The influence of maternal BMI and gestational diabetes on pregnancy outcome

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.

ip t

AUTHORS Kate E MARTIN1,2 MBBS

an

Jodie M DODD1,2 PhD

55 King William Road

ed

1. The University of Adelaide, Robinson Institute

M

INSTITUTIONAL AFFILIATIONS

Ground Floor, Norwich Centre

us

Lisa N YELLAND1 PhD

cr

Rosalie M GRIVELL1,2 PhD

Ac ce

AUSTRALIA

pt

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

Page 1 of 22

The University of Adelaide, Robinson Institute, Discipline of Obstetrics & Gynaecology Women’s and Children’s Hospital 72 King William Road

ip t

North Adelaide, South Australia 5006 AUSTRALIA

cr

Telephone: +61 8 8161 7619

us

Fax: +61 8 8161 7652

an

E-mail: [email protected]

GRANT SUPPORT

ed

Council (NHMRC), Australia (ID 519240).

M

This project was funded by a four-year project grant from the National Health and Medical Research

Ac ce

COMPETING INTERESTS

pt

JM Dodd is supported through a NHMRC Practitioner Fellowship (ID 627005).

The authors declare that they have no conflict of interest.

2

Page 2 of 22

ABSTRACT Aims:

adverse pregnancy outcomes in women who are overweight or obese.

cr

Methods:

ip t

To evaluate the effect of maternal body mass index (BMI) on gestational diabetes (GDM) and the risk of

us

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

an

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

M

mmol/L or ≥ 7.8 mmol/L after two hours. Maternal and neonatal health outcomes were evaluated. Results:

ed

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

pt

GDM were significantly less likely to give birth to an infant with birth weight above 4kg (RR 0.60; 95% CI

Ac ce

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.

3

Page 3 of 22

Key Words:

Ac ce

pt

ed

M

an

us

cr

ip t

Obesity; Gestational Diabetes; Body Mass Index; Pregnancy

4

Page 4 of 22

INTRODUCTION Overweight and obesity are recognised as significant contributors to ill-health and world-wide burden of

ip t

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

cr

approaching 50%.[4] These figures are consistent with international data, which indicate 50-60% of women

us

are overweight or obese on entering pregnancy.[5-9]

an

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

M

overgrowth, principally increased adiposity. Under this hypothesis, maternal hyperglycaemia is associated with increased placental transfer of glucose, resulting in fetal hyperglycaemia and increased insulin

ed

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,

Ac ce

pt

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]

5

Page 5 of 22

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

ip t

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

cr

to evaluate the effect of maternal overweight and obesity and gestational diabetes on adverse pregnancy

us

outcomes.

an

METHODS

This prospective cohort study is nested within the LIMIT randomised trial, evaluating the effect of an

M

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

ed

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

pt

women were randomised using a central telephone randomisation service, and a randomisation schedule

Ac ce

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.

6

Page 6 of 22

At the time of trial entry, all women had their height and weight measured, and BMI calculated. Women

ip t

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-

us

cr

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

an

(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,

M

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

ed

of glucose), according to the South Australian state-wide perinatal practice guidelines. These guidelines are

pt

based on the previous ADIPS guidelines, which were current at the time of the trial commencement.[33]

Ac ce

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

Page 7 of 22

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

ip t

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.

us

cr

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

an

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

M

(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%

ed

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

pt

GDM on the risk of each outcome was estimated. A p value of less than 0.05 was considered to indicate

Ac ce

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

Page 8 of 22

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

ip t

3.21; p=0.0002).

cr

There were no statistically significant interactions identified between maternal BMI and gestational diabetes

us

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),

an

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

M

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

ed

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

pt

of BMI or GDM. Infants of women who were diagnosed with GDM were more likely to require admission to

Ac ce

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

Page 9 of 22

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

ip t

compared with women without gestational diabetes.

cr

The need for caesarean delivery and the incidence of LGA was significantly increased in women who were

us

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

an

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

M

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

ed

outcomes, particularly among women with GDM, which limited our ability to identify interactions between

pt

maternal BMI and GDM or control for potential cofounders.

