Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05678543 |
| Other study ID # |
1234 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2023 |
| Est. completion date |
December 31, 2030 |
Study information
| Verified date |
April 2024 |
| Source |
Odense University Hospital |
| Contact |
Sine K Johnsen, PhD |
| Phone |
+45 78 45 54 85 |
| Email |
sine.knorr[@]clin.au.dk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Pregnancies in women with pre-existing diabetes are considered "high risk" pregnancies, poses
daily clinical challenges and in terms of research - a number of unanswered questions.
Therefore, the investigators wish to establish a nationwide cohort of pregnancies complicated
by pre-existing diabetes - the Danish Diabetes Birth Registry (DDBR2) The DDBR2 registry
comprises all types of pre-existing diabetes including T1D, T2D and other types (as MODY),
generating a nationwide cohort of mother/partner/children trios with accessible registry-,
clinical data and biological biobank samples. This will enable the investigators to use data
longitudinally to examine short- and long-term outcomes of pregnancies in women with
diabetes.
Description:
During pregnancy in women with type 1 and type 2 (pre-existing) diabetes development of
complications is 2-4 times higher than in the background population, as among women with
pre-existing diabetes up to 50% of the offspring becomes large for gestational age (LGA), and
one out of five are delivered preterm. Strict glycemic control and appropriate gestational
weight gain are important for a healthy pregnancy outcome. However, a large proportion of
pregnant women with diabetes do not reach the goals for glycemic control or weight gain
during pregnancy.
From 1992-2000, all pregnancies in women with type 1 diabetes were reported to the Danish
Diabetes Birth Registry (DDBR), which gave rise to several important international
publications on perinatal outcomes and long-term follow-up studies in mother and child.
During the last 20 years type 2 diabetes has become increasingly common in young women. Today
up to 60% of pregnant women with pre-existing diabetes have type 2 diabetes. In Denmark we
have no national surveillance of pregnancies in women with pre-existing diabetes. It is also
relevant to obtain information in a national setting on partner, socioeconomic factors as
well as collecting biological samples to get the information needed for a more personalized
treatment of pregnant women with pre-existing diabetes.
Offspring born to women with type 1 diabetes have a higher risk of type 1 diabetes per se
(5.3%) compared to the background population, but a lower risk compared to offspring of
fathers with type 1 diabetes (7.8%). This fact suggests that either differences in
inheritability of maternal vs. paternal susceptibility genes or maternal imprinting or
maternal diabetes (i.e., the intrauterine environment) modify a child's inherited risk of
developing type 1 diabetes.
For type 2 diabetes, genome-wide association studies have described approximately 250 loci
being associated with type 2 diabetes. However, the genetic composition of type 2 diabetes is
dominated by common alleles with small impact on the risk of disease. As opposed to type 1
diabetes, the risk of type 2 diabetes is higher in the offspring if the mother has type 2
diabetes rather than if the father has type 2 diabetes. Genetically, this can be associated
with a unique parent-of-origin transmission of the risk alleles, and it relates to genetic
programming during the intrauterine period.
However, the DNA sequence alone cannot explain the phenotypical variation seen in offspring
born to women with diabetes. Let alone, describe how the intrauterine environment can
influence the long term health of the offspring. Later in life offspring of women with
diabetes faces an increased risk of obesity, pre-diabetes and type 2 diabetes, beyond what
can be explained by the DNA sequence. This increase in risk of disease is for now
unexplained. However, the suboptimal intrauterine environment associated with diabetes in
pregnancy, may lead to epigenetic changes of the fetal DNA. Such "fetal programming of adult
disease" could provide a pathogenic explanation.
Apart from genetics and epigenetics, inflammatory markers and metabolic markers of the
intrauterine environment are interesting, as these have been described as altered among
adolescent offspring born to women with diabetes.
Taking this into account, the possibility of predicting which offspring is at risk of later
life disease is compelling and the use of proteomics, inflammatory and metabolic markers,
placental markers, genetic risk scores and microRNA/small RNAs, as well as epigenetic marks,
as biomarkers needs to be further explored.
Rationale for this study Pregnancies in women with pre-existing diabetes are still considered
"high risk" pregnancies and pose challenges in terms of daily clinical management. Therefore,
to explore this risk in a current Danish population, map the influence of both maternal and
partner factors on offspring health, and comprehend how the intrauterine environment can
influence both short- and long-term health of the offspring, the investigators wish to
establish a nationwide cohort of pregnancies complicated by pre-existing diabetes - the
Danish Diabetes Birth Registry (DDBR2).
In the DDBR2 registry the investigators wish to include data on both the woman, her partner
and the child, thereby generating a nationwide cohort of mother/partner/children trios with
accessible registry data, clinical data and biological samples. This will enable the
investigators to use data longitudinally to examine short- and long-term outcomes of
pregnancies in women with pre-existing diabetes. The DDBR2 registry will be complimented by
an associated genetic, epigenetic and metabolomic interrogation seeking to illuminate
possible pathogenic mechanisms that link maternal diabetes to the later life increased risk
of lifestyle disease in the offspring as well as a biobank for future research.
Hypotheses of the DDBR2:
The risk of maternal and neonatal complications following a pregnancy complicated by
pre-existing diabetes has decreased over the last 30 years.
Better understanding of the predictive role of socioeconomic background and maternal physical
and mental health and use of technical devices prior to pregnancy can decrease the risk of an
adverse pregnancy outcome.
Partner health and socioeconomic background influence pregnancy outcome. Measures of glucose
from continuous glucose monitoring as predictors of adverse perinatal outcomes may be
superior to HbA1c.
