994384

Effect of BMI in women with mild GDM- the CDC4G study

LTV-994384
Forskningsanslag 2024
Har INTE ett förordnande vid CKF eller en anställning vid CIFU Forskning
Ansökan påbörjad av: Maryam de Brun, 2023-09-09
Yrkestitel vid ansökningstillfället: ST-läkare
Arbetsplats vid ansökningstillfället: Kvinnokliniken
Senast ändrad / åtgärdad av: Maryam de Brun, 2024-01-31
Ansökan ställd till: Centrum för klinisk forskning i Region Västmanland
Beslutad - beviljad

Sökanden: Maryam de Brun

ST-läkare, Kvinnokliniken

Basuppgifter
namn:
Maryam de Brun

yrkestitel:
ST-läkare

Utbildning

högskole- eller universitetsexamen:

Läkarexamen

akademisk grad:
Doktorsexamen

Är detta en fortsättningsansökan?

Nej

Huvudsökanden

Kvinna

Har du tid avsatt för forskning?

Nej
Ja, forskning ingår i min tjänst
Ja, jag har extern finansiering för forskningstid

Vilket projekt söker du medel för?

I. Betydelsen av förändrade diagnoskriterier för graviditetsdiabetes i Sverige- en stepped wedge randomiserad studie,
Projektbeskrivning

Namn på lokalt ansvarig forskare/prövare

Maryam de Brun

Akronym

CDC4G

Studietyp

Annan klinisk studie/prövning (behandling t ex kirurgi, strålning, omvårdnad)

Effect of BMI in women with mild GDM- the CDC4G ...

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Multicenterstudie

Ja

Har projektet etiskt tillstånd från Etikprövningsmyndigheten?

Ja, etikansökan är godkänd. Region Västmanland finns med som forskningshuvudman i ansökan.

Etikansökningar

Ansvarig
Diarie Myndighet Grundansökan Titel Forskningshuvudman Beslut Beslutsdatum
forskare

Utvärdering av
Regionala
2016- Socialstyrelsens Helena
etikprövningsnämnden Region Örebro Län Godkänd 2016-12-07
487 nya riktlinjer för Backman
i Uppsala
Graviditetsdiabetes

Har du ansökt om godkännande från Läkemedelsverket?

Nej inte aktuellt

Finns Biobanksavtal

Nej inte aktuellt

Tidigare forskningsmeriter/forskarutbildning

Jag är disputerad

Sammanfattning av projektet (med rubrikerna Bakgrund, Syfte, Metod, Relevans och implikationer; max 1500 tecken)

B:Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy with a growing prevalence globally: to a large
extent due to the increase in overweight and obesity. Hyperglycaemia during pregnancy is associated with short- and longterm complications
for mother and child. The changing diagnostic criteria for gestational diabetes (CDC4G trial) evaluated the implementation of the WHO-2013
criteria with expected increase in women diagnosed with mild GDM. We aim to evaluate whether BMI has an altering effect on treatment in
women with milder GDM.

M: A post-hoc analysis of the CDC4G trial, a stepped wedged cluster randomised trial of the switch from the SWE- GDM criteria to the WHO-
2013 criteria during 2018. Recruitment was between Jan 1 and Dec 31, 2018, at 14 delivery units in eight clusters. For this study, the cohort of
women with fasting and 2-hour plasma glucose cut off discordant for diagnosis of GDM (between SWE-GDM and WHO-2013 criteria) were
analysed. All women were grouped in to four BMI (kg/m2) categories (WHO Classification). Primary outcomes of interest is being born large
for gestational age (LGA). Secondary neonatal and maternal outcomes will be reported.

R&I: Considering the pandemic of obesity and its association to GDM, there is a clinical relevance of evaluating whether BMI has an altering
effect on treatment in these additional women with milder GDM. These findings could have implication on the choice of treatment and
therefor outcome for the mother and neonate.

Attestant

Mats Stenberg

Redovisning av vetenskaplig kompetens i forskargruppen

Helena Backman, docent

Tidplan

2 veckor; Systematisk litteraturgenomgång, detaljplanering med styrgrupp.

Effect of BMI in women with mild GDM- the CDC4G ...

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3 veckor; Data-analys, övervägning behov av ytterliggare analys/komplettering.

3 veckor; Tolkning av data, manuscript, submitta.

