Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03713060 |
| Other study ID # |
SDUSF-2015-203 - (464) - |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 17, 2019 |
| Est. completion date |
July 11, 2022 |
Study information
| Verified date |
July 2022 |
| Source |
University of Southern Denmark |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Background Roux-en-Y gastric bypass (RYGB) is a well-established treatment of obesity, most
often performed in women during their reproductive years. Adverse events related to RYGB
include hypoglycemia. Though usually attenuated in pregnancy, the incretin response is
reinforced in subjects with RYGB and the resulting changes in insulin and glucagon responses
together with the resultant weight loss are possible underlying mechanisms for hypoglycemia.
The majorities of women who have undergone RYGB conceive shortly after RYGB and have an
increased risk for inappropriate gestational weight gain (GWG) and thereby fetal growth
restriction. However, studies of hypoglycemia and GWG in pregnant women following RYGB are
lacking.
Objective In women with previous RYGB we aim to investigate a) glucose level and incretin
response during a mixed meal test (MMT) in early and late pregnancy, b) trimester specific
incidence of postprandial hypoglycemia and c) fetal growth.
Methods 20 women with RYGB and 20 age-, BMI- and parity-matched controls will be studied with
a) 2nd and 3rd trimester 4-hour liquid MMTs, b) 6-days Continuous Glucose Monitoring (CGM)
once every trimester and post partum and c) maternal and fetal anthropometrics including
antenatal ultrasound examinations and neonatal DXA-scans. The primary outcomes are nadir
plasma glucose levels during the 4-hour liquid MMT, number of hypoglycemic episodes during
CGM and birthweight standard deviation scores.
Discussion A better understanding of maternal metabolism and fetal growth in women with RYGB
will support risk stratification, patient information and management both before and during
pregnancy.
Description:
Background Post-prandial hypoglycemia Roux-en-Y Gastric Bypass (RYGB) is a well-established
treatment of severe obesity and is performed in women most often during their reproductive
years. RYGB is a hormonal, malabsorptive as well as a restrictive surgical procedure, leading
to complications such as vitamin deficiencies and postprandial hypoglycemia, which are
exaggerated during pregnancy. Hypoglycemia usually does not occur until one year post surgery
and evolves gradually with non-specific symptoms, causing delayed diagnosis. Symptoms of
hypoglycemia include autonomic symptoms (palpitations, lightheadedness, sweating) and
neuroglycopenic symptoms (confusion, decreased attentiveness, seizure, loss of
consciousness). While severe hypoglycemia is estimated with a frequency of 0.2 % following
RYGB, the frequency of mild to moderate hypoglycemia is unknown due to a lack of recognition
of symptoms.
Insulin sensitivity increases due to weight loss and the resulting changes in insulin and
glucagon response are a possible underlying mechanism for postprandial hypoglycemia. In
pregnant women, insulin sensitivity changes from early to late pregnancy. Whilst usually
attenuated in late pregnancy, the incretin response is reinforced in subjects with RYGB.
These factors make it difficult to predict the risk of hypoglycemia in pregnancies following
RYGB.
Studies have shown that plasma insulin concentration is inappropriately elevated during the
hypoglycemic episodes and that fasting hypoglycemia is uncommon, suggesting that hypoglycemia
is primarily associated with postprandial dysregulation of insulin secretion. Beta-cell
diameter has been shown to correlate with pre-operative Body Mass Index (BMI). Accordingly,
hypertrophy of the beta-cells in the pancreas has previously been proposed as an explanation
of hyperinsulinemic hypoglycemia. However, pancreatic resection has not provided a cure for
hypoglycemia following RYGB. In a recent study, administration of a Glucagon Like Peptide-1
(GLP-1) receptor antagonist was shown to eliminate postprandial hypoglycemia in patients with
symptomatic hypoglycemia following RYGB. In this study altered gastro-intestinal function was
suggested to contribute to the altered glucose metabolism in combination with dysregulation
of insulin secretion. Hence, there is no general consensus on the subject.
