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Dc110660 2279.2284Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU)Body composition at 2 years of age ANET A. ROWAN, MBCHB MALCOLM BATTIN, MD that because of continued exposure to nu- LAINE C. RUSH, PHD TRECIA WOULDES, PHD trient excess in utero, the subcutaneous ICTOR OBOLONKIN, BSC WILLIAM M. HAGUE, MD fat stores become overloaded and, thus,the fetus develops leptin and insulin re-sistance and deposits excess nutrients as OBJECTIVE—In women with gestational diabetes mellitus, who were randomized to metfor- ectopic fat (4). Reduced insulin sensitivity min or insulin treatment, pregnancy outcomes were similar (Metformin in Gestational diabetes has been demonstrated in cord blood [MiG] trial). Metformin crosses the placenta, so it is important to assess potential effects on of infants exposed to maternal hypergly- growth of the children.
cemia (5). In a similar manner, infants of RESEARCH DESIGN AND METHODS—In Auckland, New Zealand, and Adelaide, obese women, who are also exposed to nu- Australia, women who had participated in the MiG trial were reviewed when their children were trient excess, have an increased fat mass at 2 years old. Body composition was measured in 154 and 164 children whose mothers had been birth and have been shown to be insulin randomized to metformin and insulin, respectively. Children were assessed with anthropometry, resistant (6). It is possible that metformin bioimpedance, and dual energy X-ray absorptiometry (DEXA), using standard methods.
exposure in utero might lead to improved RESULTS—The children were similar for baseline maternal characteristics and pregnancy insulin action in the fetus, resulting in a outcomes. In the metformin group, compared with the insulin group, children had larger metabolically healthier pattern of growth, mid-upper arm circumferences (17.2 6 1.5 vs. 16.7 6 1.5 cm; P = 0.002) and subscapular with more subcutaneous fat stores devel- (6.3 6 1.9 vs. 6.0 6 1.7 mm; P = 0.02) and biceps skinfolds (6.03 6 1.9 vs. 5.6 6 1.7 mm; P = oping and less ectopic fat (4,7,8).
0.04). Total fat mass and percentage body fat assessed by bioimpedance (n = 221) and DEXA (n = The aim of The Offspring Follow-Up 114) were not different.
(TOFU) study at 2 years of age was to compare body composition in children of Children exposed to metformin had larger measures of subcutaneous women who participated in the MiG trial fat, but overall body fat was the same as in children whose mothers were treated with insulinalone. Further follow-up is required to examine whether these ﬁndings persist into later life and, in particular, to compare measures of and whether children exposed to metformin will develop less visceral fat and be more adiposity. Our hypothesis was that chil- insulin sensitive. If so, this would have signiﬁcant implications for the current pandemic of dren whose mothers had been random- ized to metformin treatment would havereduced central adiposity compared with Diabetes Care 34:2279–2284, 2011 children whose mothers had been ran-domized to insulin.
(MiG) trial prospectively compared RESEARCH DESIGN AND pregnancy outcomes in women with Metformin crosses the placenta in METHODS—In the MiG trial, 751 gestational diabetes mellitus (GDM) ran- signiﬁcant amounts, so although neonatal women with GDM who required medi- domized to either metformin (plus sup- outcomes are reassuring, it is important to cation to control their hyperglycemia plemental insulin as required) or insulin examine longer term outcomes, such as were randomized to either metformin or treatment. The primary outcome, a com- body composition in childhood (2). It is insulin treatment; their pregnancy out- posite of neonatal complications, was not known that offspring of women with di- comes have been reported (1). From two signiﬁcantly different between the treat- abetes have an increased fat mass at birth recruiting sites in Auckland, New Zealand, ment arms (1). Secondary outcomes, in- but not an increase in fat-free mass (FFM) and one site in Adelaide, Australia, women cluding body anthropometry at birth, (3). An explanation of this ﬁnding may be who had consented to further follow-upwere contacted by telephone at approxi- mately the time of the child's second birth- From the 1Department of Obstetrics, National Women's Health, Auckland, New Zealand; the 2Centre for Child day to explain the follow-up study and Health Research, Auckland University of Technology, Auckland, New Zealand; the 3Department of to conﬁrm that they were still agreeable Biological Sciences, University of Auckland, Auckland, New Zealand; the 4Department of Pediatrics, Na- to participate. In Auckland, a home visit tional Women's Health, Auckland, New Zealand; the 5Department of Psychological Medicine, University of was arranged for the Auckland, Auckland, New Zealand; and the 6Department of Obstetrics, Women and Children's Hospital, ﬁrst part of the University of Adelaide, Adelaide, Australia.
