Short summary

Roux-en-Y Gastric Bypass (RYGB) is a well-established and effective treatment of obesity, but it comes at a cost. Postprandial hypoglycemia is a well-known complication, leading to decreased quality of life for the affected and in worst case has fatal consequences. The extend of the problem among pregnant post RYGB women is unknown. Insufficient weight gain during pregnancy with the risk of fetal growth restriction and in turn metabolic syndrome in the offspring is another complication to RYGB. However, it is unknown whether repeated events of maternal hypoglycemia per se are harmful to the fetus. With this project we intend to clarify these issues

Rationale

Roux-en-Y Gastric Bypass (RYGB) is a well-established treatment of obesity, most often performed in women 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 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). In worst case, a hypoglycemic episode can be the cause of accidents and deaths. 8% of deaths following RYGB have been suspected to be related to hypoglycemia. A recent Danish population-based study reported moderate to severe hypoglycemia with a frequency of 7 % 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. There is no general consensus on the cause of the hyperinsulinemic 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. 

Another adverse event related to RYGB is insufficient gestational weight gain. The majorities of women who have undergone RYGB conceive shortly after RYGB and have an increased risk of inappropriate gestational weight gain (GWG) and thereby fetal growth restriction. Studies consistently show an increased risk of Small for Gestational Age (SGA) infants in pregnancies following RYGB. Supporting this, a study in Hvidovre in 25 term infants reported lower birthweight, lower lean mass and lower fat percentage in offspring of mothers with RYGB compared to controls.

Large epidemiological studies have documented a number of adverse metabolic effects in adults with low birthweight. However, it is not known whether repeated events of maternal hypoglycemia per se are harmful to the fetus. 

These adverse effects call for further exploration of glucose metabolism and fetal growth and the need of defining optimal post-surgery timing of pregnancy, GWG, diet, vitamin supply etc.

Given the harmful effects of undernutrition, the time around pregnancy is the window of opportunity to change factors with long-term impact on the child. 

Accordingly, in women with previous RYGB we aim to investigate glucose level and incretin response during a mixed meal test (MMT) in early and late pregnancy, trimester specific incidence of postprandial hypoglycemia and fetal growth.

Description of the cohort

Study participants will be enrolled in early pregnancy at the Departments of Endocrinology and the Departments of Gynecology and Obstetrics at Odense University Hospital and Sydvestjysk Sygehus.

Inclusion criteria:

• GB group: pregnant women with RYGB (n = 20)

• non-GB group: pregnant women matched on age, prepregnancy-BMI and parity (n = 20)

• neonates: offspring of abovementioned women (n = 40)

Data and biological material

Clinical data: height, weight, age, parity, weight changes (before gastric bypass, before, during and after pregnancy), timing of gastric bypass, other medical/psychiatric illnesses, smoking, alcohol, drug use, complications to gastric bypass and/or pregnancy, symptoms of low blood sugar, estimated weight of the fetus and abdomnal circumference by prenatal ultrasounds, 

Blood samples during Continuous Glucose Monitoing, Mixed Meal Test and Oral Glucose Tolerance Test: measurements of glucose and gut hormones

Anthropometric measurements of the neonate at birth: weight, length, abdominal circumference, skinfolds, DXA-scan

Collaborating researchers and departments

Steno Diabetes Center Odense, Department of Endocrinologi and Gynechology and Obstetrics, Odense University Hospital

• Clinical professor, Dorte Møller Jensen, MD, PhD

Department of Endocrinology, Hospital of South-West Jutland

• Clinical associate professor, Claus Bogh Juhl, MD, PhD

Department of Endocrinology, Odense University Hospital

• Professor, René Klinkby Støving, MD, PhD

Department of Gynecology and Obstetrics, Odense University Hospital

• Mette Tanvig, MD, PhD
• Lise Lotte Andersen, MD

Department of Gynecology and Obstetrics, Rigshospitalet

• Kristina Renault, MD

Publications associated with the project

Tentative publications:

• Glucose excursions and incretin response in pregnant women with previous gastric bypass operation.

• The risk of postprandial hypoglycemia in pregnant women with previous gastric bypass operation

• Fetal growth in pregnancies complicated with previous gastric bypass operation