Accepted Manuscript Title: The influence of maternal BMI and gestational diabetes on pregnancy outcome Author: Kate E Martin Rosalie M Grivell Lisa N Yelland Jodie M Dodd PII: DOI: Reference:
S0168-8227(15)00038-8 http://dx.doi.org/doi:10.1016/j.diabres.2014.12.015 DIAB 6277
To appear in:
Diabetes Research and Clinical Practice
Received date: Revised date: Accepted date:
11-4-2014 21-10-2014 28-12-2014
Please cite this article as: K.E. MARTIN, R.M. GRIVELL, L.N. YELLAND, J.M. DODD, The influence of maternal BMI and gestational diabetes on pregnancy outcome, Diabetes Research and Clinical Practice (2015), http://dx.doi.org/10.1016/j.diabres.2014.12.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TITLE The influence of maternal BMI and gestational diabetes on pregnancy outcome.
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AUTHORS Kate E MARTIN1,2 MBBS
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Jodie M DODD1,2 PhD
55 King William Road
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1. The University of Adelaide, Robinson Institute
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INSTITUTIONAL AFFILIATIONS
Ground Floor, Norwich Centre
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Lisa N YELLAND1 PhD
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Rosalie M GRIVELL1,2 PhD
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AUSTRALIA
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North Adelaide, South Australia 5006
2. Discipline of Obstetrics & Gynaecology Women’s and Children’s Hospital 72 King William Road
North Adelaide, South Australia 5006 AUSTRALIA
CORRESPONDING AUTHOR Dr Kate Martin 1
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The University of Adelaide, Robinson Institute, Discipline of Obstetrics & Gynaecology Women’s and Children’s Hospital 72 King William Road
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North Adelaide, South Australia 5006 AUSTRALIA
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Telephone: +61 8 8161 7619
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Fax: +61 8 8161 7652
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E-mail: [email protected]
GRANT SUPPORT
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Council (NHMRC), Australia (ID 519240).
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This project was funded by a four-year project grant from the National Health and Medical Research
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COMPETING INTERESTS
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JM Dodd is supported through a NHMRC Practitioner Fellowship (ID 627005).
The authors declare that they have no conflict of interest.
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ABSTRACT Aims:
adverse pregnancy outcomes in women who are overweight or obese.
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Methods:
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To evaluate the effect of maternal body mass index (BMI) on gestational diabetes (GDM) and the risk of
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A prospective cohort study nested within the LIMIT randomised controlled trial. A total of 1,030 women were recruited between 10–20 weeks’ gestation, with a BMI >25kg/m2, and were grouped into BMI
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subclasses utilising World Health Organisation criteria. Women underwent a fasting oral glucose tolerance test at 26–28 weeks’ gestation, and a diagnosis of GDM was made if fasting blood glucose was ≥ 5.5
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mmol/L or ≥ 7.8 mmol/L after two hours. Maternal and neonatal health outcomes were evaluated. Results:
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The prevalence of GDM increased with increasing maternal BMI (6.74% overweight vs 13.42% obese subclass 1 vs 12.79% obese subclass 2 vs 20.00% obese subclass 3). Women who were diagnosed with
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GDM were significantly less likely to give birth to an infant with birth weight above 4kg (RR 0.60; 95% CI
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0.36 to 1.00; p=0.05). The need for caesarean delivery (RR 1.27; 95% CI 1.07 to 1.50; p=0.006) and incidence of birth weight >90% (RR 1.38; 95% CI 1.07 to 1.77; p=0.01) was significantly increased in women who were obese, independent of GDM. Conclusion:
Increasing maternal BMI is a significant risk factor for the development of GDM, and our findings demonstrate a considerably higher prevalence than has been previously described. Raised maternal BMI is a risk factor for high infant birth weight, which may be modified by lifestyle intervention.
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Key Words:
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Obesity; Gestational Diabetes; Body Mass Index; Pregnancy
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INTRODUCTION Overweight and obesity are recognised as significant contributors to ill-health and world-wide burden of
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disease,[1] estimated to affect approximately 1.3 billion adults globally.[2] In the Australian obstetric population 34% of women are overweight or obese,[3] although more recent data would suggest that this is
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approaching 50%.[4] These figures are consistent with international data, which indicate 50-60% of women
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are overweight or obese on entering pregnancy.[5-9]
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The developmental over-nutrition hypothesis (also termed the Pederson Hypothesis) was first proposed in 1954[10] in an attempt to explain the relationship between maternal diabetes during pregnancy and fetal
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overgrowth, principally increased adiposity. Under this hypothesis, maternal hyperglycaemia is associated with increased placental transfer of glucose, resulting in fetal hyperglycaemia and increased insulin
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production, the resultant effect, an increase in insulin-mediated fetal growth. The contribution of other fuel substrates, including free fatty acids, triglycerides and amino acids, was also recognised.[10] More recently,
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the hypothesis has been expanded to recognise the potential metabolic impact of maternal obesity.[11]
Increasing maternal body mass index (BMI) is a well recognised risk factor for the development of gestational diabetes,[12-16] the two conditions sharing a similar metabolic milieu characterised by insulin resistance, hyperglycaemia, hyperlipidaemia, and a low-grade state of chronic inflammation, which in turn has been documented to influence the availability and transfer of nutrients to the developing fetus.[11] Furthermore, adipose tissue, far from being an inert tissue, has a critical role in innate immune sensing, the production of varying adipocytokines (leptin, TNF-, IL-6), antagonists to the effect of insulin.[17-22]
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While many similar adverse pregnancy outcomes are observed among women who are obese,[8, 23-25] and in women who are diagnosed with gestational diabetes,[26-29] the relative contributions of maternal body mass index (BMI) and maternal glycaemia and gestational diabetes remains uncertain. Catalano and
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colleagues[30] in an analysis of the HAPO trial data[28] recently demonstrated both independent and cumulative adverse effects of GDM and obesity on pregnancy outcomes. The aim of the present study was
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to evaluate the effect of maternal overweight and obesity and gestational diabetes on adverse pregnancy
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outcomes.
