Letter to the Editor: ‘Hyperglycaemia in pregnancy: Outcomes and diagnostic accuracy of combined modalities’

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Dear Editor,

We read with great interest the recent article by Manga et al on hyperglycaemia in pregnancy and the diagnostic performance of combined fasting plasma glucose (FPG) and glycated haemoglobin (HbA₁c) modalities. The authors are to be commended for addressing this important issue within a South African tertiary-care context, where limited resources often preclude universal oral glucose tolerance testing (OGTT).1 However, we would like to raise two methodological concerns that were not fully acknowledged and which may have important implications for interpretation.

First, the study reported that 14.8% of participants were human immunodeficiency virus (HIV) positive, with 13.4% receiving antiretroviral therapy (ART). This demographic is highly relevant in the South African antenatal population, yet no stratified analysis or adjustment of HbA₁c performance by HIV or ART status was presented. This omission is noteworthy, given the established evidence suggesting potential bias in HbA₁c measurements among people living with HIV (PLWH). For instance, in a cross-sectional study of HIV-infected individuals receiving zidovudine (AZT)-based regimens, HbA₁c was shown to underestimate mean glucose concentrations by approximately 0.58% compared with non-AZT regimens, due to alterations in haematocrit and erythrocyte indices.2 Similarly, a meta-analysis of sub-Saharan African data found that ART exposure was associated with lower HbA₁c values compared with HIV-negative individuals.3 Although a recent UK-based study found no strong independent effect of HIV on HbA₁c when continuous glucose monitoring and OGTT were employed, its population comprised older men with type 2 diabetes rather than pregnant women.4 Crucially, none of these data directly reflect pregnant women in a high-HIV-burden African setting. In the mentioned study, failure to adjust or stratify diagnostic accuracy by HIV or ART status could introduce systematic misclassification, potentially under-detecting gestational hyperglycaemia in HIV-positive women or overestimating diagnostic performance among HIV-negative women. Given the proposed diagnostic threshold (HbA₁c ≥ 5.75%) and the reported area under the curve (AUC) of 0.93, this bias may not be negligible.

Second, the authors report a median gestational age at booking of 24 weeks. Conducting diagnostic testing at this stage raises the possibility of misclassifying undiagnosed pre-gestational diabetes mellitus (PGDM) as gestational diabetes mellitus (GDM). Evidence suggests that dysglycaemia identified before 20 weeks’ gestation often reflects pre-existing metabolic dysfunction rather than pregnancy-induced changes. For example, Sweeting et al demonstrated that women diagnosed with GDM before 24 weeks exhibit metabolic characteristics more akin to type 2 diabetes, including greater insulin resistance and adiposity.5 In the study by Manga et al., the absence of early pregnancy glycaemia or HbA₁c measurements limits the ability to differentiate true gestational from pre-existing hyperglycaemia. Consequently, both the estimated GDM prevalence and comparisons of clinical outcomes (GDM versus overt diabetes) may be affected, thereby constraining external validity.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Hawkar A. Nasralla: Conceptualization, Writing – original draft. Shaho F. Ahmed: Validation, Writing – review & editing. Fahmi H. Kakamad: Project administration, Supervision, Writing – review & editing.

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.