assessment during which maternal inter- Corresponding author: Janet A. Rowan, [email protected].
views and simple anthropometry mea- Received 7 April 2011 and accepted 26 May 2011.
surements of the mother and child were DOI: 10.2337/dc11-0660. Clinical trial reg. no. ACTRN12605000311651, www.anzctr.org.au.
made. A follow-up appointment was 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. See http://creativecommons.org/ made within 1 to 2 weeks of the home visit licenses/by-nc-nd/3.0/ for details.
to attend the Liggins Institute, University of See accompanying editorial, p. 2329.
Auckland, for the child to have a physical DIABETES CARE, VOLUME 34, OCTOBER 2011 MiG TOFU: 2-year-old body composition examination, a neurodevelopmental as-sessment, and a total body dual energyX-ray absorptiometry (DEXA) measure-ment. In Adelaide, women and their chil-dren were invited to the hospital and allthe assessments were performed there.
This follow-up study had ethical approvalat each contributing site, and written in-formed consent was again obtained foreach participant. The study was registeredprior to its initiation under the AustralianNew Zealand Clinical Trials Registry(ACTRN12605000311651).
Questionnaires were completed by trained researchers, including assessmentof the family's socioeconomic conditions,home environment, any drug and alcoholintake, and health of the mother andchild. Diet was assessed by 24-h recalland food frequency questionnaires. Usualactivity of the children was assessed by a24-h activity diary. The child underwent ageneral physical examination by a pediatri-cian and a neurodevelopmental assessmentby a psychologist. The neurodevelopmen-tal ﬁndings and detailed diet and activityassessments will be reported separately.
Anthropometry measurements of the mother and child included weight, height,leg length, head, chest, waist, hip and mid-upper arm circumferences, and biceps,triceps, and subscapular skinfolds. Skin-folds were performed with a Holtain skin-fold caliper (Holtain Ltd., Crymych, U.K.).
The method for each measurement was Figure 1—Offspring followed up from the MiG trial.
based on those used in a New ZealandChildren's Nutrition Survey (http://www.
moh.govt.nz/moh.nsf/0/064234A7283A04 7 8 C C 2 5 6 D D 6 0 0 0 0 A B 4 C / $ F i l e / ankle between the tibial and ﬁbular malleoli Abdominal and thigh regions of interest nzfoodnzchildren.pdf) and detailed in the and at the posterior wrist between the were deﬁned by the criteria of Ley et al.
study manual. Training of study personnel styloid processes of the radius and ulna.
(10) The abdominal fat measure was ob- was undertaken by a single person in The measurements were repeated up to tained from analysis of a region positioned Auckland to maintain consistency across three times until they were stable to with the lower horizontal border on top sites. All measurements were repeated within one ohm. The average resistance of the iliac crest and the upper border twice and the average calculated. A further value was used in the prediction equa- approximately parallel with the junction measurement was made if the difference in tion below. A BIA measurement was un- of the T12 and L1 vertebrae. The sides of measures was .0.5 cm (height and cir- dertaken similarly in the mother, and the this region were adjusted to include the cumferences) or .0.5 mm (skinfolds), FFM was calculated as FFM = 29.53 + maximum amount of abdominal tissue.
and the average of the two closest measures 0.69stature2/resistance + 0.17weight + The thigh measure was obtained by ana- was calculated and used in the analysis.
lyzing an area of identical height placed Hand-to-foot single-frequency (50 If consented to separately, a DEXA over the thighs with the upper horizontal kHz) bioimpedance analysis (BIA; BIM4, whole body scan of the child was per- border positioned immediately below Impedimed, Queensland, Australia) of formed on a Lunar Prodigy 2000 scanner the ischial tuberosities. The lateral mar- the child was performed with the child (software version 4.80 3 6.50, General gins were adjusted to follow the shape of lying supine. Areas on the hand and foot Electric, Madison, WI). Each scan was the thighs. The DEXA FFM was used as where electrodes were to be placed were graded 1, 2, or 3 for quality by a single the criterion for the development of a ﬁrst cleaned with alcohol. The current person in Auckland and a single person in prediction equation for bioimpedanceelectrodes were placed on the hand on the Adelaide. Scans that were graded 3 (poor FFM based on the following predictor distal portion of the second metacarpal quality) were excluded from this analysis.
values: weight, height2/resistance, sex and on the foot over the distal portion As well as total fat, lean, and bone mineral (dummy coded with girls = 0 and of the second metatarsal. The sensing content, an abdominal and thigh area boys = 1), and age. The equation devel- electrodes were placed at the anterior for area fat content was calculated.
oped was as follows: DIABETES CARE, VOLUME 34, OCTOBER 2011 Rowan and Associates The children seen at 2 years of age in the metformin group, but percentage DEXAkg ¼ 0:894 þ 0:421H2= included a smaller proportion of those body fat was not different (Table 3).