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METHODS
This prospective cohort study is nested within the LIMIT randomised trial, evaluating the effect of an
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antenatal dietary and lifestyle intervention for women who are overweight or obese.[31] The methodology of the LIMIT randomised trial has been described in detail previously.[31] The LIMIT trial recruited women with
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a live singleton pregnancy and a BMI of ≥25 kg/m2 between 10 and 20 weeks’ gestation, at the time of their first antenatal appointment. All women provided written informed consent to participate. Eligible, consenting
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women were randomised using a central telephone randomisation service, and a randomisation schedule
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prepared by non-clinical research staff with balanced variable blocks. Women were randomised to the Dietary and Lifestyle Advice Group or the Standard Care Group. Women in the latter group continued to receive their pregnancy care according to local hospital guidelines and comprise the cohort for this current analysis. Women who are overweight or obese receiving antenatal care according to local hospital guidelines are not routinely provided with lifestyle and behavioural advice. Women were recruited from public maternity hospitals across the South Australian metropolitan area (specifically, Women’s and Children’s Hospital, Lyell McEwin Hospital, and Flinders Medical Centre). Ethics approval was obtained from all sites.
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At the time of trial entry, all women had their height and weight measured, and BMI calculated. Women
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were then categorised according to their BMI as either overweight (BMI 25.0-29.9kg/m2) or obese (BMI >30.0kg/m2), with obesity further classified into subclass 1 (BMI 30.0-34.9kg/m2), subclass 2 (BMI 35.0-
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39.9kg/m2), and subclass 3 (BMI > 40.0kg/m2), utilising World Health Organisation criteria.[32]
To coincide with routine antenatal testing, all women were offered a fasting oral glucose tolerance test
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(OGTT) at 26 – 28 weeks’ gestation. If an OGTT was not undertaken as the initial investigation, an oral glucose challenge test (OGCT) was performed as per routine antenatal care at 26 – 28 weeks’ gestation,
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with progression to an OGTT if abnormal.[33] A diagnosis of GDM was made for results of fasting blood glucose ≥ 5.5 mmol/L or blood glucose ≥ 7.8 mmol/L two hours after a loading dose of carbohydrate (75g
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of glucose), according to the South Australian state-wide perinatal practice guidelines. These guidelines are
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based on the previous ADIPS guidelines, which were current at the time of the trial commencement.[33]
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The cohort assessed in this study is comprised of the women who were randomised to the control group or Standard Care Group of the LIMIT trial. Routine antenatal care of a woman who is diagnosed with GDM includes education by a midwife or diabetic educator regarding diet, home monitoring of blood sugar levels, and referral for treatment as needed.[33] Blood sugar monitoring is initially four times per day aiming for blood glucose between 3.5-5.5mmol/L fasting and 4-7mmol/L two hours after a meal. If good control is achieved then testing may be reduced. Medical treatment is considered if fasting values are ≥ 5.5mmol/L once or more per week, or if postprandial values are ≥7.5mmol/L twice or more per week. It is routine care to plan for delivery at 38+0 weeks in women with poor glycaemic control, polyhydramnios or suspected macrosomia, and at term in women with no spontaneous onset of labour.[33] 7
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Clinical outcomes considered included pre-eclampsia (in accordance with recognised Australasian Society for the Study of Hypertension in Pregnancy criteria)[34]; need for induction of labour; caesarean birth; infant
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macrosomia (defined as birth weight above 4000grams); gestational age at birth; large for gestational age (defined as infant birth weight ≥90% for gestational age); and admission to the neonatal intensive care unit.
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Outcomes were abstracted from the woman and infant’s case notes after birth by a research assistant.
Statistical analyses were performed with the use of SAS software, version 9.3 (Cary, NC, USA), to evaluate
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the proportion of women with and without GDM, and the proportion of women experiencing each clinical outcome of interest by both BMI category and presence or absence of GDM. The effect of BMI category
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(overweight or obese) on GDM, and the effect of both BMI and GDM on each clinical outcome, was assessed using log binomial regression models. Results are presented as relative risks (RR) with 95%
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confidence intervals. Where there was no significant interaction identified between BMI and GDM on the outcomes considered, the interaction term was removed from the model and the overall effect of BMI and
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GDM on the risk of each outcome was estimated. A p value of less than 0.05 was considered to indicate
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statistical significance (2-sided).
RESULTS
During the study period, a total of 1,030 women were included in the cohort for this analysis, with 445 (43.20%) categorised as overweight, and 585 (56.80%) as obese. Of the women with BMI >30kg/m2, 298 (28.93%) were obese subclass 1, 172 (16.70%) obese subclass 2, and 115 (11.17%) obese subclass 3. A total 709 women underwent an OGTT (68.8%) and 321 women underwent an OGCT (32.2%). Gestational diabetes was diagnosed in 115 women (11.17%), with the baseline characteristics of women at the time of pregnancy booking and clinical outcomes presented by BMI and GDM in Table 1. The incidence of 8
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gestational diabetes increased with increasing maternal BMI; 6.74% overweight vs 13.42% obese subclass 1 vs 12.79% obese subclass 2 vs 20.00% obese subclass 3 (Figure 1). Women who were obese were twice as likely to develop GDM compared with women who were overweight (RR 2.16; 95% CI 1.45 to
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3.21; p=0.0002).
