PRegnancy Outcomes and Maternal Insulin Sensitivity

Today, gestational diabetes mellitus (GDM) is affecting 1 out of 7 pregnancies
worldwide, but actual rates between regions and countries show considerable
variation. The world health organization (WHO) accounts a body mass index (BMI)
>=25 kg/m2 as a risk factor for screening GDM. However most countries, including
the Netherlands, use a BMI cut off of >=30 kg/m2. GDM is standardly diagnosed
with a 75 g carbohydrate oral glucose tolerance test (OGTT) between week 24-28
of gestation. The exact prevalence of GDM in the Netherlands is unknown but is
estimated to be between 3 to 5% using the Dutch Gynecology and Obstetrics risk
factors (NVOG)5. It is known that the OGTT is not well reproducible. In
contrast, the meal tolerance test (MTT), which contains only 50 grams of
carbohydrates, is more efficient to detect more subtle changes in postprandial
(PP) glucose more efficiently. Research has shown that about 60% of GDM
patients already have deviations in metabolic markers other than glucose in the
first or second trimester. In addition, the *hyperglycemia and adverse
pregnancy outcome* (HAPO) study demonstrated a linear relationship between the
level of hyperglycemia and adverse pregnancy outcomes, suggesting that the
current diagnostic approach may miss a part of the problems associated with
maternal GDM. The present study will 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.

1. To investigate the glucose and insulin responses after the MTT enriched with
labelled glucose early (12-16 weeks), mid pregnancy (24-28 weeks) and
postpartum (3 months)

2. Compare the MTT results with the standard OGTT testing at 24-28 weeks (in
this study in week 28) in pregnancy

3. To study possible associations of insulin sensitivity and plasma glucose and
lipid measures with defined pregnancy outcomes for both mother and child:
- Pregnancy complications,
- Postnatal insulin sensitivity recovery,
- Weight retention,
- Fetal growth,
- Birth outcomes (e.g. body weight infant),
- Infant growth
- Growth and body composition development up to 6 months of age.

4. The exploratory outcomes of the PROMIS study will inform the development of
strategies to improve outcomes via targeted nutritional, lifestyle and/or
pharmaceutical intervention during pregnancy and lactation in subsequent
studies

The PROMIS study is a prospective exploratory cohort study where maternal
insulin sensitivity during pregnancy will be monitored in association to
(adverse) offspring outcomes. In the beginning of the second trimester (week
12-16) a MTT enriched with labeled glucose will be given to the study
participants as will be done mid pregnancy (week 24-28) to compare to the
standard OGTT (week 24-28). In addition, the MTT will be given to the study
participants 3 months postpartum to study insulin sensitivity, remission of GDM
or progression from GDM to diabetes mellitus type 2 (DM2). Maternal
anthropometrics during pregnancy as well as fetal sonography and neonatal
adiposity and anthropometrics will be monitored throughout the study period.

Our study aims to monitor metabolic responses in more detail by using an MTT
and comparing the results to later (standard) assessment during pregnancy. The
addition of stable labelled glucose isotopes to the MTT will provide us more
detailed information on glucose appearance versus clearance and possible
underlying alterations in insulin responses and sensitivity prior to GDM
development. There will be a total of 8 visit moments. Participants will
undergo a 2 hour PP test 3 times during pregnancy (MTT 2x, OGTT 1x). This
requires a substantial time investment and commitment for which the participant
should be rested with an intravenous catheter from which regular blood drawings
are taken. There is a modest risk for phlebitis, an hematoma on the arm. The
stable labelled glucose isotopes do not pose any health risk for mother and
child. The child will undergo several detailed anthropometric measurements
until 6 months of age.