Beskrivning av förkortningar

Gestational diabetes mellitus (GDM)

Large for gestational age (LGA)

WHO 2013 criteria for gestational diabetes (WHO-2013)

Body mass index (BMI)

Changing diagnostic criteria for gestational diabetes (CDC4G)

Bakgrund

Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy with a growing prevalence globally: to a large
extent due to the increase in overweight and obesity 1. Hyperglycaemia during pregnancy is associated with complications for mother and
child during pregnancy, and delivery, but also associated with later type 2 diabetes and cardiovascular disease for the mother. For the child,
there is emerging evidence about risks for future obesity and co-morbidities 2-4

In the original HAPO study there was a continuous relationship between in large for gestational age (LGA) neonates, umbilical cord-c peptide
and neonatal fat mass with maternal glucose levels 5. This was also true for glucose levels below the threshold for gestational GDM diagnosis,
which led up to the WHO recommended diagnostic criteria for GDM in 2013 (WHO-2013) 6. Both maternal glucose levels and body mass index
(BMI) showed strong independent correlation to LGA infants 7. Even after adjustment for maternal glycaemia, there is a positive correlation
between neonatal fat mass, foetal hyperinsulinemia and neonatal hypoglycaemia to maternal BMI 7-9. There is one published secondary
analysis of an RCT in 958 women with mild GDM allocated to treatment or no treatment. Treatment benefit on foetal growth were seen in
women with BMI of 25-39.940 kg/m 2. These effects were not apparent for normal weight (<25 kg/m 2) and very obese women (40 kg/m 2) 10.

The changing diagnostic criteria for gestational diabetes (CDC4G) trial evaluated the implementation of the WHO-2013 criteria compared to
the former criteria Swedish for GDM (SWE- GDM criteria), treating milder hyperglycaemia during pregnancy. Implementation of the WHO-
2013 criteria for GDM is expected to lead to an increase in women diagnosed with mild GDM 11.

Syfte/frågeställning/hypotes

In this post-hoc analysis of the CDC4G trial, we aim to evaluate whether BMI has an altering effect on treatment in women with milder GDM.

Powerberäkning

Not relevent in this post-hoc analysis.

But the original study has a power calculation:

In the sample size calculation for the primary LGA (>90th percentile) outcome, 11 clusters were planned with an assumed intracluster
correlation of 0·0026. A minimum sample size of 23 958 pregnant women per trial group was estimated to have 90% statistical power to
detect an absolute reduction in LGA by 1·5% on a population level (from 10·0 to 8·5%) at a 5% significance level 14. The intracluster correlation
was estimated from the variation in LGA prevalence in the year 2012 between clusters, which varied from 7·7% to 13·3%.

Design och urval

This a post-hoc analysis of the CDC4G trial, a national stepped wedged cluster randomised trial of the switch from the SWE-GDM criteria to the
WHO-2013 criteria during 2018. The details of the trial methodology have been described previously in the trial protocol and publications 12-
14. Recruitment was between Jan 1 and Dec 31, 2018, at 14 delivery units in eight clusters. High-risk women had an oral glucose tolerance
test. All women under the care of a participating health service during the trial period were included. Clusters that did not adhere to the trial
protocol procedures and women with pre-existing diabetes, gastric bypass surgery, and multifetal pregnancies were excluded.

For this study, the cohort of women with fasting and 2-hour plasma glucose cut off discordant for diagnosis of GDM (between SWE-GDM and
WHO-2013 criteria: fasting plasma glucose 5·1-6·9 and/or 2-hour plasma glucose 8·5-8·8/8·9/9·9 mmol/L) were analysed. All women were
grouped in to four BMI (kg/m2) categories adapted from the WHO International Classification of underweight (<18.5), normal (18.5-24.9), pre-
obesity (25.0 - 29.9) and obesity class I-III (≥30.0). Primary outcomes of interest is LGA, defined as birth weight >90th percentile in the Swedish
reference population according to Marsál et al. 15, corrected for gestational age and sex. Secondary neonatal and maternal outcomes will be
reported.

Effect of BMI in women with mild GDM- the CDC4G ...