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There were no statistically significant interactions identified between maternal BMI and gestational diabetes
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for the clinical outcomes of interest, except for gestational age at delivery (GA) (Table 2). Women who were obese were significantly more likely to require caesarean birth (RR 1.27; 95% CI 1.07 to 1.50; p=0.006),
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and deliver a large for gestational age (LGA) infant (RR 1.38; 95% CI 1.07 to 1.77; p=0.01), independent of GDM. Women who were diagnosed with gestational diabetes were significantly less likely to give birth to an
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infant with birth weight above 4kg (RR 0.60; 95% CI 0.36 to 0.1.00; p=0.05), independent of BMI (Figure 2). Both women who were obese and those who had GDM were more likely to deliver at an earlier gestational
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age, and the interaction between GDM and obesity was significant (0.005). The reduction in gestational age attributable to GDM and obesity was similar. Induction of labour was not significantly increased regardless
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of BMI or GDM. Infants of women who were diagnosed with GDM were more likely to require admission to
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the neonatal intensive care unit (NICU) (RR 2.41; 95% CI 1.04, 5.61; p=0.04), independent of maternal BMI. There was a trend towards increased admission to NICU in the infants of women who were obese (RR 2.42; 95% CI 0.98 to 5.99; p=0.06) compared with women who were overweight, independent of GDM.
DISCUSSION
The findings of our prospective nested cohort study, involving over 1,000 women who were overweight or obese on entering pregnancy, indicate that the risk of gestational diabetes increases with increasing maternal body mass index. The estimated effects of maternal BMI and gestational diabetes on the risk of our pre-specified clinical outcomes were independent, with the exception of gestational age at delivery. 9
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Women who were obese were significantly more likely to require a caesarean birth and deliver a LGA infant when compared with women who were overweight. Women with gestational diabetes were significantly less likely to give birth to a macrosomic infant and more likely to have their infant admitted to intensive care
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compared with women without gestational diabetes.
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The need for caesarean delivery and the incidence of LGA was significantly increased in women who were
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obese when compared with women who were overweight, independent of the presence of GDM. This is consistent with previous reports of increased large for gestational age infants in women with a high
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maternal BMI independent of glycaemic status.[24, 35] In previous literature many other adverse pregnancy outcomes, including hypertensive disorders of pregnancy and fetal macrosomia, have been associated with
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increasing maternal BMI,[7, 8, 15, 23, 24, 35] although our study was not powered to demonstrate this for all outcomes. A limitation of our study was the relatively small number of cases observed for some clinical
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outcomes, particularly among women with GDM, which limited our ability to identify interactions between
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maternal BMI and GDM or control for potential cofounders.
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Perhaps surprisingly, our findings indicate that infants born to women who did not have gestational diabetes were significantly more likely to be macrosomic, when compared with women who did have gestational diabetes. Previous studies demonstrating a higher rate of macrosomic infants born to overweight and obese women with gestational diabetes have been conducted in populations where GDM has remained untreated.[30, 35] Our study offered a diagnostic test for GDM to all women, and those women diagnosed with gestational diabetes were routinely referred for education and treatment, including advice to modify their diet and lifestyle. Decreased risk of fetal macrosomia in this group of women is likely to reflect the effect of GDM treatment, consistent with reports from randomised trials indicating that treatment for gestational diabetes reduces both the risk of high infant birth weight and adverse infant health 10
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outcomes.[36-38] The LIMIT study found that the risk of fetal macrosomia was decreased by an antenatal lifestyle intervention in women with a high BMI, regardless of GDM status (RR 0.82; CI 95% 0.68 to 0.99; number needed to treat (NNT) 28; p=0.04).[31] Obesity and GDM share many metabolic characteristics,
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including insulin resistance, hyperinsulinaemia, hyperlipidaemia, and hyperglycaemia, which are known to have a strong, continuous, positive association with birth weight, even below the levels diagnostic for
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GDM.[24, 28, 35] Overweight and obese women share these metabolic characteristics, and likely a degree
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of impaired glucose tolerance, which is thought to increase infant birth weight.[24, 28, 35] At present, women with an increased BMI do not routinely receive dietary and lifestyle advice unless diagnosed with
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GDM, which may account for the higher rate of macrosomic and LGA infants observed in this cohort.
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Gestational age at delivery was significantly less in mothers who were obese as well as those with GDM, and there was a significant interaction between GDM and BMI. Women who were both obese and had
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GDM had a mean reduction in gestational age of greater than one week. This reduction in gestational age does not appear to be attributed to induction of labour, as the rate of induction was not significantly
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increased in either group. The rate of fetal macrosomia was most significantly reduced in women with
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obesity and GDM; this is likely to reflect a treatment effect of GDM as well as the fact that these women delivered significantly earlier.
Our findings indicate a strong association between GDM and BMI, the risk of gestational diabetes increasing with increasing maternal BMI category. While this relationship has been well described,[3, 16, 39, 40] the prevalence identified in our cohort was greater for all women (both overweight or obese) being almost 20% in women with BMI >40kg/m2, more than twice that reported in other Australian data by Callaway and colleagues.[3] Data used by Callaway and colleagues relied on retrospective analysis of routinely collected data, and universal screening for GDM was not conducted in their population. Staff 11
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uncertainty pertaining to the diagnosis of GDM and errors in documentation were also cited as potential causes for the lower prevalence of GDM reported in the Callaway study.[3] The retrospective study by Kim and colleagues[39] also demonstrates a linear increase in GDM prevalence with increasing maternal BMI,
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but again with lower absolute prevalence values of GDM than we identified. Although supporting the doseresponse relationship between BMI and GDM, data from the Kim study are limited by identification of GDM
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diagnosis from birth certificates. Sensitivity of identifying GDM using this method reportedly ranges from
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46% – 83%,[41] and likely underestimates overall prevalence. Our findings are based on prospectively collected data with universal diagnostic testing offered for GDM and clearly demonstrate a much higher
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prevalence of GDM in the overweight and obese obstetric population than previously described (Figure 3).
