on maternal gestational weight gain or preeclampsia. The EMPOWaR trials and MOP differ in several aspects: number of sites (15 vs. 3), ethnicity (white vs. multiracial), BMI cutoff (30 vs. 35 kg/m2), and metformin dose (2 g vs. 3 g). These differences, alongside higher recruitment rate (47% vs. 13%) and metformin adherence (80% vs. 67%) in MOP, may in part explain the different results between these landmark trials.
Author Disclosure Statement The authors have no conflict of interest to declare.