Ac ce

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

Page 10 of 22

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,

ip t

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

cr

GDM.[24, 28, 35] Overweight and obese women share these metabolic characteristics, and likely a degree

us

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

an

GDM, which may account for the higher rate of macrosomic and LGA infants observed in this cohort.

M

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

ed

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

pt

increased in either group. The rate of fetal macrosomia was most significantly reduced in women with

Ac ce

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

Page 11 of 22

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,

ip t

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

cr

diagnosis from birth certificates. Sensitivity of identifying GDM using this method reportedly ranges from

us

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

an

prevalence of GDM in the overweight and obese obstetric population than previously described (Figure 3).

M

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

ed

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

pt

confidently report findings of GDM prevalence relating to BMI categories. Larger studies of similar

Ac ce

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

Page 12 of 22

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

ip t

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,

cr

and treatment was initiated routinely, reflecting current clinical practice. This pragmatic approach allows

Ac ce

pt

ed

M

an

us

application of our results to everyday obstetric practice and clinical risk assessment.

13

Page 13 of 22

References

7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

ip t

cr

us

6.

an

5.

M

4.

ed

3.

pt

2.

Ezzati, M., Lopez, A.D., Rodgers, A., Vander Hoorn, S.Murray, C.J., for the Comparative Risk Assessment Collaborating Group., Selected major risk factors and global and regional burden of disease. Lancet, 2002. 360: p. 1347-1360. Organisation, W.H. WHO obesity and overweight fact sheet (number 311; September 2006): WHO; http://www.who.int/mediacentre/factsheets/fs311/en/print.html. 2006. Callaway, L.K., Prins, J.B., Chang, A.M.McIntyre, H.D., The prevalence and impact of overweight and obesity in an Australian obstetric population. Med J Aust, 2006. 184(2): p. 56-9. Chan, A., Scheil, W., Scott, J., Nguyen, A.M.Sage, L., Pregnancy outcome in South Australia 2009, S.H. Pregnancy Outcome Unit, Editor 2011, Government of South Australia: Adelaide. Ogden, C.L., Carroll, M.D., Kit, B.K.Flegal, K.M., Prevalence of obesity in the United States, 20092010. NCHS Data Brief, 2012(82): p. 1-8. Flegal, K.M., Carroll, M.D., Ogden, C.L.Curtin, L.R., Prevalence and trends in obesity among US adults, 1999-2008. JAMA, 2010. 303(3): p. 235-41. Dodd, J.M., Grivell, R.M., Nguyen, A.M., Chan, A.Robinson, J.S., Maternal and perinatal health outcomes by body mass index category. Aust N Z J Obstet Gynaecol, 2011. 51(2): p. 136-40. Owens, L.A., O'Sullivan, E.P., Kirwan, B., Avalos, G., Gaffney, G., Dunne, F., et al., ATLANTIC DIP: the impact of obesity on pregnancy outcome in glucose-tolerant women. Diabetes Care, 2010. 33(3): p. 577-9. Black, M.H., Sacks, D.A., Xiang, A.H.Lawrence, J.M., Clinical outcomes of pregnancies complicated by mild gestational diabetes mellitus differ by combinations of abnormal oral glucose tolerance test values. Diabetes Care, 2010. 33(12): p. 2524-30. Pederson, J., Weight and length at birth of infants of diabetic mothers. Acta Endocrinologica, 1954. 16: p. 330-342. Catalano, P.M. Hauguel-De Mouzon, S., Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic? Am J Obstet Gynecol, 2011. 204(6): p. 479-87. Athukorala, C., Crowther, C.A.Willson, K., Women with gestational diabetes mellitus in the ACHOIS trial: risk factors for shoulder dystocia. Aust N Z J Obstet Gynaecol, 2007. 47(1): p. 37-41. Callaway, L.K., Prins, J.B., Chang, A.M.McIntyre, H.D., The prevalence and impact of overweight and obesity in an Australian obstetric population. MJA, 2006. 184(2): p. 56-59. Dodd, J.M., Grivell, R.M., Nguyen, A.-M., Chan, A.Robinson, J.S., Maternal and perinatal health outcomes by body mass index category. ANZJOG, 2011. 51(2): p. 136-40. Sebire, N.J., Jolly, M., Harris, J.P., Wadsworth, J., Joffe, M., Beard, R.W., et al., Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord, 2001. 25(8): p. 1175-82. Chu, S.Y., Callaghan, W.M., Kim, S.Y., Schmid, C.H., Lau, J., England, L.J., et al., Maternal obesity and risk of gestational diabetes mellitus. Diabetes Care, 2007. 30(8): p. 2070-6. Sjoholm, A. Nystrom, T., Endothelial inflammation in insulin resistance. Lancet, 2005. 365: p. 610613. Han, T.S., Sattar, N., Williams, K., Gonzalez-Villalpando, C., Lean, M.E.Haffner, S.M., Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care, 2002. 25: p. 2016-2021. Duncan, B.B., Schmidt, M.I., Pankow, J.S.al, e., Low-grade systemic inflammation and the development of type 2 diabetes. Diabetes, 2003. 52: p. 1799-1805.