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The findings of our study have significant public health implications, given the high prevalence of obesity and adverse pregnancy outcomes associated with obesity and GDM, as well as the long term health
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consequences for both women and their infants. Our prospective study utilised standardised data collection with clear parameters for the diagnosis of GDM and accurate measurement of BMI, allowing us to
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confidently report findings of GDM prevalence relating to BMI categories. Larger studies of similar
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populations have been predominantly retrospective in nature, and have identified concerns regarding data collection and documentation.[3, 16, 39, 40]
The findings of our study highlight a higher prevalence of GDM among women who are overweight or obese than has been previously reported, with significant public health implications given the worldwide health burden associated with obesity among women of reproductive age. The reduction in fetal macrosomia we observed in women diagnosed with GDM likely reflects a treatment effect, consistent with the findings of the LIMIT study where macrosomia was reduced by an antenatal lifestyle intervention in women with increased BMI, regardless of GDM status.[31] Our data demonstrated an increased rate of 12
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LGA infants in women who are obese independent of GDM, which is attributable to the shared metabolic characteristics of these two conditions. These findings suggest that greater emphasis should be placed on increased maternal BMI as a risk factor for LGA, and as a target for lifestyle intervention to reduce the risk
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of fetal macrosomia. Previous studies relating to hyperglycaemia in pregnancy have been conducted in women with untreated GDM.[30, 35] The LIMIT study provided universal screening for diagnosis of GDM,
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and treatment was initiated routinely, reflecting current clinical practice. This pragmatic approach allows
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application of our results to everyday obstetric practice and clinical risk assessment.
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Obese with GDM
Obese without GDM
n=85
N=500
Maternal Age (Years): Mean (SD*)
31.9 ( 5.6)
Nulliparous: N (%)
Characteristic
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Table 1: Characteristics at study entry and clinical outcomes according to maternal BMI and gestational diabetes
Overweight with GDM
Overweight without GDM
Total
n=415
n=1030
29.1 ( 5.6)
31.5 ( 4.0)
29.7 ( 5.3)
29.6 ( 5.5)
35 (41.2)
181 (36.2)
12 (40.0)
186 (44.8)
414 (40.2)
. Caucasian
73 (85.9)
469 (93.8)
21 (70.0)
373 (89.9)
936 (90.9)
. Asian
5 (5.9)
6 (1.2)
4 (13.3)
18 (4.3)
33 (3.2)
. Aboriginal or TSI
3 (3.5)
8 (1.6)
0 (0.0)
3 (0.7)
14 (1.4)
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ep te
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Race: N (%)
. Indian/Pak/SriLank
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n=30
4 (4.7)
9 (1.8)
4 (13.3)
17 (4.2)
34 (3.4)
0 (0.0)
8 (1.6)
1 (3.3)
4 (1.0)
13 (1.3)
13 (15.3)
59 (11.8)
2 (6.7)
44 (10.6)
118 (11.5)
34 (40.0)
149 (29.8)
8 (26.7)
84 (20.0)
275 (26.7)
Pre-eclampsia or Eclampsia: N (%) 8 (9.4)
29 (5.8)
2 (6.7)
14 (3.4)
53 (5.3)
NICU Admission: N (%)
6 (7.1)
15 (3.0)
1 (3.3)
5 (1.2)
27 (2.6)
Caesarean Delivery: N (%)
39 (45.9)
199 (39.8)
11 (36.7)
130 (31.3)
379 (36.8)
Induction of Labour: N (%)
34 (40.0)
180 (36.0)
13 (43.3)
135 (32.5)
362 (35.2)
Birth Weight >= 4.0kg: N (%)
12 (14.1)
104 (20.1)
2 (6.7)
77 (18.6)
195 (18.9)
Large for gestational age: N (%)
22 (25.9)
117 (23.4)
2 (6.7)
75 (18.1)
216 (21.0)
GA at delivery (weeks): Mean(SD*) 38.0 (2.3) * Standard deviation
39.34 (1.8)
39.3 (1.5)
39.5 (1.5)
N/A
. Other Smoker: N (%)
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Family History of Diabetes: N (%)
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Table 2: Effect of maternal BMI and GDM on pregnancy outcomes Outcome
Relative Risk (95% CI) P value
Pre-eclampsia or Eclampsia - BMI x GDM Interaction
0.81
- Obese vs Overweight
1.67 (0.94, 2.98)
0.08
- GDM vs No GDM
1.69 (0.87, 3.28)
0.12
- Obese vs Overweight
2.42 (0.98, 5.99)
0.06
- GDM vs No GDM
2.42 (1.04, 5.61)
0.04
Caesarean Delivery 0.95
- Obese vs Overweight
1.27 (1.07, 1.50)
- GDM vs No GDM
1.16 (0.92, 1.45)
Induction of Labour
0.21 0.49
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- BMI x GDM Interaction
0.006
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- BMI x GDM Interaction
1.08 (0.91, 1.29)
0.35
- GDM vs No GDM
1.17 (0.92, 1.48)
0.21
- Obese vs Overweight - GDM vs No GDM
0.28
0.60 (0.36, 1.00)
0.05
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Large for GA
0.39
1.15 (0.89, 1.49)
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- BMI x GDM Interaction
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- Obese vs Overweight Birth Weight >= 4.0kg
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0.89
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- BMI x GDM Interaction
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NICU Admission
- BMI x GDM Interaction
. 0.13
- Obese vs Overweight
1.38 (1.07, 1.77)
0.01
- GDM vs No GDM
0.95 (0.65, 1.38)
0.78
GA at delivery* (wks)
- BMI x GDM Interaction
. 0.005
- Obese vs Overweight
-0.72 (-1.09, -0.34)
0.0002
- GDM vs No GDM
-0.79 (-1.17, -0.41)
S0168-8227(15)00038-8 http://dx.doi.org/doi:10.1016/j.diabres.2014.12.015 DIAB 6277
To appear in:
Diabetes Research and Clinical Practice
Received date: Revised date: Accepted date:
11-4-2014 21-10-2014 28-12-2014
Please cite this article as: K.E. MARTIN, R.M. GRIVELL, L.N. YELLAND, J.M. DODD, The influence of maternal BMI and gestational diabetes on pregnancy outcome, Diabetes Research and Clinical Practice (2015), http://dx.doi.org/10.1016/j.diabres.2014.12.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TITLE The influence of maternal BMI and gestational diabetes on pregnancy outcome.