No evidence-based guidelines for the diagnosis of postprandial hypoglycemia or investigation
of glucose-metabolism in RYGB patients exist. Continuous Glucose Monitoring (CGM) has proven
to provide high detection rates for hypoglycemia under real life conditions and can therefore
be used as an important tool for screening of hypoglycemia. Currently, the preferred method
for diagnosis of postprandial hypoglycemia is the mixed meal test (MMT), as it provides a
more physiological stimulus compared to the oral glucose tolerance test (OGTT). While the
OGTT consists of ingestion of a liquid containing 75 g glucose, the MMT consists of a liquid
meal of 55 % carbohydrate, 25 % protein and 20 % fat. Both tests are performed after fasting
with blood samples drawn during the test measuring glucose, insulin and c-peptide.
Knowledge of predictive factors for postprandial hypoglycemia in pregnancy will be an
important tool for improving dietary management and quality of life in women with RYGB.
Fetal growth During the last decades, prevalence's of obesity and diabetes have reached
epidemic proportions - even in children. This is only partly explained by sedentary
life-style and unfavorable diet. Exposure to obesity and/or a diabetic intrauterine
environment is a risk to the fetus and seems to program long-term effects. Studies have
consistently shown that offspring of diabetic mothers have an increased risk of macrosomia
and obesity and risk of metabolic syndrome in later life. These observations have contributed
to the theory of the so-called "vicious intergenerational circle of obesity".
Large epidemiological studies such as the Dutch Famine Study have documented a number of
adverse metabolic effects in adults with low birthweight. Thus, both intrauterine over- and
under-nutrition have severe consequences for fetal growth and future health. However, it is
not known whether repeated events of maternal hypoglycemia per se are harmful to the fetus.
Fetal growth restriction is a potential risk in pregnancies with limited Gestational Weight
Gain (GWG) or even weight loss - i.e. the first period of time following bariatric surgery
and certain eating disorders. Data from our own clinic show that 40% of women with previous
RYGB fail to fulfill minimum recommendations for GWG. A recent registry study from Sweden
found that pregnancies in women with bariatric surgery were associated with risk of Small for
Gestational Age (SGA) infants. Supporting this, a study in Hvidovre in 25 term infants
reported lower birthweight, fat free mass and fat percentage in offspring of mothers with
RYGB compared to controls. Furthermore, inappropriate GWG might be associated with
hyperketonaemia which have potential adverse effects on offspring CNS. These adverse effects
call for further exploration of the fetal growth and the need of defining optimal
post-surgery timing of pregnancy, GWG, diet, vitamin supply etc.
Given the harmful effects of both intrauterine over- and under-nutrition, the time around
pregnancy is the window of opportunity to change factors with long-term impact on the child.
Aims
In women with RYGB the investigators aim to study:
1. Glucose and incretin response during a 4-hour liquid MMT in early and late pregnancy
2. Trimester-specific incidence of hypoglycemia
3. Fetal growth
Study design Longitudinal, prospective cohort study
Subjects Study participants will be enrolled in early pregnancy at Departments of
Endocrinology and Departments of Gynecology and Obstetrics at Odense University Hospital and
Sydvestjysk Sygehus.
20 pregnant women with RYGB (n = 20) will be matched on age, prepregnancy-BMI and parity to
20 pregnant women without RYGB.
Exclusion criteria for GB and non-GB group
- multiple pregnancy
- age below 18 and above 45 years
- ongoing smoking and substance abuse
- severe psychiatric disorder
- severe chronic disease
- diabetes
- women with overt diabetes at inclusion (HbA1c ≥ 48 mmol/l and/or fasting p-glucose
≥ 7 mmol/l)
- women with pre-gestational diabetes (type1 or 2) prior to RYGB
- women with Gestational Diabetes Mellitus (GDM) in a previous pregnancy will not be
excluded
Methods During a two-year period the investigators aim to include 20 pregnant women with
RYGB, 20 age-, BMI- and parity-matched controls and the 40 offspring of these women.
A 2-hour 75 g OGTT, as described in the Background section, will be performed in the control
group in week 24 to detect GDM.