R þ 0:268Wt þ 0:338Sex þ 0:064Age of Polynesian ethnicity compared with Body composition measurements at the total MiG population (14 vs. 20%, 2 years of age showed three signiﬁcant (R2 = 0.857, SEE [standard error of the es- P = 0.02). Also, children seen for follow- differences (Table 3). The upper-arm cir- timate] = 0.559 kg), where H is height (cm), up had had a shorter crown-rump length cumference was larger in the metformin R is resistance (V), Wt is weight (kg), Sex at birth (33.0 vs. 33.5 cm, P = 0.005) and group (P = 0.002), and subscapular skin- (0 = girls, 1 = boys), and Age (months) (11).
smaller triceps skinfolds (4.80 vs. 5.15 folds and biceps skinfolds were bigger The bioimpedance and DEXA mea- mm, P = 0.0002) and subscapular skin- (P = 0.02 and P = 0.04, respectively).
sures of the child were performed in the folds (4.95 vs. 5.20 mm, P = 0.07) at birth These results were explored further to morning before morning tea with the than the total group. All other baseline conﬁrm that the differences related to child wearing a T-shirt and dry disposable characteristics of the mothers and chil- treatment. After adjusting for age, sex, dren and trial outcome measures were ethnicity, and maternal glucose control not different between the follow-up during pregnancy, the P values were: Statistical analysis group and the total MiG population upper-arm circumference, P = 0.005; sub- A follow-up rate of 50% was anticipated, (data not shown).
scapular skinfold, P = 0.01; and biceps recognizing that it might be difﬁcult, for In the children seen at 2 years of age, skinfold, P = 0.02. There were no differ- various social reasons, to maintain con- there were no differences between the ences in DEXA measures between the tact with the MiG trial population, as groups in the baseline characteristics of two groups by unadjusted and adjusted others have described and highlighted by the mother at randomization to treatment analysis. This included total and regional the initial 6–8 week postpartum follow- (Table 1). There were also no differences fat measures. Bioimpedance measures also up, which was achieved in 75%.
in pregnancy outcomes between the met- showed no difference between the metfor- Power calculations. A study of 240 chil- formin and insulin follow-up groups, in- min and insulin group in FFM or percent- dren (120 in each arm) would allow de- cluding the MiG trial primary outcome tection of a 2% difference in body fat composite of neonatal complications percent (based on an estimated body fat (31.2 vs. 34.7%, P = 0.97), admission to CONCLUSIONS—This study de- of 24 6 4%) with 97% power and, thus, the neonatal unit (17.5 vs. 18.3%, P = scribes the body composition in a unique allowing a clinically meaningful analysis of 0.97), and admission for .24 h (11.7 population of 2-year-olds whose mothers the groups with respect to body composi- vs. 11.6%, P = 0.98). In addition, there had GDM and were randomized to treat- tion. A study of 37 children in each treat- were no differences between the groups in ment with metformin or insulin during ment arm would have 80% power to measurements at birth, maternal glucose pregnancy. The groups were matched for detect a 2% difference in body fat percent.
control during pregnancy, and rates of baseline maternal characteristics, maternal Continuous variables were examined breast feeding at 6–8 weeks postpartum glycemia, and pregnancy outcomes.
for normal distribution. For all data (Table 2). Follow-up maternal anthropom- Our initial hypothesis was that met- presented, the distributions were normal.
etry was not different between the two formin exposure in utero would be asso- Continuous variables are presented as groups; maternal BIA showed higher FFM ciated with less central fat and, therefore, mean 6 SD. One-way ANOVA was usedto test for differences in group means, and Table 1—Children assessed at age 2 years: the maternal baseline characteristics at post hoc t tests were used to determine randomization to treatment in MiG which groups were different. The signiﬁ-cance level was set at 5%. ANCOVA was used to adjust for height, weight, and age when examining differences in fat massand FFM among ethnic groups.