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AUTHORS Kate E MARTIN1,2 MBBS
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Jodie M DODD1,2 PhD
55 King William Road
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1. The University of Adelaide, Robinson Institute
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INSTITUTIONAL AFFILIATIONS
Ground Floor, Norwich Centre
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Lisa N YELLAND1 PhD
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Rosalie M GRIVELL1,2 PhD
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AUSTRALIA
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North Adelaide, South Australia 5006
2. Discipline of Obstetrics & Gynaecology Women’s and Children’s Hospital 72 King William Road
North Adelaide, South Australia 5006 AUSTRALIA
CORRESPONDING AUTHOR Dr Kate Martin 1
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The University of Adelaide, Robinson Institute, Discipline of Obstetrics & Gynaecology Women’s and Children’s Hospital 72 King William Road
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North Adelaide, South Australia 5006 AUSTRALIA
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Telephone: +61 8 8161 7619
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Fax: +61 8 8161 7652
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E-mail: [email protected]
GRANT SUPPORT
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Council (NHMRC), Australia (ID 519240).
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This project was funded by a four-year project grant from the National Health and Medical Research
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COMPETING INTERESTS
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JM Dodd is supported through a NHMRC Practitioner Fellowship (ID 627005).
The authors declare that they have no conflict of interest.
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ABSTRACT Aims:
adverse pregnancy outcomes in women who are overweight or obese.
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Methods:
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To evaluate the effect of maternal body mass index (BMI) on gestational diabetes (GDM) and the risk of
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A prospective cohort study nested within the LIMIT randomised controlled trial. A total of 1,030 women were recruited between 10–20 weeks’ gestation, with a BMI >25kg/m2, and were grouped into BMI
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subclasses utilising World Health Organisation criteria. Women underwent a fasting oral glucose tolerance test at 26–28 weeks’ gestation, and a diagnosis of GDM was made if fasting blood glucose was ≥ 5.5
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mmol/L or ≥ 7.8 mmol/L after two hours. Maternal and neonatal health outcomes were evaluated. Results:
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The prevalence of GDM increased with increasing maternal BMI (6.74% overweight vs 13.42% obese subclass 1 vs 12.79% obese subclass 2 vs 20.00% obese subclass 3). Women who were diagnosed with
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GDM were significantly less likely to give birth to an infant with birth weight above 4kg (RR 0.60; 95% CI
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0.36 to 1.00; p=0.05). The need for caesarean delivery (RR 1.27; 95% CI 1.07 to 1.50; p=0.006) and incidence of birth weight >90% (RR 1.38; 95% CI 1.07 to 1.77; p=0.01) was significantly increased in women who were obese, independent of GDM. Conclusion:
Increasing maternal BMI is a significant risk factor for the development of GDM, and our findings demonstrate a considerably higher prevalence than has been previously described. Raised maternal BMI is a risk factor for high infant birth weight, which may be modified by lifestyle intervention.
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Key Words:
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Obesity; Gestational Diabetes; Body Mass Index; Pregnancy
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INTRODUCTION Overweight and obesity are recognised as significant contributors to ill-health and world-wide burden of
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disease,[1] estimated to affect approximately 1.3 billion adults globally.[2] In the Australian obstetric population 34% of women are overweight or obese,[3] although more recent data would suggest that this is
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approaching 50%.[4] These figures are consistent with international data, which indicate 50-60% of women
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are overweight or obese on entering pregnancy.[5-9]
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The developmental over-nutrition hypothesis (also termed the Pederson Hypothesis) was first proposed in 1954[10] in an attempt to explain the relationship between maternal diabetes during pregnancy and fetal
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overgrowth, principally increased adiposity. Under this hypothesis, maternal hyperglycaemia is associated with increased placental transfer of glucose, resulting in fetal hyperglycaemia and increased insulin
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production, the resultant effect, an increase in insulin-mediated fetal growth. The contribution of other fuel substrates, including free fatty acids, triglycerides and amino acids, was also recognised.[10] More recently,
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the hypothesis has been expanded to recognise the potential metabolic impact of maternal obesity.[11]
Increasing maternal body mass index (BMI) is a well recognised risk factor for the development of gestational diabetes,[12-16] the two conditions sharing a similar metabolic milieu characterised by insulin resistance, hyperglycaemia, hyperlipidaemia, and a low-grade state of chronic inflammation, which in turn has been documented to influence the availability and transfer of nutrients to the developing fetus.[11] Furthermore, adipose tissue, far from being an inert tissue, has a critical role in innate immune sensing, the production of varying adipocytokines (leptin, TNF-, IL-6), antagonists to the effect of insulin.[17-22]
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While many similar adverse pregnancy outcomes are observed among women who are obese,[8, 23-25] and in women who are diagnosed with gestational diabetes,[26-29] the relative contributions of maternal body mass index (BMI) and maternal glycaemia and gestational diabetes remains uncertain. Catalano and
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colleagues[30] in an analysis of the HAPO trial data[28] recently demonstrated both independent and cumulative adverse effects of GDM and obesity on pregnancy outcomes. The aim of the present study was
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to evaluate the effect of maternal overweight and obesity and gestational diabetes on adverse pregnancy
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outcomes.