Postprandial hypoglycemia At inclusion (gestational week 12-14) and at week 34 a 4-hour
liquid MMT with concomitant mea-surements of glucose-, insulin-, glucagon and GLP-1 levels by
blood samples will be performed in all participants.
Glucose levels during everyday life will be assessed in each trimester and 4-6 weeks
post-partum by 6 days CGM combined with Self-Monitoring of Blood Glucose (SMBG) for
calibration of CGM system (24 hours). CGM consists of a sensor inserted under the skin to
measure glucose in the interstitial fluid surrounding skin cells. One sensor lasts 6 days.
The sensor measures glucose every 5-10 seconds averaging the values every 5 minutes and
storing the data in the monitor's memory. The device is equipped with an alarm, which will be
turned off, blinding the women. CGM provides information of fluctuations over time whereas
SMBG only provides a snapshot.
Hypoglycemia will be defined as blood glucose <3.0 mmol/L. The women will report any
hypoglycemic symptoms. Fasting blood beta-Hydroxybutyrate will be measured at home each
morning before breakfast during 6 days CGM with registration of nightly meals.
Maternal clinical information on time for RYGB, weight trajectories (before RYGB,
pre-gestational, gestational, post-partum), post-operative and pregnancy related
complications, blood pressure etc. will be gathered.
Fetal growth Antenatal serial ultrasound measurements will be performed at gestational week
24, 28 and 34.
Measurements will include abdominal circumference (AC) and calculation of fetal weight
deviation.
Postnatally, anthropometric measures including birthweight and length, AC, skinfold
measurements and DXA-scans within 72 hours after birth will be performed. DXA-scans will be
performed, when the newborn has fallen asleep after breastfeeding/formula feeding. The
examination will last for about 5 minutes and is not associated with any pain or discomfort.
Perspectives Due to new national guidelines for bariatric surgery the investigators expect an
increase in pregnant women having undergone this operation. A better understanding of
maternal metabolism and fetal growth in women with previous RYGB surgery will support risk
stratification and development of treatments both before and during pregnancy.
This study will contribute with valuable knowledge about the body composition of children of
women with RYGB. The children will be compared with children of weight-matched, obese and
lean controls thereby increasing the understanding of how the mothers' nutritional status
affect the children's body composition.
Power Calculations To our knowledge, there are no published studies on effect of a MMT in
pregnant women after RYGB. Based on MMT's in women before and one year after RYGB a SD of 0.5
in BG is expected. In order to provide a power greater than beta=80% (type 2-error), and a
significance of alfa=5% (type 1-error) for observing a difference of (MIREDIF) = 0.5 mmol a
sample size of 16 women should be included in each group.
Due to the unknown variance parameters regarding fetal growth and body composition, the
investigators plan to include 20 women in each group.
Ethics All projects described have been approved by the local Ethics Committee (project ID
S-20160134) and will be performed in accordance with the principles in Helsinki Declaration
II.
The DXA-scanner used in this study will be a Hologic 4500A (Waltham, MA, USA) which applies
low radiation (approximately 0.02 mSv per scan). The lifetime risk of developing
radiation-induced lethal cancer is 0.012% per mSv for children. Thus, the exposure of 0.02
mSv onto 1 million children could lead to 2 deaths by cancer as a consequence of radiation.
The radiation is negligible in comparison with the background radiation of 4 mSv a year and
the method is classified as category 1, which does not poses a health hazard for the neonate
(effective dose < 0.03 mSv). The examination is not associated with any pain or discomfort
for the neonate.
Handling and archiving data The protocol will be registered on the Region of Southern
Denmark's record over processing activities and the documents and materials related to the
clinical study will be stored in REDCap and OPEN Analyse according to the Danish Data
Protection Legislation and the EU GDPR (General Data Protection Regulation).
Finance The study is 100 % non-profit, completely independent from commercial interests.
There will be applied for public and private grants to finance the study.
The primary investigator and the supervisors have taken the initiative to the study. The
primary investigator has no association to the funders.
There will not be provided salary for participation in the study. The study participants will
be shown gratitude by dispensing printed ultrasound photos at the extra ultrasound
examinations.
