|Year : 2023 | Volume
| Issue : 1 | Page : 50-56
The study of offspring and mothers with gestational diabetes treated with metformin or glibenclamide in a randomized controlled trial after 9 years
Praveen George Paul1, Beena Ruth Kingsbury2, Hilda Yenuberi2, Richa Sasmita Tirkey2, Santosh Joseph Benjamin2, Swati Rathore2, Babuji Manimegalai3, Antonisamy Belavendra4, Jiji Elizabeth Mathews2
1 Department of Pediatrics, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Obstetrics and Gynaecology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Dietetics, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Bio-Statistics, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||24-Aug-2022|
|Date of Decision||10-Oct-2022|
|Date of Acceptance||13-Oct-2022|
|Date of Web Publication||17-Jan-2023|
Dr. Richa Sasmita Tirkey
Department of Obstetrics and Gynaecology, Christian Medical College, Ida Scudder Road, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Introduction: Follow-up of the mothers and their offspring recruited to a randomized controlled trial comparing neonatal outcomes in women with gestational diabetes treated with metformin or glibenclamide was conducted 9 years ago. A significant decrease in neonatal hypoglycemia in the group treated with metformin was seen in the original study. Methodology: Results of clinical examination, blood sample collection, and dual-energy X-ray absorptiometry (DEXA) scan not published in a brief communication are described in this study. The nutritional status was assessed using a 3-day recall method using the Indian Food Composition Table 2017. The physical activity of offspring was assessed using the Global Physical Activity Questionnaire. Results: The overall follow-up rate of the cohort was 49% and similar in both the groups. The anthropometric details, blood tests, and DEXA in the women and their offspring were similar except that the offspring of the group on metformin had higher triglyceride values than the offspring of the women treated with glibenclamide. The average body mass index of the offspring was similar and was 18. Currently, women who were treated with glibenclamide 9 years ago had higher fasting plasma glucose levels (9.2 [7.3, 12.6]) than the metformin group (7.2 [6.1, 8.4] median [interquartile range]), P = 0.02. They also had significantly higher diastolic blood pressure readings 77.1mmHg (8.9) and 72.1mmHg (11.7) mean (SD), P = 0.035. (Information from the previously published brief communication). Conclusion: No significant adverse outcome was seen in women treated with metformin and the offspring 9 years later.
Keywords: Follow-up, glibenclamide, metformin, offspring, pregnancy
|How to cite this article:|
Paul PG, Kingsbury BR, Yenuberi H, Tirkey RS, Benjamin SJ, Rathore S, Manimegalai B, Belavendra A, Mathews JE. The study of offspring and mothers with gestational diabetes treated with metformin or glibenclamide in a randomized controlled trial after 9 years. Curr Med Issues 2023;21:50-6
|How to cite this URL:|
Paul PG, Kingsbury BR, Yenuberi H, Tirkey RS, Benjamin SJ, Rathore S, Manimegalai B, Belavendra A, Mathews JE. The study of offspring and mothers with gestational diabetes treated with metformin or glibenclamide in a randomized controlled trial after 9 years. Curr Med Issues [serial online] 2023 [cited 2023 Feb 1];21:50-6. Available from: https://www.cmijournal.org/text.asp?2023/21/1/50/367868
| Introduction|| |
Treatment for gestational diabetes mellitus (GDM) could include metformin and glibenclamide., Results of a study on GDM mothers treated with metformin or glibenclamide were published, with metformin showing better neonatal outcomes. Children of these mothers with gestational diabetes may be at increased risk of metabolic syndrome in later life.,,,, We published the findings of the 9-year follow-up of the study as a brief communication., Metformin crosses the placental barrier while glibenclamide may not cross the placenta.,, There is very little information globally on the long-term effects on offspring and their mothers who were treated with metformin or glibenclamide for GDM.
| Methodology|| |
This research was done in a large tertiary center that has around 14,000 deliveries a year after institutional ethics committee approval (IRB No. 10238) was obtained on August 24, 2016.
The follow-up of a randomized controlled trial.
Nine-year follow-up of a randomized controlled trial was done between 2007 and 2019. The present study was done between 2016 and 2019.,
Women recruited to the randomized trial done in our department registered under the Clinical Trials Registry of India (CTRI) CTRI/2014/02/004418 were approached to participate in the trial.
Several telephonic calls or house visits to mothers from the database of the study were made. After informed consent, history, examination, and blood sample collection from children and mothers were carried out. Children with other medical conditions requiring steroids or any other medications that could affect insulin sensitivity were excluded. Demographic profile, anthropometry, nutritional history, biochemical tests, and dual-energy X-ray absorptiometry (DEXA) scan for body fat composition and lean mass were performed for mothers and their offspring. A 3-day diet recall method was used to obtain dietary intake. The nutrients were calculated by using the Indian Food Composition Table 2017. The Global Physical Activity Questionnaire was used to assess the activity of the offspring. The outcomes were assessed in the pediatric department. The drug with which the mother was treated was not revealed to the assessors.
