Pregnancy Outcomes and Maternal Insulin Sensitivity

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.

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