Introduction
The obesity epidemic has become a major healthcare problem in industrialised and developing countries and is strongly associated with reduced health-related quality of life [
1] and an increased risk for metabolic and cardiovascular disorders [
2]. Bariatric surgery is recommended as a possible treatment for morbid obesity if conservative interventions fail to achieve satisfactory weight reduction [
3,
4]. Hereby, Roux-en-Y gastric bypass (RYGB) is the most commonly performed technique and has long-lasting effects regarding weight loss (up to 30%) and prevention or improvement of type 2 diabetes [
5,
6].
An increase in the prevalence of obesity is already being seen in younger populations [
7], meaning that weight-loss surgery is emerging as a treatment option even in women of reproductive age. Previous retrospective reports and register studies have addressed pregnancy complications and pregnancy outcomes following gastric bypass and have demonstrated beneficial effects such as reduced incidence of pre-existing and gestational diabetes mellitus (GDM) [
8,
9], possibly contributing to a lower prevalence of large for gestational age (LGA) offspring [
10‐
12]. However, a marked increase in the prevalence of small for gestational age (SGA) neonates, along with a small increase in the rates of stillbirths or neonatal deaths, indicates a higher risk for perinatal morbidity and mortality [
13,
14]. In addition, studies in non-pregnant women suggest that gastric bypass surgery is also characterised by an exaggerated postprandial rise in blood glucose followed by hyperinsulinaemic hypoglycaemia, despite long-term improvements in type 2 diabetes onset or management [
15]. These effects might also occur during gestation, with possible implications for pregnancy and GDM screening. However, data from detailed examination of glucose metabolism in pregnancies following RYGB surgery are currently not available.
This study aims to evaluate physiological changes in glucose regulation in pregnant women with a history of gastric bypass surgery, including dynamic measurements of glucose, insulin, C-peptide and glucagon after oral glucose stimulation as a primary objective. Therefore, variables of glucose disposal (insulin sensitivity, insulin secretion and beta cell function representing the major components of altered glucose metabolism) were examined during pregnancy and after delivery. Frequently sampled OGTT and IVGTT were used to quantify gut-dependent and gut-independent effects. These variables were compared between mothers who had undergone RYGB surgery and two control groups (a normal weight and an obese group). Changes in glucose regulation after pregnancy and associations between maternal glucose metabolism and neonatal weight were assessed as secondary objectives.
Methods
Study participants and experimental methods
Participants were consecutively recruited among visitors to our pregnancy outpatient department (Department of Obstetrics and Gynecology, Division of Obstetrics and Feto-maternal Medicine, Medical University of Vienna) between April 2014 and February 2016. A total of 63 women participated in the study. Participants included 25 women with a history of RYGB, 19 non-operated obese women (pre-conceptional BMI ≥ 35 kg/m2) and 19 normal weight control women (normal glucose tolerant and pre-conceptional BMI < 25 kg/m2). The calculation of pre-conceptional BMI was based on self-reported pre-gestational weight. The median time (IQR) after RYGB surgery was 3.3 years (2.3–5.7). Women who received insulin or glucose-lowering drugs at time of recruitment were excluded.
To further control for possible bias owing to differences in status of overweight or obesity, some comparisons were repeated after matching the RYGB and control groups; we used 1:1 nearest-neighbour matching (with a caliper of 0.25 SD of the propensity score) to create two groups (14 matched pairs) that were optimally balanced for BMI at the first visit [
16]. The BMI-matched group contained
n = 6 non-operated obese and
n = 8 normal weight control women. Since there were fewer study participants in both control groups, matching observations were not found for the remaining
n = 11 women in the RYGB group. Additional inclusion of the participant’s age into the matching algorithm did not substantially improve the balance of the covariates and was therefore omitted.
A detailed metabolic characterisation of the study population was performed between 24 and 28 weeks of gestation and included routine laboratory assessments and anthropometric measurements in addition to an extended 3 h 75 g OGTT after at least 8 h of fasting with measurements of glucose, insulin, C-peptide and glucagon (at 0, 30, 60, 90, 120, 150 and 180 min). In a short, frequently sampled IVGTT performed on a second study day, glucose (300 mg/kg body weight) was infused for 30 s, starting at time 0, and insulin (0.05 U/kg) was infused from 20 to 25 min. Plasma concentrations of glucose, insulin and C-peptide were assessed at fasting as well as at 3, 4, 5, 6, 8, 10, 15, 20, 30, 40, 50 and 60 min after glucose infusion. The experiments were repeated 3–6 months after delivery. At the postpartum examination, 15 women reported that they breastfed their infants (RYGB,
n = 4; obese,
n = 3; normal weight,
n = 8) and four used hormonal contraceptives (RYGB,
n = 0; obese,
n = 1; normal weight,
n = 3). A detailed overview of missing examinations (OGTT or IVGTT or both) is provided in the electronic supplementary material (ESM) Fig.
