No deleterious effect of an additional pregnancy on glucose metabolism in women with previous gestational diabetes mellitus

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Abstract

Objective

Women with gestational diabetes mellitus (GDM) often develop type 2 diabetes later in life. It remains unclear whether this results solely from a common underlying predisposition or, whether a pregnancy itself persistently impairs glucose metabolism in predisposed women. We therefore examined how an additional pregnancy affected different aspects of glucose metabolism in women with previous GDM.

Research design and methods

Nested case-control study within the prospective cohort study PPSDiab, recruited in Munich, Germany from 2011-16. Cases (n = 41): women with previous GDM who completed an additional pregnancy; controls: no additional pregnancy, pairwise matching. Endpoints: change of the area under the glucose curve (AUGC) of an oral glucose tolerance, of plasma glucose at 60′ of the test (PG 60′), of the insulin sensitivity index (ISI) and of the disposition index (DI), all between before and after the additional pregnancy in cases/the corresponding observation period in controls.

Results

We observed no significant difference between cases and controls in the primary [ratio AUGC 1.05(0.92–1.15) vs. 0.97(0.85–1.14); p = 0.21] and in the secondary endpoints [difference PG 60′, ratio ISI and ratio DI.

Conclusion

We did not find a deleterious effect of an additional pregnancy on glucose metabolism in women with previous GDM.

Introduction

Women with gestational diabetes mellitus (GDM) are at high risk for developing type 2 diabetes later during their lifetime [1], [2], [3]. This high risk is, at least in part, caused by a common underlying predisposition for GDM and type 2 diabetes that is exemplified by a large overlap in genetic risk polymorphisms for both diseases [4], [5].

Yet, every pregnancy promotes insulin resistance [6], [7] and it could be that this temporary metabolic stress results in persistent damage to glucose metabolism in predisposed women. This damage, in turn, could contribute to the high risk for future type 2 diabetes and for a recurrence of GDM in a subsequent pregnancy. This assumption was formed after Peters et al. [8] demonstrated a more than tripled risk of type 2 diabetes after GDM in Hispanic women with an additional pregnancy. However other studies have not confirmed this finding [9], [10], [11]. The recurrence rate of GDM in a subsequent pregnancy varied between 41.3% and 49.3% in previous studies [12], [13], [14].

Determining the effect of an additional pregnancy in women with previous GDM remains problematic because many other factors, such as body weight changes, nutrition, and physical activity habits influence glucose metabolism and, therefore, the risk of type 2 diabetes [15]. These factors are difficult to control for in long-term observational studies, which may be the reason for the conflicting results thus far.

To circumvent this problem, we analyzed the metabolic effect of an additional pregnancy in women with previous GDM in a precisely phenotyped and closely followed cohort of women. We used a nested case-control design and the change in the area under the glucose curve of a 5-point oral glucose tolerance test (ogtt) as the primary endpoint of this analysis. With this approach, we observed no detrimental effect of an additional pregnancy.

Section snippets

Study cohorts and matching

We conducted a nested case-control study of women drawn from our prospective, monocenter observational study Prediction, Prevention, and Subclassification of Type 2 Diabetes (PPSDiab). For PPSDiab, women after a pregnancy complicated by GDM (n = 199) and women after a normoglycemic pregnancy (n = 100) were recruited 3–16 months after delivery and remain followed yearly thereafter over a period of ten years. All participants provided written informed consent and the study was approved by the

Results

Forty-seven women from the PPSDiab cohort and with a history of GDM completed an additional pregnancy between two eligible visits (Fig. 2). We excluded 6 women from the analysis: two due to missing measurements of plasma glucose 90′ (n = 1) and body weight (n = 1) at V1, two because they developed type 1 diabetes during follow-up, one because of two pregnancies between V1 and V2, and one because of a very high BMI (44 kg/m2) that precluded finding a matching partner. Thus, we examined 41 pairs

Discussion

We tested whether or not an additional pregnancy persistently impairs glucose metabolism in women with previous GDM. Using a nested case-control design, we found no deleterious effect on the primary endpoint AUGC ratio and on the secondary endpoints Δ PG 60′, ISI ratio, and DI ratio, all between before and after the additional pregnancy.

Cases and controls were matched for baseline BMI, weight gain during the observation period, and duration of observation. This should have isolated any

Author contributions

L.F. was the main author of the paper and contributed to the study design, the analysis and interpretation of data, and the drafting and revision of the manuscript. M.R. performed the statistical analysis and contributed to the interpretation of data and writing the manuscript. C.G. was involved in the conception of the study, contributed to the discussion, and reviewed and edited the manuscript. A.P. contributed to writing and revising the manuscript. J.K. contributed to the discussion and to

Funding

The Diabetes Research Group receives funding from the Helmholtz Zentrum München, Klinikum der Universität München, and the German Center for Diabetes Research.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The authors thank all women for their participation in the PPSDiab study. We also thank Mary Carlyle White Scholz for language editing and Vanessa Sacco, Mandy Meisel, and Carmen Sommer for expert technical assistance.

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