Clinical trial NCT04315545: Pregnancy Outcomes and Maternal Insulin Sensitivity
Official title: Pregnancy Outcomes and Maternal Insulin Sensitivity
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Gestational Diabetes
Other "Heavy-For-Dates" Infants
Small for Gestational Age Infant
Diabetes Mellitus, Type 2
Keywords: Insulin sensitivity
Insulin insensitivity
Pregnancy
Metabolism
Neonatal outcomes
glucose metabolism
Oral glucose tolerance test
Meal tolerance test
neonatal health
maternal health
maternal insulin sensitivity
gestational weight gain
diagnostic tool
early screening
prevention
overweight
obesitiy
metabolic health
neonatal adiposity
maternal adiposity
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
First posted: 2020-03-19
Enrollment: 30
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study population will be pregnant women with a BMI ≥25 kg/m2 with a moderate to high 'at risk' of developing gestational diabetes throughout pregnancy

Brief summary: The PROMIS study will focus on maternal insulin sensitivity thourghout pregnancy and postpartum in a moderate to high risk population (BMI ≥25 kg/m2) in developing adverse pregnancy outcomes. Next to the OGTT, the meal tolerance test (MTT) will be used as a tool for metabolic testing.

The investigators hypothesize that (early) pregnancy assessment of maternal glucose-insulin metabolism with a MTT in a moderate to high risk group identify more mothers at risk for adverse pregnancy outcomes compared with standard OGTT testing at 24-28 weeks.

Detailed description: The worldwide prevalence of overweight and obesity is rapidly increasing, also affecting women of reproductive age. The prevalence of overweight women between 30-40 years in the Netherlands in 2017 was 39%. Women with a BMI ≥25 kg/m2 have excess adipose tissue which reduces insulin sensitivity and explains the correlated adverse outcomes for both mother and child.

Insulin sensitivity changes over the course of pregnancy due to the effect of placental hormones and is therefore normally decreased by the end of the second trimester to ensure a continuous supply of nutrients towards the growing fetus. Insulin resistance leads to beta-cell proliferation and larger volume of individual beta-cells, returning to non-pregnant levels after parturition. When beta-cell proliferation is not or inadequately increased, this may lead to hyperglycemia. It is shown that small increases in maternal glucose levels have a linear relationship with adverse outcomes. Maternal adverse outcomes are pre-eclampsia, caesarian section and gestational diabetes mellitus (GDM) on the short term and increased risk of weight retention and non-communicable diseases like cardiovascular diseases and diabetes mellitus type 2 (DM2) on the longer term. Adverse outcomes in infants are macrosomia, large for gestational age (LGA), small for gestational age (SGA) on the short term and a higher risk on childhood obesity and non-communicable diseases on the longer term. Adequate maternal insulin sensitivity throughout pregnancy is therefore critical.

Small maternal glucose increases could already be detected in an early stage of pregnancy. In the Netherlands hyperglycemia is standardly examined at the end of the second trimester in an at risk population by an oral glucose tolerance test (OGTT). This test is less suitable to detect mild hyperglycemia in early stages of pregnancy, with merely blood glucose levels as a result, and shows a lot of within subject variability. However markers of insulin sensitivity and related metabolic adaptations, for instance in lipid metabolism, may be a more straightforward measure that could potentially be detected earlier and allow for early intervention. An integration of postprandial responses of glucose/insulin following a meal challenge combined with lipid markers could provide clearer insights in maternal metabolic function. A test that could be used to examine this in more detail is a liquid meal tolerance test (MTT) which contains a balanced macro- and micronutrient composition. Assessing glucose homeostasis is not possible by only measuring glucose concentrations as there are numerous perturbations where glucose production and its utilization increases or decreases to the same extent without any changes in concentrations. For the understanding of the physiology and pathophysiology of glucose uptake and metabolism during pregnancy, glucose tracers should be followed.

The PROMIS study will specifically focus on the associations between insulin sensitivity in the mother in early pregnancy and fetal and neonatal outcomes with emphasis on growth and body composition. The investigators therefore hypothesize that when overweight pregnant women are challenged in early pregnancy with a MTT, the group of women with disturbed insulin sensitivity could be identified much earlier, and can therefore have a predictive role in adverse outcomes.