1.
Sex- and age-adjusted birthweight percentiles of the Austrian population were assessed using local growth standard curves. After excluding data from nine women with multiple pregnancies (RYGB, n = 5; obese, n = 3; normal weight, n = 1) and six women without this data, as they gave birth at another institution, neonatal biometry was available in a subgroup of 48 women (RYGB, n = 16; obese, n = 16; normal weight, n = 16).
This study was approved by the Ethics Committee of the Medical University of Vienna and was performed in accordance with the Declaration of Helsinki. All participants gave written informed consent to participate in this study.
Discussion
In this study, we aimed to assess glucometabolic consequences for pregnancy following gastric bypass surgery and observed severely altered glucose regulation, mainly characterised by an early glucose peak and concomitant rise in insulin secretion within the first 60 min following an oral glucose stimulation. Thereby, maximum concentrations of insulin and C-peptide were comparable between the RYGB group and more insulin-resistant women with pre-gestational obesity (obese group), resulting in hypoglycaemia in 90% of mothers who had previously undergone RYGB. Of note, this exaggerated pancreatic insulin response was not observed after parenteral glucose administration (IVGTT-derived insulin response was comparable between the post RYGB and normal weight group) and is therefore likely attributed to the specific anatomical rearrangements after gastric bypass surgery, with possible consequences for pregnancy and pregnancy outcomes.
The disparity between outcomes of OGTT and IVGTT has been observed in previous studies of patients who had previously undergone RYGB and could be explained by the different physiological meanings of these test outcomes [
26]; while IVGTTs reflect the sole ‘intrinsic’ effect of plasma glucose on beta cell secretion, OGTTs additionally provide information on potentiating intestinal (‘extrinsic’) mechanisms of insulin release. Indeed, several studies have identified a fundamental role for intestinal incretin peptides, particularly glucagon-like peptide-1 (GLP-1), in modulating pancreatic insulin secretion in non-pregnant patients (men and women) who had undergone RYGB [
27‐
29]. One prominent theory suggests that enhanced GLP-1 release is mainly caused by direct stimulation of the intestinal mucosa following accelerated delivery of undigested nutrients (hindgut hypothesis) [
30,
31]. However, the exact mechanisms underlying how the specific gastrointestinal anatomy after RYGB surgery leads to alteration of insulin response are not fully understood; the loss of inhibitory feedback mechanisms owing to bypassing the upper part of the duodenum might be involved (foregut hypothesis) [
32‐
34]. It is not the scope of this report to further investigate this complex interaction between gut and pancreas. Nevertheless, our study design allows a detailed examination of insulin secretion after oral and i.v. glucose load and allows a qualitative interpretation of the postulated ‘extrinsic’ effect on insulin secretion. This effect was increased in the RYGB group during pregnancy (as an exaggerated insulin release was observed only during the OGTT and not during the IVGTT) and likely contributed to the high glycaemic variability seen after oral glucose administration. In line with our results, a recent study that used continuous subcutaneous glucose monitoring to evaluate glucose profiles in 35 bariatric pregnancies, suggested that abnormal glucose variability occurred in real-life conditions [
35]. It is also worth noting that we found an exaggerated glucagon release immediately after glucose ingestion in the RYGB group. Although supported by other studies in the literature (e.g. [
36]), this is somewhat paradoxical when considering the concomitant rise in plasma glucose and its inhibitory effect on alpha cell function [
37]. Whether this observation represents a physiological adaptation for maintaining euglycaemia [
38], or rather reflects an increased release of inactive proglucagon because of stimulation of intestinal L cells interfering with glucagon assays [
26], is debatable.