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METHODS
This prospective cohort study is nested within the LIMIT randomised trial, evaluating the effect of an
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antenatal dietary and lifestyle intervention for women who are overweight or obese.[31] The methodology of the LIMIT randomised trial has been described in detail previously.[31] The LIMIT trial recruited women with
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a live singleton pregnancy and a BMI of ≥25 kg/m2 between 10 and 20 weeks’ gestation, at the time of their first antenatal appointment. All women provided written informed consent to participate. Eligible, consenting
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women were randomised using a central telephone randomisation service, and a randomisation schedule
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prepared by non-clinical research staff with balanced variable blocks. Women were randomised to the Dietary and Lifestyle Advice Group or the Standard Care Group. Women in the latter group continued to receive their pregnancy care according to local hospital guidelines and comprise the cohort for this current analysis. Women who are overweight or obese receiving antenatal care according to local hospital guidelines are not routinely provided with lifestyle and behavioural advice. Women were recruited from public maternity hospitals across the South Australian metropolitan area (specifically, Women’s and Children’s Hospital, Lyell McEwin Hospital, and Flinders Medical Centre). Ethics approval was obtained from all sites.
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At the time of trial entry, all women had their height and weight measured, and BMI calculated. Women
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were then categorised according to their BMI as either overweight (BMI 25.0-29.9kg/m2) or obese (BMI >30.0kg/m2), with obesity further classified into subclass 1 (BMI 30.0-34.9kg/m2), subclass 2 (BMI 35.0-
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39.9kg/m2), and subclass 3 (BMI > 40.0kg/m2), utilising World Health Organisation criteria.[32]
To coincide with routine antenatal testing, all women were offered a fasting oral glucose tolerance test
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(OGTT) at 26 – 28 weeks’ gestation. If an OGTT was not undertaken as the initial investigation, an oral glucose challenge test (OGCT) was performed as per routine antenatal care at 26 – 28 weeks’ gestation,
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with progression to an OGTT if abnormal.[33] A diagnosis of GDM was made for results of fasting blood glucose ≥ 5.5 mmol/L or blood glucose ≥ 7.8 mmol/L two hours after a loading dose of carbohydrate (75g
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of glucose), according to the South Australian state-wide perinatal practice guidelines. These guidelines are
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based on the previous ADIPS guidelines, which were current at the time of the trial commencement.[33]
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The cohort assessed in this study is comprised of the women who were randomised to the control group or Standard Care Group of the LIMIT trial. Routine antenatal care of a woman who is diagnosed with GDM includes education by a midwife or diabetic educator regarding diet, home monitoring of blood sugar levels, and referral for treatment as needed.[33] Blood sugar monitoring is initially four times per day aiming for blood glucose between 3.5-5.5mmol/L fasting and 4-7mmol/L two hours after a meal. If good control is achieved then testing may be reduced. Medical treatment is considered if fasting values are ≥ 5.5mmol/L once or more per week, or if postprandial values are ≥7.5mmol/L twice or more per week. It is routine care to plan for delivery at 38+0 weeks in women with poor glycaemic control, polyhydramnios or suspected macrosomia, and at term in women with no spontaneous onset of labour.[33] 7
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Clinical outcomes considered included pre-eclampsia (in accordance with recognised Australasian Society for the Study of Hypertension in Pregnancy criteria)[34]; need for induction of labour; caesarean birth; infant
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macrosomia (defined as birth weight above 4000grams); gestational age at birth; large for gestational age (defined as infant birth weight ≥90% for gestational age); and admission to the neonatal intensive care unit.
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Outcomes were abstracted from the woman and infant’s case notes after birth by a research assistant.
Statistical analyses were performed with the use of SAS software, version 9.3 (Cary, NC, USA), to evaluate
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the proportion of women with and without GDM, and the proportion of women experiencing each clinical outcome of interest by both BMI category and presence or absence of GDM. The effect of BMI category
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(overweight or obese) on GDM, and the effect of both BMI and GDM on each clinical outcome, was assessed using log binomial regression models. Results are presented as relative risks (RR) with 95%
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confidence intervals. Where there was no significant interaction identified between BMI and GDM on the outcomes considered, the interaction term was removed from the model and the overall effect of BMI and
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GDM on the risk of each outcome was estimated. A p value of less than 0.05 was considered to indicate
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statistical significance (2-sided).
RESULTS
During the study period, a total of 1,030 women were included in the cohort for this analysis, with 445 (43.20%) categorised as overweight, and 585 (56.80%) as obese. Of the women with BMI >30kg/m2, 298 (28.93%) were obese subclass 1, 172 (16.70%) obese subclass 2, and 115 (11.17%) obese subclass 3. A total 709 women underwent an OGTT (68.8%) and 321 women underwent an OGCT (32.2%). Gestational diabetes was diagnosed in 115 women (11.17%), with the baseline characteristics of women at the time of pregnancy booking and clinical outcomes presented by BMI and GDM in Table 1. The incidence of 8
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gestational diabetes increased with increasing maternal BMI; 6.74% overweight vs 13.42% obese subclass 1 vs 12.79% obese subclass 2 vs 20.00% obese subclass 3 (Figure 1). Women who were obese were twice as likely to develop GDM compared with women who were overweight (RR 2.16; 95% CI 1.45 to
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3.21; p=0.0002).
