Gestational Diabetes Mellitus

Abstract

Formally recognized by O’Sullivan and Mahan in 1964, gestational diabetes mellitus (GDM) is defined as any degree of hyperglycaemia recognized for the first time in the pregnancy, including type 2 diabetes mellitus diagnosed during pregnancy, as well as true GDM which develops in pregnancy. GDM is currently the most prevalent medical complication during gestation, affecting approximately 15% of pregnancies worldwide. Important risk factors for GDM include being obese, advanced maternal age and having a family history of diabetes mellitus. Expectant mothers with GDM face the risk of developing gestational hypertension, pre-eclampsia, and necessitating cesarean section for pregnancy termination. Moreover, GDM amplifies the likelihood of complications such as cardiovascular disease, obesity, and abnormal carbohydrate metabolism, consequently increasing the chances of type 2 diabetes (T2D) development in both the mother and the child. Pregnancy itself places stress on the body’s insulin production and utilization, and some women are unable to produce enough insulin to overcome the insulin resistance caused by pregnancy hormones. While gestational diabetes usually resolves after pregnancy, the experience of insulin resistance during pregnancy can unmask an underlying predisposition to insulin resistance, which is a key factor in the development of T2D.

1. Introduction

Gestational diabetes mellitus, the most common metabolic complication of pregnancy, is a state of hyperglycemia (fasting plasma glucose ≥5.1 mmol/L, 1 h ≥ 10 mmol/L, 2 h ≥ 8.5 mmol/L during a 75 g oral glucose tolerance test according to WHO criteria) diagnosed the first time during pregnancy [1]. The prevalence is increasing consistent with the global increase in obesity and diabetes. GDM affects 14% of pregnancies worldwide, representing approximately 20 million births per year [2].

It is associated with an increased risk of maternal complications like gestational hypertension, pre-eclampsia and termination of pregnancy via cesarean section, as well as neonatal complication as macrosomia, neonatal hypoglycemia, neonatal respiratory distress and birth trauma. In addition, mothers with this condition are at risk of developing cardiovascular disease, obesity and impaired carbohydrate metabolism, leading to the development of T2D in both mother and infant. This relationship between gestational diabetes and the risk of developing type 2 diabetes in the future is thought to be due to shared risk factors, such as genetics, obesity, and insulin resistance. Inadequate control and treatment can lead to major adverse health complications of the mother and child but it is important to note that not all cases of GDM carry the same risk of adverse outcomes. Both clinical and metabolic differences among individuals with GDM may modify the impact of the condition on maternal and fetal health [3].

Historically, screening for GDM consisted of obtaining the patient’s medical history and focused primarily on past obstetric outcomes and a family medical history of T2D. The International Association of Diabetes and Pregnancy Study Group (IADPSG) recommend the universal 75 g of glucose, 2 h tolerance test. American College of Gynaecologists and Obstetricians supports the two-step process. At this moment the clinicians can choose to use either the IADPSG’s recommendations or ACOG’s [4].

The pathogenesis of GDM consists of an intricate mechanism of interaction of many genetic, metabolic and environmental factors. The treatment methods for GDM include an appropriate diet and increased physical activity, and when those are not sufficient, pharmacotherapy, usually insulin is used [5]. Adequate screening, prevention and treatment of GDM are needed to reduce the morbidity complications and economic burden of GDM that affect society.

2. GDM definition and classification

Outside of pregnancy, three distinct forms of diabetes mellitus are described: autoimmune diabetes (type I), diabetes occurring on the background of insulin resistance (type II), and diabetes as a result of other causes, including genetic mutation, diseases of the exocrine pancreas, and drug- or chemical-induced diabetes. While there is evidence that diabetes can occur in all three settings, the vast majority of GDM cases present as β-cell dysfunction on a background of chronic insulin resistance, to which the normal insulin resistance of pregnancy is partially additive [6]. Thus, affected women tend to have an even higher degree of insulin resistance than healthy pregnant women, and therefore have further reductions in glucose utilization and increased glucose production and free fatty acids concentration. It is thought that β-cell deteriorates due to excessive insulin production in response to excess energy consumption and insulin resistance, exhausting the cells over time [7]. Mainly, GDM is defined as a condition in which carbohydrate intolerance develops during pregnancy. Gestational diabetes that is adequately controlled without medication is often termed diet-controlled GDM or class A1GDM. Gestational diabetes that requires medication to achieve euglycemia is often termed class A2GDM. GDM is usually diagnosed in the second and third trimesters. First-trimester hyperglycemia is usually caused by an un-diagnosticated Ty II DM [5].

