Gestational diabetes mellitus and retinal microvasculature

Gestational diabetes mellitus (GDM) is defined as glucose intolerance during pregnancy among women without pre-pregnancy diabetes mellitus and is mainly diagnosed in the second or third trimester [1]. Women with GDM are not only at risk of short-term pregnancy complications such as pre-eclampsia, but also have increased long-term risk of obesity, dyslipdemia and type 2 diabetes mellitus (T2DM) [1, 2]. The latter conditions, in turn, are major risk factors for cardiovascular disease [3, 4], perhaps through endothelial and small-vessel dysfunction [5, 6].

Retinal vascular imaging is now a non-invasive tool for assessing the microvascular dysfunction in health and disease [7‐9]. T2DM has been linked to a series of abnormalities in retinal vascular measures such as retinal arteriolar narrowing, retinal venular widening, greater retinal vascular tortuosity, and retinal vascular fractal dimension reduction [8]. Such evidence suggests that small-vessel disease might be an important consequence of insulin resistance and chronic hyperglycemia. Whether small-vessel dysfunction is also present in GDM has not been well studied, however, owing to the difficulty in assessing the microvasculature in vivo. There has been a lack of work studying changes in the maternal retinal microvasculature during pregnancy, specifically with GDM.

Our group has recently investigated retinal microvasculature changes during pregnancy, with findings suggesting abnormal retinal vascular morphological changes associated with elevated blood pressure, maternal obesity, antenatal depression, and poor sleep quality [10‐12]. In this study, we studied the relationship between GDM and retinal vascular changes in expectant mothers, a proxy for small-vessel dysfunction, at 26–28 weeks of pregnancy.

Among the 1136 GUSTO women with an OGTT performed, 542 had further retinal images taken. No statistically significant differences were observed between mothers with and without retinal photography done, except for age (30.4 years vs. 31.2 years, p = 0.02) (Table 1). None of the 542 participants had a history of pre-pregnancy diabetes. Of these 542, 88 (16.8%) had developed GDM by 26–28 weeks pregnancy.

Mothers who developed GDM were significantly older (mean 32.8 vs 30.0 years, P < 0.001), had a higher pre-pregnancy BMI (24.4 vs. 22.5 kg/m², P < 0.01), experienced lower weight gain by 26–28 weeks gestation (7.6 vs. 8.8 kg, P = 0.02), and were more likely to have a family history of diabetes (28.4 vs. 19.4%, P = 0.06), and a past history of GDM (8.0 vs. 0.9%, P < 0.001) (Table 2). Furthermore, GDM mothers had significantly narrower retinal arteriolar caliber (118.8 vs. 121.3 μm), narrower retinal venular caliber (168.4 vs. 171.9 μm), reduced retinal arteriolar fractal dimension (1.24 vs. 1.26 Df), decreased retinal venular fractal dimension (1.22 vs. 1.23 Df), and larger retinal arteriolar branching angle (84.5 vs. 82.2°) than non-GDM mothers (Table 2).

In multiple linear regression after adjusted for social demographic confounders including age, ethnicity, and maternal education (Table 3; Model 1), GDM subjects had narrower retinal arteriolar caliber (1.6 μm; 95% CI: –3.1 μm, –0.2 μm), reduced retinal arteriolar fractal dimension (–0.01 Df; 95% CI: –0.02 Df, –0.001Df), and larger retinal arteriolar branching angle (1.8°; 95% CI: 0.3°, 3.3°) than non-GDM subjects. After further adjustment for GDM risks in Model 3 (Table 2), the associations of GDM and retinal arteriolar caliber and fractal dimension were attenuated, while that of GDM and larger retinal arteriolar branching angle remained (2.0°; 95% CI: 0.5°, 3.6°) (Table 3, Model 2). An example with all these differences in retinal microvascular measures between GDM and non-GDM mothers were shown in Fig. 2.

No evidence was found for effect modification or interaction between exposure variables in our study.

In this study of Singaporean mothers, abnormal retinal arteriolar measures, including narrower arteriolar caliber, reduced fractal dimension, and larger branching angle, were observed in expectant mothers with GDM diagnosed at 26–28 weeks of gestation. Even after statistical adjustment for conventionally recognized risk factors of GDM, the association and statistical significance between GDM and retinal arteriolar branching angle persisted.