RESULTS—Of the women recruited At booking (before 20 weeks' gestation) into MiG at the two Auckland sites, 189 of 282 (67%) and 33 of 114 (28.9%) were Gestational age at recruitment (weeks) seen for follow-up. In Adelaide, 101 of 181 (55.8%) were seen, giving a total of 323 women (Fig. 1). Body composition measurements were performed in 318 children, of whom 154 mothers and 164 Chinese and other Southeast Asian mothers had been randomized to metfor- min and insulin treatment during preg- Tertiary education nancy, respectively. A bioimpedance Smoking in pregnancy measurement was performed in 103 and Chronic hypertension 118 children in the metformin and insulin arms, respectively. DEXA measurements Fasting plasma glucose (mmol/L) were performed in 140 children: 114 grade 2-h plasma glucose(mmol/L) 1 and 2 scans were analyzed, 57 in each HbA1c at recruitment (%) treatment arm.
Data expressed as mean 6 SD or n (%). OGTT, oral glucose tolerance test.
DIABETES CARE, VOLUME 34, OCTOBER 2011 MiG TOFU: 2-year-old body composition Table 2—Children assessed at age 2 years: pregnancy outcome data readily release fatty acids and inﬂamma-tory adipocytokines (12). These changesare associated with insulin resistance, as opposed to insulin-sensitive obesity, which is associated with proportionally more healthy subcutaneous fat cells and Gestational age at birth (weeks) less visceral fat (8,13,14). A more insulin- 3,325 6 558 3,356 6 530 sensitive pattern of growth would be a Birth weight percentile plausible consequence of metformin ex- Birth weight below 10th percentile posure in utero, based on our under- Birth weight above 90th percentile standing of metformin action (7). To Head circumference (cm) examine this question further, ongoing Crown-heel length (cm) follow-up will be important to determine Crown-rump length (cm) whether differences persist and to measure Chest circumference (cm) visceral and subcutaneous fat and insulin Abdominal circumference (cm) sensitivity. Longitudinal follow-up is also Mid-upper arm circumference (cm) important in that postnatal inﬂuences on Triceps skinfold thickness (mm) growth may override any effect of metfor- Subscapular skinfold thickness (mm) min exposure during late pregnancy (15).
Ponderal index (birth weight [g] 3 There are no other similar studies for 100/crown-heel length [cm]3) comparison, so our data are novel. There are studies looking at subsequent growth Glycemic control from randomization until delivery of children whose mothers have had di- Mean fasting capillary glucose abetes in pregnancy (16–20). Compared Tertile 1 (mean 4.6 6 0.3 mmol/L) with children whose mothers did not Tertile 2 (mean 5.1 6 0.1 mmol/L) have diabetes, they were more likely to Tertile 3 (mean 5.9 6 0.6 mmol/L) be obese and have features of insulin re- Mean postprandial capillary glucose sistance, which is felt to be the result of Tertile 1 (mean 5.6 6 0.2 mmol/L) both genetic and intrauterine and post- Tertile 2 (mean 6.2 6 0.2 mmol/L) natal environmental factors. It is possible Tertile 3 (mean 7.2 6 0.7 mmol/L) that there are critical windows where in- tervention might improve these outcomes Gestational hypertension (21). There are two randomized trials showing that treatment of mild GDM Infant feeding 6–8 weeks postpartum (predominantly with diet) compared with standard pregnancy care was associ- ated with improved pregnancy outcomes Both breast and bottle (22,23), but initial follow-up of children in one trial did not show a signiﬁcant dif- Data expressed as mean 6 SD or n (%) unless otherwise detailed.
ference in BMI at 4–5 years of age (24). Itis unclear whether the intervention in less insulin resistance in the offspring.
of central fat may not be adequate for pregnancy was too late or inadequate or However, we found no differences be- determining the potential effects of in whether a difference will appear at subse- tween groups in central fat measures, utero exposure to metformin. The central quent follow-up. More detailed measures total fat mass, percentage body fat, or fat measures used in this study provided a of visceral fat in those children would also central-to-peripheral fat as measured by combined measure of subcutaneous and be of interest. A further study has shown waist-to-hip ratio and DEXA-calculated visceral fat, so further studies will be that treating women with GDM resulted abdominal-to-thigh fat ratios. Instead, we needed to conﬁrm whether the children in fewer overweight children at 5–7 years found that the children who were exposed exposed to metformin have less visceral fat.