Eligibility criteria: Inclusion Criteria:

* Healthy singleton pregnant women (10-12 weeks of gestation)
* BMI ≥25 kg/m2
* FPG ≤7.0 mmol/l
* Dutch or English speaking
* Written informed consent

Exclusion Criteria:

* Serious health complications (Hypertension, Hyperlipidemia, Asthma, Haemochromatosis) or medication use that influence the glucose metabolism or fetal growth (e.g. corticosteroids).
* Multiple pregnancy
* pre-existing Diabetes type 1 and 2 defined as FPG ≥7.0 mmol/l or use of diabetes medication
* Participation in any other studies involving the investigation of medication or nutritional products or severe illness or antibiotic use in the two weeks prior to entry into the study
* HIV/Hepatitis
* Expectation of non-compliance to the study protocol, among others, a fear of needles
* Known allergies or intolerances for one or more nutritional ingredients in the MTT
* Psychological dysfunctions

Primary outcomes:
measure: fasting glucose
timeFrame: T=0 min, before intake of test drink
measure: postprandial glucose
timeFrame: T=10 min postprandial
measure: postprandial glucose
timeFrame: T=20 min postprandial
measure: postprandial glucose
timeFrame: T=30 min postprandial
measure: postprandial glucose
timeFrame: T=45 min postprandial
measure: postprandial glucose
timeFrame: T=60 min postprandial
measure: postprandial glucose
timeFrame: T=90 min postprandial
measure: postprandial glucose
timeFrame: T=120 min postprandial
measure: fasting and postprandial glucose
timeFrame: AUC and postprandial curve
measure: fasting insulin
timeFrame: T=0 min, before intake of test drink
measure: postprandial insulin
timeFrame: T=10 min postprandial
measure: postprandial insulin
timeFrame: T=20 min postprandial
measure: postprandial insulin
timeFrame: T=30 min postprandial
measure: postprandial insulin
timeFrame: T=45 min postprandial
measure: postprandial insulin
timeFrame: T=60 min postprandial
measure: postprandial insulin
timeFrame: T=90 min postprandial
measure: postprandial insulin
timeFrame: T=120 min postprandial
measure: fasting and postprandial insulin
timeFrame: AUC and postprandial curve
Secondary outcomes:
measure: Triglycerides
timeFrame: T=0 min, before intake of test drink
measure: Total cholesterol
timeFrame: T=0 min, before intake of test drink
measure: HDL-cholesterol
timeFrame: T=0 min, before intake of test drink
measure: Free fatty acids
timeFrame: T=0 min, before intake of test drink
measure: Hba1c
timeFrame: T=0 min, before intake of test drink
measure: Fasting stable glucose isotopes
timeFrame: T=0, before intake of test drink
measure: postprandial stable glucose isotopes
timeFrame: T=10 min postprandial
measure: postprandial stable glucose isotopes
timeFrame: T=20 min postprandial
measure: postprandial stable glucose isotopes
timeFrame: T=30 min postprandial
measure: postprandial stable glucose isotopes
timeFrame: T=45 min postprandial
measure: postprandial stable glucose isotopes
timeFrame: T=60 min postprandial
measure: postprandial stable glucose isotopes
timeFrame: T=90 min postprandial
measure: postprandial stable glucose isotopes
timeFrame: T=120 min postprandial
measure: fasting and postprandial stable glucose isotopes
timeFrame: AUC and postprandial curve
Other outcomes:
measure: FFQ
timeFrame: between week 12-16 of gestation
measure: FFQ
timeFrame: between 24-28 of gestation
measure: FFQ
timeFrame: 1 month postpartum
measure: FFQ
timeFrame: 3 months postpartum
measure: AEBQ