Epigenetic alterations in offspring cord blood reflects the intrauterine environment and can
be used as markers for later life health.
Genetic risk scores for both parents and child can be used to predict risk for later life
disease.
Clinical proteomics can identify novel biomarkers for maternal and offspring risk.
Micro RNA and other small RNAs can provide new insight in pathophysiology related to maternal
and offspring risk.
Low-grade inflammation during pregnancy may negatively influence the glucose tolerance of the
mother and perinatal outcomes.
Specific endpoints
The following endpoints apply in women with pre-existing diabetes and in their offspring in
both the DDBR2 registry:
Primary endpoints Primary maternal endpoint: HbA1c levels at end of pregnancy (35 weeks)
Primary offspring endpoint: Offspring birth weight adjusted for gestational age and gender
(standard deviation (SD) score)
Secondary endpoints HbA1c levels during pregnancy at inclusion, 21, 33 and 35 weeks The
average glucose level and percentage of time spent in the continuous glucose monitoring (CGM)
target range 3.5-7.8 mmol/L, below target range (glucose <3.5 mmol/L) or above target range
(glucose >7.8 mmol/L). The levels will be evaluated at night-time (24 pm to 6 am) and over 24
h, respectively, in pregnancy, during delivery and in the first one-month period after
delivery.
The incidence of severe hypoglycemia in the year preceding pregnancy, during pregnancy and in
the first one-month period after delivery Maternal gestational weight gain and weight
retention one month after delivery In women on insulin pump therapy: insulin pump settings
(mainly basal rates, carbohydrate ratio and sensitivity) in pregnancy, around delivery and
the first month after delivery during lactation The prevalence of fetal overgrowth, defined
as the offspring birth weight SD score >90th percentile Pregnancy complications: prevalence
of induced abortion (including indication for abortion), miscarriage, gestational
hypertension, preeclampsia, need for maternal corticosteroid treatment for fetal lung
maturation, diabetic ketoacidosis, urinary tract infection, early preterm delivery (before 34
completed weeks), preterm delivery (before 37 completed weeks), preterm prelabour rupture of
the membranes Birth complications: shoulder dystocia, birth canal trauma, mode of delivery
(vaginal, cesarean section, instrumental delivery), postpartum hemorrhage, maternal death,
antihypertensive treatment given one month after delivery Neonatal morbidity (neonatal
hypoglycemia, jaundice, respiratory distress, transient tachypnoea, duration of stay in
neonatal intensive care unit, total number of admission days), cord blood pH, stillbirths,
infant death within one month Major congenital malformations (ICD10 Q00-Q99 or requiring
medical or surgical treatment) Infant growth and health at one month of age Maternal and
Partner Quality of Life in pregnancy and one month postpartum Maternal mental health in
pregnancy and one month postpartum Average glucose level and the percentage of time in the
first one-month period after delivery spent in the CGM target range 3.9-10.0 mmol/L, below
target range (glucose <3.5 mmol/L) or above target range (glucose >7.8 mmol/L) at night-time
(24 pm to 6 am) and over 24 h, respectively
3. Methods DDBR2 is a prospective combined clinical and register-based cohort study including
all pregnant women with pre-existing diabetes aged ≥18 years in Denmark, their children and
their partners corresponding to ~400 pregnant women each year (250 type 1 diabetes, 150 type
2 diabetes and 5-10 other types), a total of 2000 trios during the inclusion period. The
inclusion period is from 1st Jan. 2023- 31st Dec. 2027. The registry will include data from
electronic patient charts, CGM data, fetal ultra sound data, clinical data, background
information on socioeconomic background, online questionnaires and biological samples.
4. Statistics A two-sided p-value <0.05 will be regarded as statistically significant in all
statistical analyses.
For the primary outcomes we plan to use Mann-Whitney U test or Chi2 test. Regression analysis
will be performed to determine predictors for maternal and perinatal outcomes. Sub analysis
for type 1 diabetes and type 2 diabetes with and without the use of diabetes technology will
be performed separately. Using a two-level approach for degree of participation, we expect a
participation rate of ≈80%. In the previous DDBR registry the participation rate was 75-93%
depending on inclusion site12.
5. Biological material
In the DDBR2 study the investigators wish to extract blood samples from both the parents and
the offspring with the aim of answering the following research questions:
If differences in offspring cord blood methylation status is induced by intrauterine
hyperglycemia, maternal obesity or hereditary predisposition.
If parental small RNAs levels during pregnancy and offspring small RNAs levels after delivery
can be associated to neonatal outcome (e.g., birthweight).
If specific proteins, identified by proteomics, in either maternal, partner or offspring
blood associated with maternal or neonatal morbidity.
How maternal, paternal and child genetic risk scores for type 1 diabetes, type 2 diabetes and
other cardiometabolic traits (i.e., glucose levels, blood pressure, lipid levels, insulin
secretion, insulin resistance, BMI, weight, waist corrected for BMI) can predict later life
risk of disease.
Parent-of-origin transmission of risk alleles for type 1 and type 2 diabetes If parental and
offspring levels of inflammatory cytokines, such as TNFa, IFNg, CD163, various chemokines and
interleukins and vascular factors are associated with maternal or neonatal morbidity.
Parental and offspring levels of metabolic biomarkers, such as C-peptid, FGF 21, leptin,
adiponectin, GDF-15, CD-59, adrenomedullin, apo-lipo protein, cortisol, cortisol binding
hormone and prolactin and offspring morbidity.
Level of placental serum markers, such as PLGF, s-FLt, PAPP-A and placenta derived exosomes
as predictors of pregnancy and birth outcome.