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Redovisning av intervention

The intervention was the implementation of the WHO-2013 criteria for GDM; moving from a two point fasting (≥7·0 mmol/L) and 2-hour (8⸱9-
11⸱1 mmol/L) to a three point venous OGTT with fasting plasma glucose, one hour and/or two hour diagnostic thresholds of ≥5·1, ≥10·0 and
≥8·5 mmol/L (WHO-2013 criteria) at cluster level.

Metod och datainsamling/ -bearbetning

Data sources (registers and electronic case report form) is used 13 14. Merging of data was performed by the Swedish National Board of
Health and Welfare based on personal identification numbers.
Recommended analyses for SW-CRT will be followed 16. Binary outcomes, including the primary outcome, will be analysed using multilevel
mixed logistic regression to compare the WHO-2013 and SWE-GDM criteria groups with clusters as a random factor and calendar time period
(January-March, April-June, July-September, October-December) as a fixed factor. Logistic regression gave odds ratios (OR) with 95%
confidence intervals (CI) as effect measures. Secondary categorical outcomes with more than two categories will be analysed in the same way
using mixed multinominal regression, continuous outcomes using linear mixed regression and count data outcomes using negative binomial
mixed regression. Adjustment will be made for the potential confounding variables for LGA: maternal age, chronic hypertension, smoking
habits and Swedish snuff habits in early pregnancy, country of birth classified according to the International Diabetes Federation Diabetes Atlas
and parity.

Beskrivning av projektets logistik

This is not relevant since the study is already performed. The details of the trial methodology have been described previously in the trial
protocol and publications 12-14. Detailed updates registered at ISRCTN (41918550).

Referenser

1. World Health Organization. Global report on diabetes. Geneva, Switzerland: World Health Organization, 2016.

2. Lowe WL, Scholtens DM, Kuang A, et al. Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal gestational
diabetes mellitus and childhood glucose metabolism. Diabetes Care 2019;42(3):372-80.

3. Lowe WL, Scholtens DM, Lowe LP, et al. Association of gestational diabetes with maternal disorders of glucose metabolism and childhood
adiposity. JAMA 2018;320(10):1005-16.

4. Xie W, Wang Y, Xiao S, et al. Association of gestational diabetes mellitus with overall and type specific cardiovascular and cerebrovascular
diseases: systematic review and meta-analysis. BMJ 2022;378

5. Hapo Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. NEJM 2008;358(19):1991-2002. doi:
10.1056/NEJMoa0707943 [doi]

6. World Health Organization. Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy. Geneva, Switzerland: World
Health Organization, 2013.

7. HAPO Study Cooperative Research Group. Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study: associations with maternal body
mass index. BJOG 2010;117(5):575-84.

8. García-Patterson A, Aulinas A, María MÁ, et al. Maternal body mass index is a predictor of neonatal hypoglycemia in gestational diabetes
mellitus. The Journal of Clinical Endocrinology 2012;97(5):1623-28.

9. Sewell MF, Huston-Presley L, Super DM, et al. Increased neonatal fat mass, not lean body mass, is associated with maternal obesity. Am J
Obstet Gynecol 2006;195(4):1100-03.

10. Casey BM, Mele L, Landon MB, et al. Does maternal body mass index influence treatment effect in women with mild gestational diabetes?
Am J Perinatol 2014:093-100.

11. Saeedi M, Cao Y, Fadl H, et al. Increasing prevalence of Gestational Diabetes Mellitus when implementing the IADPSG criteria: a systematic
review and meta-analysis. DRCP 2020

12. de Brun M, Magnuson A, Montgomery S, et al. Changing diagnostic criteria for gestational diabetes (CDC4G) in Sweden: a stepped wedge
cluster randomised controlled trial Forthcoming 2023

13. Fadl H. Impact on pregnancy outcomes when changing diagnostic criteria for gestational diabetes in Sweden [Internet]. ISRCTN 2017
[updated 2022 Dec 19; cited 2023 Apr 22]. Available from: https://doi.org/10.1186/ISRCTN41918550 accessed Dec 19 2023.

14. Fadl H, Saeedi M, Montgomery S, et al. Changing diagnostic criteria for gestational diabetes in Sweden-a stepped wedge national cluster
randomised controlled trial-the CDC4G study protocol. BMC Pregnancy Childbirth 2019;19(1):398.

15. Maršál K, Persson PH, Larsen T, et al. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr
1996;85(7):843-48.

Effect of BMI in women with mild GDM- the CDC4G ...