Small-vessel dysfunction has been shown to be a consequence of T2DM [8, 17], possibly as a result of endothelial dysfunction and inflammation resulting from chronic hyperglycemia [18, 19]. Hyperglycemia leads to vasoconstriction, reduces blood flow and exacerbates tissue hypoxia, with eventual compensatory vasodilation [7, 20]. Owing to the non-invasive and reproducible nature of the retinal microvasculature imaging, changes in retinal vascular geometry have been extensively studied and validated as proxies for small-vessel dysfunction, particularly in diabetes and other microvascular disorders [8].

Pregnancy is characterized by an altered inflammatory profile compared to the non-pregnant state, with a fine balance between pro- and anti-inflammatory cytokines needed for normal fetal development [21]. In up-regulated inflammatory conditions like obesity, this balance is altered and may compromise normal pregnancy [22]. Even though the pathophysiology of GDM is not fully understood, GDM is associated with the up-regulation of leptin and pro-inflammatory cytokines (e.g., interleukin-6 and tumor necrosis factor α) [23, 24]. Therefore, a heightened inflammatory response imposed by GDM during pregnancy may affect adipose tissue, placental and vascular endothelium, which in turn might lead to adverse clinical outcomes such as pre-eclampsia [25].

We found that abnormalities in retinal arterioles, but not in retinal venules, were associated with GDM. These microvascular changes include narrower retinal arteriolar caliber, reduced retinal arteriolar fractal dimension, and larger retinal arteriolar branching angle. Since hyperglycemia is presumed to have an initial vaso-constrictive effect, followed by irreversible vasodilatation [7], the same principle may apply in GDM: transient hyperglycemia results first in vasoconstriction and is reflected by retinal arteriolar narrowing.

We also assessed retinal arteriolar geometry in terms of branching angle and fractal dimensions. The larger the branching angle, the greater the workload and energy spent in maintaining efficient blood circulation [26]. Larger branching angles have been linked to atherosclerosis [27], disrupted blood flow [28], and endothelial damage [29]. Fractal dimension, on the other hand, quantifies the degree of geometric complexity, with reduced fractal dimension reflecting a sparser branching pattern and lower vascular structural complexity [30]. We found that both reduced retinal arteriolar fractal dimension and larger retinal arteriolar branching angle were associated with GDM. These morphological abnormalities may have been due to the hypoxic state of the retina consequent to a hyperglycemic environment in GDM.

Similar to retinal imaging studies obtained in patients with diabetes, we postulate that investigating microvascular changes in GDM may provide valuable insights into such pregnancy complications. To the best of our knowledge, ours is the first study demonstrating that changes in the maternal retinal microvasculature, specifically the retinal arterioles, are associated with GDM and may reflect the role of small-vessel dysfunction as its pathophysiological consequence.

Strengths of our study include a large sample size of pregnant women and GDM cases, standardized protocols using validated assessments of GDM and retinal vasculature, and detailed information on a range of potential confounders and risk factors for GDM. However, several methodological limitations are also noted. First, only approximately half of all recruited subjects were included in our analyses, and selection bias cannot be excluded. However, as shown in Table 1, mothers with and without retinal vessel assessments were similar in baseline factors, and it seems likely that our results are generalizable to our overall study cohort. Second, our study was cross-sectional, hence the causal relationship between GDM and retinal microvascular changes warrants further investigation. In some studies, retinal arteriolar narrowing and impaired microvascular perfusion have been suggested to delay the access of glucose and insulin to target tissues, which leads to insulin resistance—a major mechanism underlying type 2 diabetes [31]. Third, measurement error may have occurred in maternal recall of covariates such as pre-pregnancy weight, past history of GDM, and family history of diabetes. Any such errors, however, are likely to have been non-differential with respect to the microvascular changes we studied, and thus would tend to bias true associations toward the null.

In summary, we observed abnormalities in the retinal arteriolar microvasculature, including narrower caliber, reduced fractal dimensions and larger branching angle, in expectant mothers with GDM during the late second trimester of pregnancy. Further research is required to investigate whether the vascular changes we observed persist after pregnancy, and whether they predict the later development of type 2 diabetes or cardiovascular disease.