During a healthy pregnancy, the maternal body goes through a series of physiological transformations to meet the needs of the fetus. These changes encompass various systems such as cardiovascular, renal, hematologic, respiratory, and metabolic. One significant metabolic adaptation involves insulin sensitivity. Throughout gestation, insulin sensitivity fluctuates depending on the demands of pregnancy. In early gestation, insulin sensitivity increases, facilitating the uptake of glucose into adipose stores to prepare for the energy requirements of later pregnancy [8]. Yet, as pregnancy advances, an increase in nearby and placental hormones like estrogen, progesterone, leptin, cortisol, placental lactogen, and placental growth hormone, collaboratively bring about a condition of reduced responsiveness to insulin [8]. Consequently, plasma glucose levels rise slightly. Glucose is readily transported across the placenta to nourish fetal growth. This mild insulin resistance also stimulates endogenous glucose production and the breakdown of fat stores, leading to further elevation of plasma glucose levels and free fatty acids concentrations. Animal studies suggest that pregnant women compensate for these changes by hypertrophy and hyperplasia of pancreatic β-cells, as well as an increase in glucose-stimulated insulin secretion (GSIS), to maintain glucose homeostasis [9]. The involvement of placental hormones in this process is evident from the fact that maternal insulin sensitivity returns to pre-pregnancy levels shortly after delivery [10].

3. Epidemiology

Overweight and obesity represent a growing problem around the world which significantly contributes to the steady increase in the incidence of diabetes, including gestational diabetes of women of reproductive age. According to the 2019 report of the International Diabetes Federation (IDF), more than 20 million women presented with disorders of carbohydrate metabolism, of which approximately 80% were GDM. About 1 in 6 pregnancies is affected by GDM [1]. South-East Asia had the highest prevalence of GDM at 24%, while the lowest prevalence was seen in Africa at 10%. Almost 90% of cases of hyperglycemia in pregnancy occurred in low- and middle-income countries. Even within countries, GDM prevalence varies depending on race/ethnicity and socioeconomic status (Figure 1) [11].

Figure 1.

Global incidence of gestational diabetes.

4. Risk factors

Inconsistencies in the diagnosis criteria for GDM and measurements of the risk factors make it difficult to compare findings across studies. Despite these, several risk factors emerge consistently. These are obesity, overweight, advanced maternal age, excessive gestational weight gain, ethnicity, genetic polymorphism, family or personal history of GDM and other diseases of insulin resistance such as polycystic ovary syndrome (PCOS) [12, 13, 14, 15, 16, 17]. The incidence of hyperglycemia in pregnancy increases with age. IDF data is showing the highest percentage of pregnancies with GDM at ages 45–49, reaching 37%. The delivery of a macrosomic child is another important factor that may increase the risk of both GDM and T2DM by up to 20%. GDM in a previous pregnancy increases the risk of reoccurrence by more than six times [18]. In women with a BMI of at least 30 kg/m², the frequency of GDM is 12% and in women with first-degree relatives with DM is 11%. The combination of these two factors increases the risk by up to 61%. Women who had prior treatment for PCOS showed an occurrence of gestational diabetes mellitus (GDM) at a rate more than double that of other pregnancies [19].

Gestational diabetes, characterized by a fasting plasma glucose (FPG) level of ≥5.1 mmol/L in the early stages of pregnancy, presents correlations with elevated body weight and BMI at the initiation of pregnancy. Furthermore, it is linked to a heightened propensity for necessitating insulin therapy and is associated with augmented birth weight outcomes. Using IADPSG criteria to diagnose gestational diabetes in the initial phases of pregnancy unveils a subset of pregnant individuals exhibiting discernible contrasts in anthropometric indicators and the trajectory of pregnancy compared to those diagnosed at later stages. Krystynik et al. showed that the early diagnosis of gestational diabetes (indicated by FPG ≥ 5.1 mmol/L) is concomitant with amplified body weight and BMI upon the commencement of pregnancy. Simultaneously, an early diagnosis of gestational diabetes coincides with more frequent utilization of insulin treatment and higher weight at birth [20].

Each of these risk factors is either directly or indirectly linked to the impairment of β-cell function and/or insulin sensitivity. For instance, the association between overweight and obesity with impaired β-cell function and insulin signaling pathways arises from prolonged and excessive calorie intake. This excessive intake overwhelms the capacity of β-cells to produce insulin.

5. Pathophysiology of GDM

As previously discussed GDM is mainly the result of β-cell dysfunction on a background of chronic insulin resistance during pregnancy. Therefore, both β-cell dysfunction and insulin resistance represent critical components of the pathophysiology of GDM. These impairments exist, usually, before the pregnancy and can be progressive. The brain, liver, muscle adipose tissue and placenta contribute to the development of GDM.

