Ignite Creation Date:
2024-05-06 @ 6:28 PM
Last Modification Date:
2024-10-26 @ 2:49 PM
Study NCT ID:
NCT05678543
Status:
RECRUITING
Last Update Posted:
2024-04-12
First Post:
2022-12-16
Brief Title:
Danish Diabetes Birth Registry 2
Sponsor:
Odense University Hospital
Organization:
Odense University Hospital
Study Overview
Official Title:
Danish Diabetes Birth Registry 2
Status:
RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
DDBR2
Brief 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 motherpartnerchildren 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
Detailed 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 53 compared to the background population but a lower risk compared to offspring of fathers with type 1 diabetes 78 This fact suggests that either differences in inheritability of maternal vs paternal susceptibility genes or maternal imprinting or maternal diabetes ie the intrauterine environment modify a childs 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 microRNAsmall 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 motherpartnerchildren 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 35-78 mmolL below target range glucose 35 mmolL or above target range glucose 78 mmolL 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 39-100 mmolL below target range glucose 35 mmolL or above target range glucose 78 mmolL 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 005 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 eg 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 ie 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
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 53 compared to the background population but a lower risk compared to offspring of fathers with type 1 diabetes 78 This fact suggests that either differences in inheritability of maternal vs paternal susceptibility genes or maternal imprinting or maternal diabetes ie the intrauterine environment modify a childs 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 microRNAsmall 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 motherpartnerchildren 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 35-78 mmolL below target range glucose 35 mmolL or above target range glucose 78 mmolL 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 39-100 mmolL below target range glucose 35 mmolL or above target range glucose 78 mmolL 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 005 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 eg 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 ie 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None