Among the anthropometric measurements, the body mass index (BMI), waist circumference, hip circumference, waist/hip ratio, triceps, biceps, subscapular skinfold thickness, and mid-arm circumference were measured for the mothers and the offspring. Skinfold thickness was measured using a Harpenden skinfold caliper. The biceps skinfold was measured at the anterior surface of the arm above the biceps brachii muscle with the arm completely relaxed and the palm facing forward. The triceps skinfold was measured midway between the acromion and olecranon processes in the posterior part of the left arm, with arms by the side of the body and elbow extended. The subscapular skinfold was measured below the angle of the scapular with the arm by the side of the body. Blood investigations for the offspring included glucose tolerance test (GTT), fasting insulin, cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). GTT was performed after an overnight fast of 10–12 h. Children were administered 1.75 g/kg of oral flavored glucose up to a maximum of 75 g and plasma glucose was measured at 60 and 120 min after the oral glucose load. For the mother, fasting, postprandial sugar, and lipid profile were checked. Glucose was measured by enzymatic method, insulin by chemiluminescence immunoassay, and lipid profile by automated chemistry analyzer using colorimetric enzymatic endpoint with esterase, oxidase, and peroxidase method. Total fat, regional fat, and lean body mass assessment were performed using the DEXA machine (Hologic QDR series Discovery A) for both the mother and offspring. The trunk fat, right and left leg fat, right and left arm fat, trunk-to-thigh fat ratio, and android/gynoid ratio were calculated.
A sample size of 126 children (63/group) was required to detect a 2% difference in body fat percentage between the two groups of offspring of mothers with gestational diabetes, who received metformin or glibenclamide with 80% power, 5% level of significance, and a common standard deviation (SD) of 4. We assumed that the mean body fat percentage was 14% and 16% in the metformin and glibenclamide groups, respectively. Data entry and assessment were carried out by researchers who were blinded to the treatment allocation of the mother. Excel spreadsheets with validation criteria to avoid entry errors were maintained and they were linked to the original study database.
Demographic and baseline clinical characteristics at birth and follow-up were summarized as counts and percentages for categorical variables and mean and SD or median and interquartile range for continuous variables between the two groups. Two sample t-tests or Wilcoxon rank sum-test and Chi-squared statistics were used to compare the outcome variables of the metformin and glibenclamide groups. The difference between the outcome variables and with P values was estimated. All statistical analyses were performed using the statistical software STATA version 13 (StataCorp, College Station, TX, USA). Univariate analyses were done to assess if there was any significant difference between the two groups.
The comprehensive current health status of the mother and offspring was described in the table that was published in the brief communication.
| Results|| |
A total of 78 mothers and offspring among the 159 randomized in the original study group (49%) were followed up at a mean age of 9 years. [Table 1] shows a comparison of the baseline characteristics of mothers with two modes of treatment, whose offspring were followed up. The characteristics were similar in most aspects except that the 1st-h GTT value in the group treated with metformin was significantly higher when compared to the group treated with glibenclamide. Fasting triglyceride levels were also higher in the metformin group. The baseline characteristics of women whose offspring were followed up and those whose offspring were not followed up were similar except that the group that was followed up was more likely to have a family history of diabetes [Table 2]. In [Table 3] and [Table 4], the demographic details, anthropometric measurements, and other features not captured in the brief communication of mothers and offspring between the two groups were compared. Most characteristics were similar except that the group on metformin had higher triglyceride values. Triglyceride levels were 0.7 mmol/l (0.6, 1.0) in the glibenclamide group and 0.9 mmol/l (0.7, 1.3) in the metformin group, P = 0.03. The average BMI of offspring which was similar in both the groups was 18. The fat measurements on DEXA in offspring of the two treatment groups were compared and were shown to be similar in both the groups. None of these offspring had diabetes mellitus. However, 8.3% of the offspring in the glibenclamide group and 10% of the offspring in the metformin group were prediabetic. The nutritional intake of mother and offspring [Table 5] and the physical activity [Table 6] of the offspring in the two groups were also compared and found to be mostly similar. Women treated with glibenclamide 9 years before were significantly more likely to have higher fasting glucose levels compared to women who were treated with metformin. They also had a significantly increased diastolic blood pressure when compared to the metformin group. No other significant differences were seen between the two groups. Forty-six percent of women in the glibenclamide group and 42% of women in the metformin group had diabetes mellitus. Seventy-eight percent of the women in the glibenclamide group and 73% in the metformin group had metabolic syndrome by the International Diabetes Federation (IDF) criteria. The nutritional intake was similar in both the groups of women.