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There were no statistically significant interactions identified between maternal BMI and gestational diabetes
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for the clinical outcomes of interest, except for gestational age at delivery (GA) (Table 2). Women who were obese were significantly more likely to require caesarean birth (RR 1.27; 95% CI 1.07 to 1.50; p=0.006),
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and deliver a large for gestational age (LGA) infant (RR 1.38; 95% CI 1.07 to 1.77; p=0.01), independent of GDM. Women who were diagnosed with gestational diabetes were significantly less likely to give birth to an
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infant with birth weight above 4kg (RR 0.60; 95% CI 0.36 to 0.1.00; p=0.05), independent of BMI (Figure 2). Both women who were obese and those who had GDM were more likely to deliver at an earlier gestational
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age, and the interaction between GDM and obesity was significant (0.005). The reduction in gestational age attributable to GDM and obesity was similar. Induction of labour was not significantly increased regardless
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of BMI or GDM. Infants of women who were diagnosed with GDM were more likely to require admission to
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the neonatal intensive care unit (NICU) (RR 2.41; 95% CI 1.04, 5.61; p=0.04), independent of maternal BMI. There was a trend towards increased admission to NICU in the infants of women who were obese (RR 2.42; 95% CI 0.98 to 5.99; p=0.06) compared with women who were overweight, independent of GDM.
DISCUSSION
The findings of our prospective nested cohort study, involving over 1,000 women who were overweight or obese on entering pregnancy, indicate that the risk of gestational diabetes increases with increasing maternal body mass index. The estimated effects of maternal BMI and gestational diabetes on the risk of our pre-specified clinical outcomes were independent, with the exception of gestational age at delivery. 9
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Women who were obese were significantly more likely to require a caesarean birth and deliver a LGA infant when compared with women who were overweight. Women with gestational diabetes were significantly less likely to give birth to a macrosomic infant and more likely to have their infant admitted to intensive care
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compared with women without gestational diabetes.
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The need for caesarean delivery and the incidence of LGA was significantly increased in women who were
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obese when compared with women who were overweight, independent of the presence of GDM. This is consistent with previous reports of increased large for gestational age infants in women with a high
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maternal BMI independent of glycaemic status.[24, 35] In previous literature many other adverse pregnancy outcomes, including hypertensive disorders of pregnancy and fetal macrosomia, have been associated with
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increasing maternal BMI,[7, 8, 15, 23, 24, 35] although our study was not powered to demonstrate this for all outcomes. A limitation of our study was the relatively small number of cases observed for some clinical
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outcomes, particularly among women with GDM, which limited our ability to identify interactions between
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maternal BMI and GDM or control for potential cofounders.
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Perhaps surprisingly, our findings indicate that infants born to women who did not have gestational diabetes were significantly more likely to be macrosomic, when compared with women who did have gestational diabetes. Previous studies demonstrating a higher rate of macrosomic infants born to overweight and obese women with gestational diabetes have been conducted in populations where GDM has remained untreated.[30, 35] Our study offered a diagnostic test for GDM to all women, and those women diagnosed with gestational diabetes were routinely referred for education and treatment, including advice to modify their diet and lifestyle. Decreased risk of fetal macrosomia in this group of women is likely to reflect the effect of GDM treatment, consistent with reports from randomised trials indicating that treatment for gestational diabetes reduces both the risk of high infant birth weight and adverse infant health 10
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outcomes.[36-38] The LIMIT study found that the risk of fetal macrosomia was decreased by an antenatal lifestyle intervention in women with a high BMI, regardless of GDM status (RR 0.82; CI 95% 0.68 to 0.99; number needed to treat (NNT) 28; p=0.04).[31] Obesity and GDM share many metabolic characteristics,
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including insulin resistance, hyperinsulinaemia, hyperlipidaemia, and hyperglycaemia, which are known to have a strong, continuous, positive association with birth weight, even below the levels diagnostic for
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GDM.[24, 28, 35] Overweight and obese women share these metabolic characteristics, and likely a degree
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of impaired glucose tolerance, which is thought to increase infant birth weight.[24, 28, 35] At present, women with an increased BMI do not routinely receive dietary and lifestyle advice unless diagnosed with
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GDM, which may account for the higher rate of macrosomic and LGA infants observed in this cohort.
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Gestational age at delivery was significantly less in mothers who were obese as well as those with GDM, and there was a significant interaction between GDM and BMI. Women who were both obese and had
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GDM had a mean reduction in gestational age of greater than one week. This reduction in gestational age does not appear to be attributed to induction of labour, as the rate of induction was not significantly
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increased in either group. The rate of fetal macrosomia was most significantly reduced in women with
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obesity and GDM; this is likely to reflect a treatment effect of GDM as well as the fact that these women delivered significantly earlier.
Our findings indicate a strong association between GDM and BMI, the risk of gestational diabetes increasing with increasing maternal BMI category. While this relationship has been well described,[3, 16, 39, 40] the prevalence identified in our cohort was greater for all women (both overweight or obese) being almost 20% in women with BMI >40kg/m2, more than twice that reported in other Australian data by Callaway and colleagues.[3] Data used by Callaway and colleagues relied on retrospective analysis of routinely collected data, and universal screening for GDM was not conducted in their population. Staff 11
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uncertainty pertaining to the diagnosis of GDM and errors in documentation were also cited as potential causes for the lower prevalence of GDM reported in the Callaway study.[3] The retrospective study by Kim and colleagues[39] also demonstrates a linear increase in GDM prevalence with increasing maternal BMI,
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but again with lower absolute prevalence values of GDM than we identified. Although supporting the doseresponse relationship between BMI and GDM, data from the Kim study are limited by identification of GDM
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diagnosis from birth certificates. Sensitivity of identifying GDM using this method reportedly ranges from
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46% – 83%,[41] and likely underestimates overall prevalence. Our findings are based on prospectively collected data with universal diagnostic testing offered for GDM and clearly demonstrate a much higher
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prevalence of GDM in the overweight and obese obstetric population than previously described (Figure 3).