5.1 β-Cell dysfunction

The primary function of β-cells is to store and secrete insulin in response to glucose load. β-Cell dysfunction is defined by the impaired ability to adequately sense plasma glucose concentration or release sufficient insulin. The exact mechanisms underlying β-cell dysfunction can be varied and complex, occurring at different stages of the insulin production process [21].

Various susceptibility genes associated with GDM are related to β-cell function. Minor deficiencies in β-cell machinery may only manifest during metabolic stress, such as pregnancy. β-Cell dysfunction is worsened by insulin resistance, as reduced insulin-stimulated glucose uptake leads to hyperglycemia, burdening the β-cells to produce additional insulin. Glucotoxicity, the direct contribution of glucose to β-cell failure, further exacerbates the dysfunction. Thus, once β-cell dysfunction begins, a vicious cycle of hyperglycemia, insulin resistance and further β-cell destruction is set in motion [22]. Animal studies indicate that β-cell number is crucial for glucose homeostasis. Reductions in β-cell mass overload the remaining β-cells, impairing glucose-stimulated insulin secretion and depleting internal insulin stores [23]. Loss of β-cell mass has been linked to epigenetic downregulation of pancreatic transcription factors and inadequate β-cell proliferation [24].

In summary, β-cell dysfunction reduced β-cell mass or number, and impaired β-cell hyperplasia all play a role in the development of GDM, depending on the individual.

5.2 Chronic insulin resistance

Insulin resistance occurs when cells fail to adequately respond to insulin, resulting in impaired insulin signaling and reduced plasma membrane translocation of glucose transporter 4 (GLUT4), the primary glucose transporter in cells. In GDM, insulin-stimulated glucose uptake is significantly reduced compared to normal pregnancy.

Insulin resistance in GDM is often characterized by altered insulin receptor signaling at the molecular level. While insulin receptor abundance is generally unaffected, changes in the phosphorylation of tyrosine or serine/threonine residues on the insulin receptor dampen insulin signaling. Downstream regulators of insulin signaling, including insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), and GLUT4, also exhibit altered expression and/or phosphorylation patterns in GDM. These disruptions in insulin signaling and GLUT4 translocation can persist beyond the pregnancy, indicating the long-term effects of GDM [25].

5.3 Neurohormonal dysfunction

The neurohormonal network regulates appetite, active energy expenditure and basal metabolic rate and is highly regulated by the circadian rhythm. The network contributed to GDM by influencing adiposity and glucose utilization. Some of the most important regulators of neurohormonal metabolic control are adipokines-cell signaling proteins that are secreted primarily by the adipose tissue. These include leptin and adiponectin.

Leptin is a hormone produced by the adipocytes in response to sufficient energy stores in the body. Its primary function is to regulate appetite and increase energy expenditure. Leptin acts on specific neurons in the hypothalamus, particularly in the arcuate nucleus, where it suppresses appetite-stimulating substances like neuropeptide Y (NPY) and agouti-related peptide (AgRP), while activating the anorexigenic polypeptide pro-opiomelanocortin (POMC) [26]. Initially, leptin was considered a potential obesity treatment, but it was later discovered that most obese individuals have developed leptin resistance and do not respond to leptin therapy. As a result of leptin resistance, obese individuals tend to have elevated levels of leptin in their blood (hyperleptinemia), and the concentration of leptin is generally proportional to the degree of adiposity. Leptin resistance can occur due to impaired transport of leptin across the blood-brain barrier or through mechanisms similar to insulin resistance within cells. Leptin resistance also occurs to some extent during normal pregnancy, likely to support increased fat storage beyond the non-pregnant state. In GDM, leptin resistance is further heightened, leading to hyperleptinemia [27]. However, it’s important to note that pre-pregnancy body mass index (BMI) is a stronger predictor of circulating leptin levels compared to GDM itself. During pregnancy, the placenta also secretes leptin, and it becomes the primary source of circulating leptin. In GDM, placental insulin resistance contributes to increased production of leptin by the placenta, resulting in elevated levels of leptin in the mother’s bloodstream. This heightened leptin secretion is believed to enhance the transfer of amino acids across the placenta, potentially contributing to fetal macrosomia.