Ac ce

1.

14

Page 14 of 22

27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

ip t

cr

26.

us

25.

an

24.

M

23.

ed

22.

pt

21.

Lyon, C.J., Law, R.E.Hsueh, W.A., Minireview: adiposity, inflammation and atherogenesis. Endocrinology, 2003. 144: p. 2195-2200. Pradhan, A.D., Manson, J.E., Rifai, N., Buring, J.E.Ridker, P.M., C-reactive protein, interleukin-6 and risk of developing type 2 diabetes mellitus. JAMA, 2001. 286: p. 327-334. Greenberg, A.S. Obin, M.S., Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr, 2006. 83: p. 461-465. Cedergren, M.I., Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstet Gynecol, 2004. 103(2): p. 219-24. Group, H.S.C.R., Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study: associations with maternal body mass index. BJOG, 2010. 117(5): p. 575-84. Gunatilake, R.P. Perlow, J.H., Obesity and pregnancy: clinical management of the obese gravida. Am J Obstet Gynecol, 2011. 204(2): p. 106-19. O'Sullivan, E.P., Avalos, G., O'Reilly, M., Dennedy, M.C., Gaffney, G., Dunne, F., et al., Atlantic Diabetes in Pregnancy (DIP): the prevalence and outcomes of gestational diabetes mellitus using new diagnostic criteria. Diabetologia, 2011. 54(7): p. 1670-5. Metzger, B.E., Gabbe, S.G., Persson, B., Buchanan, T.A., Catalano, P.A., Damm, P., et al., International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care, 2010. 33(3): p. 676-82. Group, H.S.C.R., Metzger, B.E., Lowe, L.P., Dyer, A.R., Trimble, E.R., Chaovarindr, U., et al., Hyperglycemia and adverse pregnancy outcomes. N Engl J Med, 2008. 358(19): p. 1991-2002. Landon, M.B., Mele, L., Spong, C.Y., Carpenter, M.W., Ramin, S.M., Casey, B., et al., The relationship between maternal glycemia and perinatal outcome. Obstet Gynecol, 2011. 117(2 Pt 1): p. 218-24. Catalano, P.M., McIntyre, H.D., Cruickshank, J.K., McCance, D.R., Dyer, A.R., Metzger, B.E., et al., The hyperglycemia and adverse pregnancy outcome study: associations of GDM and obesity with pregnancy outcomes. Diabetes Care, 2012. 35(4): p. 780-6. Dodd, J.M., Turnbull, D., McPhee, A.J., Deussen, A.R., Grivell, R.M., Yelland, L.N., et al., Antenatal lifestyle advice for women who are overweight or obese: LIMIT randomised trial. BMJ, 2014. 348: p. g1285. Organisation, W.H., Obesity: preventing and managing the global epidemic. WHO Technical Report Series Number 894., 2000, World Health Organisation: Geneva. Guidelines, S.P.P. Diabetes mellitus and abnormal glucose tolerance (Chapter 65). [cited 2012 http://www.health.sa.gov.au/ppg/Default.aspx?PageContentID=2118&tabid=100%5D. Brown, M.A., Hague, W.M., Higgins, J., Lowe, S., McCowan, L., Oats, J., et al., The detection, investigation and management of hypertension in pregnancy: full consensus statement. ANZJOG, 2000. 40(2): p. 139-155. Black, M.H., Sacks, D.A., Xiang, A.H.Lawrence, J.M., The relative contribution of prepregnancy overweight and obesity, gestational weight gain, and IADPSG-defined gestational diabetes mellitus to fetal overgrowth. Diabetes Care, 2013. 36(1): p. 56-62. Crowther, C.A., Hiller, J.E., Moss, J.R., McPhee, A.J., Jeffries, W.S., Robinson, J.S., et al., Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. New England Journal of Medicine, 2005. 352(24): p. 2477-2486. Landon, M.B., Thom, E., Spong, C.Y., Carpenter, M., Mele, L., Johnson, F., et al., The National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network randomized clinical trial in progress: standard therapy versus no therapy for mild gestational diabetes. Diabetes Care, 2007. 30 Suppl 2: p. S194-9.