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The findings of our study have significant public health implications, given the high prevalence of obesity and adverse pregnancy outcomes associated with obesity and GDM, as well as the long term health
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consequences for both women and their infants. Our prospective study utilised standardised data collection with clear parameters for the diagnosis of GDM and accurate measurement of BMI, allowing us to
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confidently report findings of GDM prevalence relating to BMI categories. Larger studies of similar
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populations have been predominantly retrospective in nature, and have identified concerns regarding data collection and documentation.[3, 16, 39, 40]
The findings of our study highlight a higher prevalence of GDM among women who are overweight or obese than has been previously reported, with significant public health implications given the worldwide health burden associated with obesity among women of reproductive age. The reduction in fetal macrosomia we observed in women diagnosed with GDM likely reflects a treatment effect, consistent with the findings of the LIMIT study where macrosomia was reduced by an antenatal lifestyle intervention in women with increased BMI, regardless of GDM status.[31] Our data demonstrated an increased rate of 12
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LGA infants in women who are obese independent of GDM, which is attributable to the shared metabolic characteristics of these two conditions. These findings suggest that greater emphasis should be placed on increased maternal BMI as a risk factor for LGA, and as a target for lifestyle intervention to reduce the risk
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of fetal macrosomia. Previous studies relating to hyperglycaemia in pregnancy have been conducted in women with untreated GDM.[30, 35] The LIMIT study provided universal screening for diagnosis of GDM,
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and treatment was initiated routinely, reflecting current clinical practice. This pragmatic approach allows
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application of our results to everyday obstetric practice and clinical risk assessment.
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Page 16 of 22
ip t cr
Obese with GDM
Obese without GDM
n=85
N=500
Maternal Age (Years): Mean (SD*)
31.9 ( 5.6)
Nulliparous: N (%)
Characteristic
us
Table 1: Characteristics at study entry and clinical outcomes according to maternal BMI and gestational diabetes
Overweight with GDM
Overweight without GDM
Total
n=415
n=1030
29.1 ( 5.6)
31.5 ( 4.0)
29.7 ( 5.3)
29.6 ( 5.5)
35 (41.2)
181 (36.2)
12 (40.0)
186 (44.8)
414 (40.2)
. Caucasian
73 (85.9)
469 (93.8)
21 (70.0)
373 (89.9)
936 (90.9)
. Asian
5 (5.9)
6 (1.2)
4 (13.3)
18 (4.3)
33 (3.2)
. Aboriginal or TSI
3 (3.5)
8 (1.6)
0 (0.0)
3 (0.7)
14 (1.4)
M
ep te
d
Race: N (%)
. Indian/Pak/SriLank
an
n=30
4 (4.7)
9 (1.8)
4 (13.3)
17 (4.2)
34 (3.4)
0 (0.0)
8 (1.6)
1 (3.3)
4 (1.0)
13 (1.3)
13 (15.3)
59 (11.8)
2 (6.7)
44 (10.6)
118 (11.5)
34 (40.0)
149 (29.8)
8 (26.7)
84 (20.0)
275 (26.7)
Pre-eclampsia or Eclampsia: N (%) 8 (9.4)
29 (5.8)
2 (6.7)
14 (3.4)
53 (5.3)
NICU Admission: N (%)
6 (7.1)
15 (3.0)
1 (3.3)
5 (1.2)
27 (2.6)
Caesarean Delivery: N (%)
39 (45.9)
199 (39.8)
11 (36.7)
130 (31.3)
379 (36.8)
Induction of Labour: N (%)
34 (40.0)
180 (36.0)
13 (43.3)
135 (32.5)
362 (35.2)
Birth Weight >= 4.0kg: N (%)
12 (14.1)
104 (20.1)
2 (6.7)
77 (18.6)
195 (18.9)
Large for gestational age: N (%)
22 (25.9)
117 (23.4)
2 (6.7)
75 (18.1)
216 (21.0)
GA at delivery (weeks): Mean(SD*) 38.0 (2.3) * Standard deviation
39.34 (1.8)
39.3 (1.5)
39.5 (1.5)
N/A
. Other Smoker: N (%)
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Family History of Diabetes: N (%)
17
Page 17 of 22
Table 2: Effect of maternal BMI and GDM on pregnancy outcomes Outcome
Relative Risk (95% CI) P value
Pre-eclampsia or Eclampsia - BMI x GDM Interaction
0.81
- Obese vs Overweight
1.67 (0.94, 2.98)
0.08
- GDM vs No GDM
1.69 (0.87, 3.28)
0.12
- Obese vs Overweight
2.42 (0.98, 5.99)
0.06
- GDM vs No GDM
2.42 (1.04, 5.61)
0.04
Caesarean Delivery 0.95
- Obese vs Overweight
1.27 (1.07, 1.50)
- GDM vs No GDM
1.16 (0.92, 1.45)
Induction of Labour
0.21 0.49
M
- BMI x GDM Interaction
0.006
an
- BMI x GDM Interaction
1.08 (0.91, 1.29)
0.35
- GDM vs No GDM
1.17 (0.92, 1.48)
0.21
- Obese vs Overweight - GDM vs No GDM
0.28
0.60 (0.36, 1.00)
0.05
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Large for GA
0.39
1.15 (0.89, 1.49)
pt
- BMI x GDM Interaction
ed
- Obese vs Overweight Birth Weight >= 4.0kg
cr
0.89
us
- BMI x GDM Interaction
ip t
NICU Admission
- BMI x GDM Interaction
. 0.13
- Obese vs Overweight
1.38 (1.07, 1.77)
0.01
- GDM vs No GDM
0.95 (0.65, 1.38)
0.78
GA at delivery* (wks)
- BMI x GDM Interaction
. 0.005
- Obese vs Overweight
-0.72 (-1.09, -0.34)
0.0002
- GDM vs No GDM
-0.79 (-1.17, -0.41)