|Table 1: The comparison of mothers' baseline characteristics at randomization between the two treatment groups that were followed up|
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|Table 2: Comparison of baseline characteristics at randomization between mothers of offspring that were followed up with that of mothers that were not followed up|
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|Table 3: Comparison of the health status of offspring according to the treatment groups at randomization|
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|Table 4: Comparison of the current health status of mothers according to the treatment groups at randomization|
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|Table 5: Comparison of nutritional intake of offspring and mother according to the treatment groups|
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|Table 6: Comparison of offspring's physical activity according to the treatment groups using the Global Physical Activity Questionnaire|
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| Discussion|| |
The follow-up study to our knowledge is probably the only study that has compared and followed up women treated with glibenclamide and metformin and their offspring, 9 years after delivery. The significant finding of this study is that women in the glibenclamide group, 9 years later, were more likely to have higher glucose levels and higher diastolic blood pressure. The glucose values of these cohorts were principally similar at randomization, except that the GTT levels in the group treated with metformin had higher glucose levels at the 1st h. The treatment with metformin which was previously associated with better neonatal outcomes showed a significant increase in triglyceride levels when compared to the offspring of mothers treated with glibenclamide. However, there was no difference in the blood glucose levels, fasting insulin, cholesterol, LDL, and HDL levels. The other salient feature is that we had a 50% follow-up rate even after 9 years. This detailed publication captures all the other parameters that were collected and could not be presented in the brief communication.
Over the years, there has been an increasing incidence of Type 2 diabetes mellitus and metabolic syndrome in the pediatric population in our region. Data from multiple studies suggest that the Asian population as compared to other races is at an increased risk for diabetes and associated cardiovascular complications Hillier et al. followed up over 9000 offspring of mothers with GDM.,, They observed that hyperglycemia and worsening fasting glucose values were associated with an increased risk of obesity in the offspring. Krishnaveni et al. subsequently demonstrated that their cohort of children born to mothers with GDM had features of increased adiposity, insulin resistance, and systolic blood pressure when compared to healthy controls. It is believed that the in utero action of metformin may have a role in decreasing adiposity and insulin resistance in the offspring. This however was not demonstrated in our cohort of children, where no difference in the anthropometric measurements, metabolic parameters, or adiposity was seen between the offspring of the two treatment groups. The offspring of the metformin cohort had a significant increase in fasting high triglyceride levels with no significant increase in the rest of the lipid profile when compared to the offspring of the glibenclamide group. The levels were within the normal range.
The Mig TOFU 2-year offspring study was conducted on the similar premise that metformin had a positive influence on the offspring. In this study, they observed an increase in the subscapular and biceps skin thickness in the offspring of mothers with GDM who received insulin and metformin in comparison to those whose mothers received only insulin. However, no difference in total body fat was seen. They inferred that children exposed to metformin had more fat being stored peripherally and this would result in lesser visceral fat distribution and insulin resistance. Interestingly, when these children were followed at 7–9 years, there was no demonstrable difference in the metabolic parameters or total and abdominal fat percentage in the two groups. The offspring in our cohort have much lower BMI compared to other races as was seen in the previous studies., We could not comment on the total subcutaneous central body fat seen in these studies as we did not have a control group. Nine years after randomization, almost 50% of our cohort of women were diabetic and 75% had metabolic syndrome.
We are not clear if the association of inferior glycemic control and increased diastolic blood pressure in women treated with glibenclamide, 9 years after randomization, was an incidental finding. However, it is a finding that would warrant the need for more research. The significance of the higher triglyceride in the offspring in the metformin group with an otherwise normal lipid profile is also unknown. Although we had a 50% follow-up rate, the limitation of our study was that the sample size required was not achieved and it did not have a control arm of offspring of nondiabetic women. Our study has provided some important information about the long-term health outcomes of this cohort and their offspring that has the potential to drive more research that can impact public health policy.
| Conclusion|| |
Currently, with the limited information from this study, we would still favor the use of metformin in pregnancy.
The major limitation of the study is that we could contact only 50% of the participants of the initial study.
The information from this study would have been more meaningful if we had included offspring of normal mothers and infants exposed to insulin or insulin and oral hypoglycemic.
We thank the mothers and children who participated in the study and the research officers and medical staff who cared for these patients. This trial was registered under the CTRI CTRI/2014/02/004418.
The study is approved by ethics committees of Christian Medical College, Vellore (IRB no. 10238) and was obtained on 24.08.2016.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]