Ac ce

20.

15

Page 15 of 22

ip t

cr

us an M

41.

ed

40.

pt

39.

Bonomo, M., Corica, D., Mion, E., Goncalves, D., Motta, G., Merati, R., et al., Evaluating the therapeutic approach in pregnancies complicated by borderline glucose intolerance: a randomized clinical trial. Diabet Med, 2005. 22(11): p. 1536-41. Kim, S.Y., England, L., Wilson, H.G., Bish, C., Satten, G.A.Dietz, P., Percentage of gestational diabetes mellitus attributable to overweight and obesity. Am J Public Health, 2010. 100(6): p. 104752. Dennedy, M.C. Dunne, F., The maternal and fetal impacts of obesity and gestational diabetes on pregnancy outcome. Best Pract Res Clin Endocrinol Metab, 2010. 24(4): p. 573-89. Devlin, H.M., Desai, J.Walaszek, A., Reviewing performance of birth certificate and hospital discharge data to identify births complicated by maternal diabetes. Matern Child Health J, 2009. 13(5): p. 660-6.

Ac ce

38.

16

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 (%)

Ac c

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

Ac ce

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)

<.0001

Includes all women randomised who had a live birth and did not withdraw consent to use their data. The treatment effects were relative risks (95% CI) using a log binomial model that included BMI and GDM, unless otherwise indicated. No adjustment was made for other variables what may be related to the outcomes.*: The treatment effect was mean difference (95% CI) using a linear regression model which included BMI, GDM, and the interaction between BMI and GDM interaction. 18

Page 18 of 22

Figure 1. Prevalence of GDM by BMI category

Ac ce

pt

ed

M

an

us

cr

ip t

251658240

19

Page 19 of 22

Ac ce

pt

ed

M

an

us

cr

ip t

Figure 2. Risk of fetal macrosomia by maternal BMI category and GDM status

20

Page 20 of 22

Figure 3. Prevalence of GDM by BMI category

Ac ce

pt

ed

M

an

us

cr

ip t

251658240

21

Page 21 of 22

June 30, 2014 The Editor Diabetes Research and Clinical Practice Dear Sir/Madam

ip t

Regarding our manuscript, which we are pleased to resubmit with revisions as suggested, reference: DIAB-D-14-00429. In brief, our highlights for review are as follows:

us

cr

1. Title change to: The influence of maternal BMI and gestational diabetes on pregnancy outcome

an

2. Inclusion of additional data from 20 participants with changes in outcome data, Specifically, the significance of increased NICU admission in obese women became a trend (RR 2.42; 95% CI 0.98 to 5.99; p=0.06) while the rate of NICU admission with GDM became significant (RR 2.41; 95% CI 1.04, 5.61; p=0.04).

M

3. Inclusion of outcomes: large for gestational age, and gestational age at delivery

ed

4. More detailed description of LIMIT trial methodology as requested

Ac ce

pt

5. Inclusion of percentage of women undergoing oral glucose tolerance testing vs oral glucose challenge testing

6. Expansion of discussion regarding the outcome of decreased fetal macrosomia in women who were diagnosed with GDM

On behalf of the authors I thank you for your consideration of this revised submission. Dr Kate Martin Discipline of Obstetrics and Gynaecology The University of Adelaide Women’s and Children’s Hospital 72 King William Rd North Adelaide SA 5006 Ph 81617619 Fax 81617652 [email protected] 22

Page 22 of 22