Gestational diabetes mellitus (GDM) is a manifestation of glucose intolerance first diagnosed during pregnancy (gestation) (McIntyre et al., 2019). In this condition, a hormone produced by the placenta interferes with the body's ability to use insulin properly. As opposed to being taken in by the cells, glucose accumulates in the blood (McIntyre et al., 2019). GDM is the metabolic condition that affects pregnant women the most frequently (Alfadhli, 2015). The standardized global prevalence of GDM was 14% as per the international diabetes federation (IDF) in 2021 (Wang et al., 2022). Alarmingly, within the last two decades, the prevalence of GDM has surged by more than 30% in numerous nations (Zhu and Zhang, 2016). There is an inherent danger of short-term and long-term consequences for both mother and child due to the manifestation of GDM. Several medical complications, including macrosomia, birth trauma, respiratory distress syndrome, hypoglycemia, an increased likelihood of primary cesarean sections, preterm labor, fetal development retardation, and neonatal hypocalcemia, could arise due to GDM. Moreover, children of mothers with GDM have been observed to exhibit a higher lifetime risk of obesity, diabetes, and cardiovascular diseases (McIntyre et al., 2019). Major GDM risk factors include maternal overweight, late childbearing age, multiple pregnancies, family history of T2DM, and ethnicity (McIntyre et al., 2019). Accumulating evidence has implicated significant connections between higher iron storage and changes in glucose metabolism, including an increased risk of T2DM in non-pregnant people (Díaz-López et al., 2020, Wang et al., 2021). However, the evidence regarding the role of iron dysregulation in GDM is uncertain. Furthermore, there is a lack of evidence regarding markers that can distinguish between GDM identified at early and later stages of pregnancy.

Iron homeostasis disruption can result from either depleted iron stores or an overload of the labile iron pool. Insufficient dietary intake is the primary cause of iron deficiency, while iron overload can be influenced by various factors. The presence of primary, genetically inherited defects in genes regulating iron homeostasis can lead to iron overload, a condition referred to as hereditary hemochromatosis (Wallace, 2016). Moreover, secondary iron overload can occur due to excessive dietary iron consumption, frequent blood transfusions, and various hematological disorders that prompt the body to absorb and store more iron than required (Wallace, 2016). Deficiency of the micronutrient iron is associated with unfavorable pregnancy outcomes, including low birth weight, preterm, intrauterine growth restriction, and increased maternal illness (Georgieff, 2020). In pregnant women already replete with iron, prophylactic iron supplementation could raise the risk of pregnancy complications, including GDM, given the toxic characteristics of excess iron (Petry, 2022). An iron overload primes the cells to a novel type of iron-dependent lipid peroxidation-mediated cell death termed ferroptosis. Notably, ferroptosis of pancreatic beta cells has been attributed to play a critical role in the pathogenesis of T2DM (Miao et al., 2023). Physiologically, ferroptosis is tightly regulated by glutathione-mediated detoxification pathways driven by SLC7A11/GPX4 axis (Liu et al., 2022, p. 11). In a condition such as GMD, where there is likely alteration of iron status, it is unknown whether the latter participates in the pathogenesis of the disease. Iron status is generally estimated by measuring various markers, including serum iron, ferritin, and transferrin concentrations. While total iron storage is reflected through the measurement of serum ferritin levels, iron transportation is indicated by transferrin saturation values, which fall before anemia sets in (Pfeiffer and Looker, 2017). Recently, the role of Lactoferrin, a nutrient belonging to the transferrin family, has received the spotlight, especially after the COVID-19 pandemic (Kell et al., 2020), owing to its immunological and anti-anemic properties.

Lactoferrin is an 80-kDa single polypeptide and iron-binding nutrient first identified in mammalian milk. It is naturally secreted by the exocrine glands (such as those that produce tears or maternal milk) and can also be produced as secondary granules from neutrophils (Kell et al., 2020). Moreover, Lactoferrin has also been widely studied as a nutritional oral supplement (Kell et al., 2020, Lönnerdal, 2009). A cationic glycosylated protein, human Lactoferrin consists of 691 amino acids, of which 60% share sequence identity with serum transferrin. However, Lactoferrin is distinct from transferrin in the aspect of biological functions. Unlike transferrin, Lactoferrin can bind and sequester iron even at low pH conditions, often prevalent during inflammation. By sequestration of free iron, its role as an immune regulator controlling immune responses against toxic reactive oxygen species and oxidative stress has been highlighted (Artym et al., 2021). Of interest, serum Lactoferrin was observed to be markedly reduced in individuals with T2DM (Moreno-Navarrete et al., 2009). Higher circulating Lactoferrin levels were associated with better insulin sensitivity, weight control, and glucose regulation (Moreno-Navarrete et al., 2009). However, no studies have investigated the circulatory levels of Lactoferrin in a setting of GDM subjects where both iron status and glucose tolerance could be markedly altered. Moreover, the role of Lactoferrin in regulating pathogenic ferroptosis, particularly in the background of hyperglycemia, is unknown.