The study of offspring and mothers with gestational diabetes treated with metformin or glibenclamide in a randomized controlled trial after 9 years

Praveen George Paul; Beena Ruth Kingsbury; Hilda Yenuberi; Richa Sasmita Tirkey; Santosh Joseph Benjamin; Swati Rathore; Babuji Manimegalai; Antonisamy Belavendra; Jiji Elizabeth Mathews

doi:10.4103/cmi.cmi_95_22

ORIGINAL ARTICLE

Year : 2023 | Volume : 21 | 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

Correspondence Address:
Dr. Richa Sasmita Tirkey
Department of Obstetrics and Gynaecology, Christian Medical College, Ida Scudder Road, Vellore - 632 004, Tamil Nadu
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/cmi.cmi_95_22

Abstract

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 Jun 6];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.^[1],[2] Results of a study on GDM mothers treated with metformin or glibenclamide were published, with metformin showing better neonatal outcomes.^[3] Children of these mothers with gestational diabetes may be at increased risk of metabolic syndrome in later life.^{[4],[5],[6],[7],[8]} We published the findings of the 9-year follow-up of the study as a brief communication.^[3],[9] Metformin crosses the placental barrier while glibenclamide may not cross the placenta.^{[10],[11],[12]} 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.^[13]

Methodology

Study setting

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.

Design

The follow-up of a randomized controlled trial.

Period

Nine-year follow-up of a randomized controlled trial was done between 2007 and 2019. The present study was done between 2016 and 2019.^[3],[11]

Inclusion criteria

Women recruited to the randomized trial^[3] 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.

Statistical methods

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 1^st-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.^[9] 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^[9]

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Table 4: Comparison of the current health status of mothers according to the treatment groups at randomization^[9]

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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.^[9] 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 1^st 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.^[14] 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.^{[15],[16],[17]} 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.^[6] 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.^[8] 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.^[13] The offspring in our cohort have much lower BMI compared to other races as was seen in the previous studies.^[18],[19] 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.

Limitations

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.

Acknowledgment

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.

Ethical statement

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

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343:1134-8.
2.	Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003-15.
3.	George A, Mathews JE, Sam D, Beck M, Benjamin SJ, Abraham A, et al. Comparison of neonatal outcomes in women with gestational diabetes with moderate hyperglycaemia on metformin or glibenclamide – A randomised controlled trial. Aust N Z J Obstet Gynaecol 2015;55:47-52.
4.	Simeoni U, Barker DJ. Offspring of diabetic pregnancy: Long-term outcomes. Semin Fetal Neonatal Med 2009;14:119-24.
5.	Whitaker RC, Pepe MS, Seidel KD, Wright JA, Knopp RH. Gestational diabetes and the risk of offspring obesity. Pediatrics 1998;101:E9.
6.	Krishnaveni GV, Veena SR, Hill JC, Kehoe S, Karat SC, Fall CH. Intrauterine exposure to maternal diabetes is associated with higher adiposity and insulin resistance and clustering of cardiovascular risk markers in Indian children. Diabetes Care 2010;33:402-4.
7.	Chandler-Laney PC, Bush NC, Rouse DJ, Mancuso MS, Gower BA. Maternal glucose concentration during pregnancy predicts fat and lean mass of prepubertal offspring. Diabetes Care 2011;34:741-5.
8.	Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): Body composition at 2 years of age. Diabetes Care 2011;34:2279-84.
9.	Paul P, Priyambada L, Abraham A, Manimegalai B, Paul TV, Princy S, et al. Follow-up of offspring and mothers with gestational diabetes treated with metformin or glibenclamide: A randomized controlled trial. Int J Gynaecol Obstet 2021;152:446-7.
10.	Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: Old or new insights? Diabetologia 2013;56:1898-906.
11.	Elliott BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. American Journal of Obstetrics and Gynecology Volume 1991;165:807-812. Available from: https://doi.org/10.1016/0002-9378(91)90421-M.
12.	Hebert MF, Ma X, Naraharisetti SB, Krudys KM, Umans JG, Hankins GD, et al. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther 2009;85:607-14.
13.	Rowan JA, Rush EC, Plank LD, Lu J, Obolonkin V, Coat S, et al. Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): Body composition and metabolic outcomes at 7-9 years of age. BMJ Open Diabetes Res Care 2018;6:e000456.
14.	Baxi R, Vasan SK, Hansdak S, Samuel P, Jeyaseelan V, Geethanjali FS, et al. Parental determinants of metabolic syndrome among adolescent Asian Indians: A cross-sectional analysis of parent-offspring trios. J Diabetes 2016;8:494-501.
15.	Ramachandran A, Ma RC, Snehalatha C. Diabetes in Asia. Lancet 2010;375:408-18.
16.	Ramachandran A, Snehalatha C, Yamuna A, Murugesan N, Narayan KM. Insulin resistance and clustering of cardiometabolic risk factors in urban teenagers in southern India. Diabetes Care 2007;30:1828-33.
17.	Hillier TA, Pedula KL, Schmidt MM, Mullen JA, Charles MA, Pettitt DJ. Childhood obesity and metabolic imprinting: The ongoing effects of maternal hyperglycemia. Diabetes Care 2007;30:2287-92.
18.	Chandalia M, Abate N, Garg A, Stray-Gundersen J, Grundy SM. Relationship between generalized and upper body obesity to insulin resistance in Asian Indian men. J Clin Endocrinol Metab 1999;84:2329-35.
19.	Yajnik CS, Lubree HG, Rege SS, Naik SS, Deshpande JA, Deshpande SS, et al. Adiposity and hyperinsulinemia in Indians are present at birth. J Clin Endocrinol Metab 2002;87:5575-80.