of age compared with children whose to metformin in utero had larger upper- Size and location of fat cells are mothers had elevated glucose tolerance arm circumferences and bigger biceps and important predictors of insulin resistance test results during pregnancy but did subscapular skinfolds. This suggests that and adverse metabolic consequences of not reach the threshold for a diagnosis exposure to metformin in utero has led to obesity (4,8,12). Subcutaneous fat cells and treatment of GDM (25). These data more fat being stored in subcutaneous provide an important physiological store also highlight the need for further studies sites, which may in turn mean there is less of extra nutrients. They have a limited ca- looking at how different treatments for ectopic or visceral fat in these children.
pacity and are normally under homeo- GDM inﬂuence long-term outcomes to These ﬁndings are important for two static regulation, providing feedback better understand how to optimize the reasons: ﬁrst, they suggest that maternal about food intake and satiety. In situa- health of future generations.
metformin treatment during pregnancy tions of ongoing excessive nutrient in- The major strength of this follow-up may lead to a more favorable pattern of fat take, the adipocytes become large and study is that the offspring were well distribution for exposed children; sec- dysfunctional and excess fat is deposited matched, enabling valid comparisons ond, they suggest that simple measures in visceral adipocyte depots, which between treatment groups. Also, body DIABETES CARE, VOLUME 34, OCTOBER 2011 Rowan and Associates Table 3—Two-year-old measurements In conclusion, 2-year-old offspring of women with GDM, who were exposed tometformin in utero, had larger subscapular and biceps skinfolds but showed no dif- ference in total or percentage body fat Adjusted age (months) compared with children whose mothers Sex: male/female (n) were treated during pregnancy with insulin alone. Whether this will translate to a more insulin-sensitive pattern of growth requires Leg length (cm) (height minus further examination. The ﬁndings are re- assuring for clinicians who are using met- Head circumference (cm) formin during pregnancy.
Chest circumference (cm) Upper-arm circumference (cm) Waist circumference (cm) Acknowledgments—This study was sup- Hip circumference (cm) ported by funding from the Health Research Waist-to-hip ratio Council, New Zealand; the Auckland Medical Triceps skinfold thickness (mm) Research Council; the Evelyn Bond Trust, Subscapular skinfold thickness (mm) Auckland; and the National Health and Med- ical Research Council, Australia.
Biceps skinfold thickness (mm) W.M.H. was an invited speaker at the Merck European Association for the Study of Diabe- tes symposium on metformin in Stockholm, Abdominal fat (g) Sweden, September 2010. No other potential conﬂicts of interest relevant to this article were Abdominal-to-thigh fat ratio J.A.R. researched and interpreted data and Lean body mass (g) wrote the manuscript. E.C.R. researched and Bone mineral content (g) analyzed data, contributed to the writing of the manuscript, and reviewed and edited the manuscript. V.O. analyzed data, contributed to the methods, and reviewed the manuscript.
Abdominal fat (% of fat mass) M.B., T.W., and W.M.H. researched data and Thigh fat (% of fat mass) reviewed and edited the manuscript.
Arm fat (% of fat mass) Parts of this study were presented in ab- stract form at the International GDM Meeting, Pasadena, California, 9–11 April 2010; the Inter- national Society of Obstetric Medicine Meeting, Maternal measures at 2-year assessment Melbourne, Australia, 1–2 October 2010; and the Australasian Diabetes in Pregnancy Meeting, Sydney, Australia, 3 –4 September 2010, as well as in talks without abstracts at the International Diabetes in Pregnancy Meeting, Salzburg, Head circumference (cm) Austria, 23–26 March 2011; the Medical Waist circumference (cm) Complications of Pregnancy Meeting, Lon- Upper-arm circumference (cm) don, England, 3–5 November 2010; the Leb- Hip circumference (cm) anese Society of Endocrinology Meeting, Beirut, Triceps skinfold thickness (mm) Lebanon, 13 November 2010; and the Repro- Subscapular skinfold thickness (mm) ductive Biology Meeting, Sydney, New South Biceps skinfold thickness (mm) Wales, Australia, 29–31 August 2010.
Waist-to-hip ratio The authors would like to acknowledge the additional people who performed clinical as-sessments and recorded data through the study: Aida Siegers, Jenny Rafferty, and Mariam Buksh from National Women's Health, Auckland,New Zealand; Suzette Coat from the Universityof Adelaide, Australia; and Jewel Wen, Neil composition was measured by several at birth, compared with the total group.
Snowling, Jennifer Crowley, and Sarah Bristow methods, and the differences found were Otherwise, they were representative of the from the Auckland University of Technology, consistent with a biologically plausible ef- whole group and the study was adequately New Zealand.
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