Pancreatic insulin secretion is strongly related to the extent of insulin action in different target tissues (i.e. mainly liver and skeletal muscle). Consequently, altered insulin secretion and its possible impact on glucose kinetics following RYGB surgery need to be interpreted in relation to the specific degree of insulin resistance. In this context, we observed an improvement in fasting and dynamic indices of insulin action at 24–28 weeks of gestation in women post RYGB vs obese pregnant women. In addition, analysis of IVGTT data revealed subtle alterations in insulin sensitivity and beta cell function during pregnancy in the RYGB group vs the normal weight control group, which could be explained by their higher degree of pre-gestational overweight and obesity. However, it may be important that fasting (hepatic) and dynamic insulin sensitivity during the OGTT (representing whole-body insulin action) remained significantly improved in the RYGB group vs the BMI-matched control group, indicating that bariatric surgery also has body-weight-independent effects on glucose disposal during gestation. This notion is also supported by studies in non-pregnant women post RYGB (for detailed reviews, see [
26,
30]), mainly suggesting that improved fasting insulin sensitivity, which is already evident in the first week after gastric bypass, is related to energy restriction and reduced liver fat content rather than to changes in body weight. Such an early improvement in insulin sensitivity is not observed during the hyperinsulinaemic–euglycaemic clamp (characterising insulin action in the skeletal muscle), where improvement occurs months after surgery, together with ongoing weight loss [
36]. Hence, we conclude that the degree of insulin sensitivity in pregnant women after RYGB seems to be a consequence of at least two mechanisms: energy restriction and the amount of weight lost after surgery. However, it must be mentioned that the action of insulin changes during gestation [
39]; in normal pregnancy insulin sensitivity is unchanged or improved in early gestation, followed by a constant decrease (up to 60%) until the third trimester. Hence, it might be a limitation of our study that women were examined only once during gestation. Nevertheless, owing to a lack of information on this topic our study represents the first attempt to assess the underlying physiological mechanisms associated with bariatric surgery during pregnancy. We decided to perform our examinations in accordance with the timing of standard GDM screening, although it is actually unclear how the physiological adaptation of glucose homeostasis during pregnancy interacts with disturbed glucose disposal after gastric bypass and this needs to be addressed in future investigations.
We observed that insulin sensitivity and DI (using IVGTT data) was improved in the RYGB group after delivery. Of note, the improvement in IVGTT-derived insulin sensitivity was greater in the RYGB group than in obese women. This was somewhat unexpected but might be related to the metabolic effects of gastric bypass surgery (as discussed above) or to several changes that interact with insulin sensitivity in the postpartum period (such as weight loss, dietary patterns and breast feeding). The weight change did not differ significantly between the groups in our study. However, it has to be mentioned as a limitation that several participants dropped out of the study at the postpartum visit and so this issue needs further investigation. The postpartum glucose nadir during the OGTT and risk for hypoglycaemia in the RYGB group were comparable with our findings at 24–28 weeks of gestation.
Further consequences for pregnancy and pregnancy outcomes after RYGB surgery need to be addressed. First, one must question the reliability of recommended diagnosis criteria (e.g. [
40]) for identifying or ruling out hyperglycaemia in pregnancies following gastric bypass. In our study, the RYGB group had improved fasting glucose despite higher pre-gestational body weight; however, they showed increased peak glucose concentrations after oral ingestion, mostly at a median time of 30 min. It is not clear whether the standard OGTT, which includes glucose measurements at fasting and at 60 and 120 min after ingestion of glucose, can adequately reflect a rise in plasma glucose before 60 min. Second, the increased risk for hypoglycaemia during later periods of the OGTT is another important limitation of this test. We recently examined glucose profiles during a 2 h OGTT screening for GDM in a larger but retrospective sample of women after gastric bypass and observed that hypoglycaemia (< 3.34 mmol) occurred in more than 50% of individuals [
41]. This is in accordance with our current study, providing further evidence to support the consideration of postprandial hypoglycaemia as a frequent and potentially harmful side-effect of OGTT screening in pregnancy after RYGB. Third, some studies have reported an increased incidence of SGA offspring after gastric bypass surgery as well as a trend towards higher perinatal morbidity [
13,
14,
41]. Therefore, our finding that fetal growth of RYGB offspring was associated with the glucose nadir during the OGTT might be of importance, possibly suggesting that the higher level of glycaemic variability and incidence of postprandial hypoglycaemia after gastric bypass has an impact on fetal development. While the restricted sample size of our study must be noted, this association indicates the need for further examinations containing continuous longitudinal glucose profiles during pregnancy, providing detailed information on glucose variability, duration of hyper- and hypoglycaemic episodes, and variables of glucose disposal and their relation to fetal growth.
In summary, we observed that glucose metabolism is notably altered in pregnancies after gastric bypass. This is due to changes in insulin action and exaggerated insulin release early after ingestion of glucose (mainly a consequence of a strong interaction between the gut and pancreas), potentially affecting glucose kinetics during the OGTT or in real-life conditions. These physiological changes could have potential implications for pregnancy, indicating the need for further longitudinal investigations.