timeFrame: between week 12-16 of gestation
measure: AEBQ
timeFrame: between 24-28 of gestation
measure: AEBQ
timeFrame: 1 month postpartum
measure: AEBQ
timeFrame: 3 months postpartum
measure: BEBQ
timeFrame: 1 month postpartum in child
measure: BEBQ
timeFrame: 3 months postpartum in child
measure: EQ
timeFrame: Between week 12-16 of gestation
measure: EQ
timeFrame: between week 24-28 of gestation
measure: EQ
timeFrame: 1 month postpartum
measure: EQ
timeFrame: 3 months postpartum
measure: PA
timeFrame: between week 12-16 of gestation
measure: PA
timeFrame: between week 24-28 of gestation
measure: PA
timeFrame: 1 month postpartum
measure: PA
timeFrame: 3 months postpartum
measure: MP
timeFrame: In week 24 of gestation
measure: MP
timeFrame: In week 25 of gestation
Locations:
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Leeuwarden
country: Netherlands
facility: Medical Center Leeuwarden
Study officials:
affiliation: University Medical Center Groningen
name: Eline M van der Beek, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Koning SH, Hoogenberg K, Lutgers HL, van den Berg PP, Wolffenbuttel BH. Gestational Diabetes Mellitus:current knowledge and unmet needs. J Diabetes. 2016 Nov;8(6):770-781. doi: 10.1111/1753-0407.12422. Epub 2016 Jul 28.
citation: Venkataraman H, Ram U, Craik S, Arungunasekaran A, Seshadri S, Saravanan P. Increased fetal adiposity prior to diagnosis of gestational diabetes in South Asians: more evidence for the 'thin-fat' baby. Diabetologia. 2017 Mar;60(3):399-405. doi: 10.1007/s00125-016-4166-2. Epub 2016 Dec 2.
citation: World Health Organization. World health statistics 2016: Monitoring health for the SDGs sustainable development goals. World Health Organization; 2016.
citation: Ko GT, Chan JC, Woo J, Lau E, Yeung VT, Chow CC, Cockram CS. The reproducibility and usefulness of the oral glucose tolerance test in screening for diabetes and other cardiovascular risk factors. Ann Clin Biochem. 1998 Jan;35 ( Pt 1):62-7. doi: 10.1177/000456329803500107.
citation: Maegawa Y, Sugiyama T, Kusaka H, Mitao M, Toyoda N. Screening tests for gestational diabetes in Japan in the 1st and 2nd trimester of pregnancy. Diabetes Res Clin Pract. 2003 Oct;62(1):47-53. doi: 10.1016/s0168-8227(03)00146-3.
citation: Seshiah V, Cynthia A, Balaji V, Balaji MS, Ashalata S, Sheela R, Thamizharasi M, Arthi T. Detection and care of women with gestational diabetes mellitus from early weeks of pregnancy results in birth weight of newborn babies appropriate for gestational age. Diabetes Res Clin Pract. 2008 May;80(2):199-202. doi: 10.1016/j.diabres.2007.12.008. Epub 2008 Feb 4.
citation: HAPO Study Cooperative Research Group; Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008 May 8;358(19):1991-2002. doi: 10.1056/NEJMoa0707943.
citation: NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet. 2017 Dec 16;390(10113):2627-2642. doi: 10.1016/S0140-6736(17)32129-3. Epub 2017 Oct 10.
citation: Chen C, Xu X, Yan Y. Estimated global overweight and obesity burden in pregnant women based on panel data model. PLoS One. 2018 Aug 9;13(8):e0202183. doi: 10.1371/journal.pone.0202183. eCollection 2018.
citation: Catalano PM, Ehrenberg HM. The short- and long-term implications of maternal obesity on the mother and her offspring. BJOG. 2006 Oct;113(10):1126-33. doi: 10.1111/j.1471-0528.2006.00989.x. Epub 2006 Jul 7.
citation: Zhu Y, Zhang C. Prevalence of Gestational Diabetes and Risk of Progression to Type 2 Diabetes: a Global Perspective. Curr Diab Rep. 2016 Jan;16(1):7. doi: 10.1007/s11892-015-0699-x.