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16. Hemming K, Haines TP, Chilton PJ, et al. The stepped wedge cluster randomised trial: rationale, design, analysis, and reporting. Bmj
2015;350

Etikbeslut

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Etikansökan

Jag intygar att jag bifogat etikansökan som bilaga nedan.

Bilagor

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Medel jag söker

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Vilken kunskapslucka/or avser projektet att fylla och hur?

The internationally recommended WHO-2013 GDM criteria are being implemented due to the potential benefits in maternal and neonatal
outcomes. Two previous RCT have studied the change from locally used, to the WHO-2013 criteria without significant reduction in birthweight
of neonates. One of the studies have shown a reduction in LGA in the cohort with mild GDM. A post-hoc analysis of an RCT with treatment of
mild GDM compared to placebo showed significant treatment benefits in women with BMI between 25-39.9kg/m2, but not normal weight/
BMI >40kg/m2. Considering the pandemic of obesity and its association to GDM, there is a clinical relevance of evaluating whether BMI has an
altering effect on treatment in these additional women with milder GDM. This large national intervention (CDC4G) trial data is gives us a
unique opportunity to study subgroups. These findings could have implication on the choice of treatment according to BMI and therefor
outcome for the mother and neonate.

Bedömning av projektets betydelse

There is no consensus regarding management of gestational diabetes (GDM), which is the most common medical complication of pregnancy.
The expected increase in prevalence on implementing the WHO-2013 criteria for GDM is associated with increased resource use and costs for
the already burdened maternal healthcare. On an individual level, labelling these women as GDM affects their quality of life, with certainties in
treatment effect in these additional women with milder GDM. The data on the treatment effect in the subgroup will be published elsewhere,
but we have a chance to further investigate the treatment effects in different BMI subgroups. The results of the study is of high clinical
significance and importance nationally and internationally regarding implementing the debated WHO-2013 criteria. There might be a need to
tailor our treatment so more women and neonates benefit from offered treatment. In this sense, the study is important from a societal,
healthcare and individual perspective.

Arbetet är planerat att publiceras som

Intern rapport
Artikel i nationell tidskrift
Artikel i internationell tidskrift
Annat

Effect of BMI in women with mild GDM- the CDC4G ...

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Beslut
Beslutsdatum: 2023-12-13

Beslut

Äskade medel 178 788

Beviljade medel 41 695

Kommentar till beslut

Maryam de Brun
LTV-994384

Angående ditt projekt, Effect of BMI in women with mild GDM- the CDC4G study:
Centrum för klinisk forskning har genom sin bedömningsgrupp nöjet att meddela att du har beviljats 2 veckors forskningstid för 2024! Grattis!
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forskningsmedel, samt ett extratillskott på 600 000 kronor för forskningsmedel. Bedömningsgruppen har fått prioritera hårt mellan de
sökande.
Den totala sökta summan för årets ansökningar omfattar drygt 4,9 miljoner kronor för forskningstid och drygt 2,6 miljoner kronor för
omkostnader i projekt.

Som återkoppling inför utformningen av framtida ansökningar vill bedömningsgruppen göra dig uppmärksam på följande:

Överlag noteras vissa brister i beskrivningen av projektet. Detta gör att granskarna upplever att det är svårt att förstå vad sökanden avser göra
och således svårt att fullt ut bedöma genomförbarhet/tidsplan. Exempelvis saknas uppgifter om typ av behandling och det upplevs att
frågeställning och effektmått inte överensstämmer. Lite otydligt kring secondary outcomes. Det är noggrant beskrivet vad sökta medel ska
användas till, det går att läsa mellan raderna att data finns tillgängligt och sökanden har säkerligen goda kunskaper kring materialet. Dock
behöver ansökan justeras så att det går lättare att förstå hur det är tänkt att frågeställningarna i detta intressanta projekt kan besvaras.
Observera att du inte kan erhålla medel och/eller forskningstid innan du har alla myndighetsgodkännanden på plats samt att alla lokala krav
för att bedriva forskning ska vara uppfyllda. För din del innebär detta att nämnd vetenskaplig kompetens behöver bjudas in till projektet i
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Förbrukningsperiod
Sista förbrukningsdag av tilldelade medel: 2024-12-31

Effect of BMI in women with mild GDM- the CDC4G ...