citation: Koning SH, van Zanden JJ, Hoogenberg K, Lutgers HL, Klomp AW, Korteweg FJ, van Loon AJ, Wolffenbuttel BHR, van den Berg PP. New diagnostic criteria for gestational diabetes mellitus and their impact on the number of diagnoses and pregnancy outcomes. Diabetologia. 2018 Apr;61(4):800-809. doi: 10.1007/s00125-017-4506-x. Epub 2017 Nov 22.
citation: Koning SH, Hoogenberg K, Scheuneman KA, Baas MG, Korteweg FJ, Sollie KM, Schering BJ, van Loon AJ, Wolffenbuttel BH, van den Berg PP, Lutgers HL. Neonatal and obstetric outcomes in diet- and insulin-treated women with gestational diabetes mellitus: a retrospective study. BMC Endocr Disord. 2016 Sep 29;16(1):52. doi: 10.1186/s12902-016-0136-4.
citation: Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care. 2002 Oct;25(10):1862-8. doi: 10.2337/diacare.25.10.1862.
citation: Feig DS, Zinman B, Wang X, Hux JE. Risk of development of diabetes mellitus after diagnosis of gestational diabetes. CMAJ. 2008 Jul 29;179(3):229-34. doi: 10.1503/cmaj.080012.
citation: Yang X, Hsu-Hage B, Zhang H, Zhang C, Zhang Y, Zhang C. Women with impaired glucose tolerance during pregnancy have significantly poor pregnancy outcomes. Diabetes Care. 2002 Sep;25(9):1619-24. doi: 10.2337/diacare.25.9.1619.
citation: Langer O, Umans JG, Miodovnik M. The proposed GDM diagnostic criteria: a difference, to be a difference, must make a difference. J Matern Fetal Neonatal Med. 2013 Jan;26(2):111-5. doi: 10.3109/14767058.2012.734874. Epub 2012 Oct 30.
citation: Hadlock FP, Harrist RB, Sharman RS, Deter RL, Park SK. Estimation of fetal weight with the use of head, body, and femur measurements--a prospective study. Am J Obstet Gynecol. 1985 Feb 1;151(3):333-7. doi: 10.1016/0002-9378(85)90298-4.
citation: Ferrara A, Peng T, Kim C. Trends in postpartum diabetes screening and subsequent diabetes and impaired fasting glucose among women with histories of gestational diabetes mellitus: A report from the Translating Research Into Action for Diabetes (TRIAD) Study. Diabetes Care. 2009 Feb;32(2):269-74. doi: 10.2337/dc08-1184. Epub 2008 Nov 4.
citation: Malcolm J, Lawson ML, Gaboury I, Keely E. Risk perception and unrecognized type 2 diabetes in women with previous gestational diabetes mellitus. Obstet Med. 2009 Sep;2(3):107-10. doi: 10.1258/om.2009.080063. Epub 2009 Sep 1.
citation: Noctor E, Dunne FP. Type 2 diabetes after gestational diabetes: The influence of changing diagnostic criteria. World J Diabetes. 2015 Mar 15;6(2):234-44. doi: 10.4239/wjd.v6.i2.234.
citation: Cobelli C, Man CD, Sparacino G, Magni L, De Nicolao G, Kovatchev BP. Diabetes: Models, Signals, and Control. IEEE Rev Biomed Eng. 2009 Jan 1;2:54-96. doi: 10.1109/RBME.2009.2036073.
citation: Sonagra AD, Biradar SM, K D, Murthy D S J. Normal pregnancy- a state of insulin resistance. J Clin Diagn Res. 2014 Nov;8(11):CC01-3. doi: 10.7860/JCDR/2014/10068.5081. Epub 2014 Nov 20.
citation: Catalano PM, Huston L, Amini SB, Kalhan SC. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol. 1999 Apr;180(4):903-16. doi: 10.1016/s0002-9378(99)70662-9.
citation: Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol. 2007 Dec;50(4):938-48. doi: 10.1097/GRF.0b013e31815a5494.
citation: Catalano PM, Kirwan JP, Haugel-de Mouzon S, King J. Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus. J Nutr. 2003 May;133(5 Suppl 2):1674S-1683S. doi: 10.1093/jn/133.5.1674S.