Adiponectin, like leptin, is a hormone primarily secreted by adipocytes. However, the concentration of adiponectin in the blood is inversely related to adipose tissue mass, with lower levels found in obese individuals [28]. Similarly, GDM is associated with decreased adiponectin levels. Unlike leptin, adiponectin has a stronger association with insulin resistance rather than adiposity, indicating its role in the development of GDM independent of obesity. Adiponectin has several beneficial effects on metabolism. It enhances insulin signaling, promotes fatty acid oxidation, and inhibits gluconeogenesis. These effects are mediated by the activation of AMP-activated protein kinase (AMPK) within insulin-sensitive cells, facilitating insulin receptor substrate-1 (IRS-1) action. Adiponectin also activates the transcription factor peroxisome proliferator-activated receptor alpha (PPAR-alpha) in the liver [29]. Additionally, adiponectin stimulates insulin secretion by increasing the expression of insulin genes and promoting the release of insulin from pancreatic beta cells. In the placenta, adiponectin is expressed at low levels and regulated by cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interferon-gamma (IFN-gamma), and leptin. The role of placental adiponectin in normal and GDM pregnancies is not fully understood. However, emerging evidence suggests that adiponectin may impair insulin signaling and hinder amino acid transport across the placenta, leading to restricted fetal growth. Methylation of the adiponectin gene in the placenta has been associated with maternal glucose intolerance and fetal macrosomia, further emphasizing its potential impact on pregnancy outcomes [30].

5.4 Adipose tissue

Adipose tissue is now recognized as an essential endocrine organ that regulates energy storage and secretes important factors. Adequate storage of excess calories in adipose tissue is crucial for metabolic health. In GDM, reduced adipocyte differentiation and increased adipocyte size hinder the tissue’s ability to safely dispose of excess energy, leading to glucose- and lipo-toxicity in other organs. Obesity, T2D, and GDM are associated with increased inflammation in the adipose tissue. Pro-inflammatory cytokines secreted by resident adipose tissue macrophages contribute to insulin resistance by impairing insulin signaling and inhibiting insulin release from pancreatic β-cells [31].

The dysfunction of adipose tissue stands as a well-established factor contributing to heightened levels of insulin resistance. Recent findings have unveiled alterations in the expression of adipokines within women affected by GDM, indicating a pivotal role of malfunctioning adipose tissue and its compromised endocrine function in the progression of hyperglycemia during pregnancy. Among the adipokines, adiponectin and adipocyte fatty acid-binding protein (A-FABP) emerge as prominent members, closely associated with insulin resistance [32].

In a distinct avenue, fibroblast growth factor-19 (FGF-19) assumes the role of a gut hormone, exerting manifold effects. This hormone, predominantly synthesized by the small intestine in response to dietary intake, transcends its involvement in bile acid homeostasis. FGF-19 additionally triggers an insulin-independent endocrine pathway, orchestrating hepatic protein and glycogen metabolism, restraining gluconeogenesis, and fostering glucose uptake within adipocytes. Fibroblast growth factor (FGF)-19 has been shown to improve glycemic homeostasis and lipid metabolism in animal models. In humans, decreased FGF-19 level has been described in diabetes. Women with GDM had significantly lower mRNA and protein expressions of FGF-19 than control women in the placenta and rectus muscle. FGF-19 expressions are decreased in the placenta and rectus muscle of women with GDM [33].

Women with GDM have significantly lower adiponectin and higher A-FABP levels compared to healthy pregnant, while there are no significant differences in FGF-19 between the groups. Women with GDM showed altered adipokine production even in the first trimester of pregnancy [32].

5.5 Liver

GDM is associated with increased hepatic glucose production (gluconeogenesis), leading to elevated fasting plasma glucose levels. Factors such as insulin signaling pathways and excess gluconeogenesis substrate from increased protein intake and muscle breakdown contribute to this effect. However, the liver is not considered a primary driver of T2D or GDM [5].

5.6 Skeletal and cardiac muscle

Insulin resistance in skeletal muscle is now viewed as a consequence of hyperglycemia rather than a causal factor in diabetes. Skeletal and cardiac muscles develop insulin resistance as a protective measure to divert excess energy to adipose tissue. Treating GDM by targeting skeletal muscle insulin resistance alone, without reducing plasma glucose concentrations, may not be beneficial [34].

5.7 Oxidative stress

Oxidative stress, characterized by an imbalance between pro-oxidants and antioxidants, is implicated in the pathogenesis of GDM. Hyperglycemia and impaired free-radical scavenging mechanisms in GDM women result in increased production of reactive oxygen species (ROS). ROS interfere with insulin signaling and glucose uptake, contributing to insulin resistance. Iron supplementation, homocysteine, and deficiencies of certain micronutrients are associated with oxidative stress in GDM [35, 36].

5.8 Placental transport

The placenta contributes to insulin resistance during GDM by secreting hormones and cytokines. Maternal hyperglycemia affects the placental transport of glucose, amino acids, and lipids. There is strong evidence of changes in the expression of transporters and placental gene expression alterations in lipid pathways in GDM cases (Figure 2) [37].

Figure 2.

Organs involved in the pathophysiology of GDM.

Pregnancy is a phase characterized by heightened metabolic activity in which the maintenance of glucose balance is crucial. When elevated plasma glucose concentrations are detected in pregnant women, it is referred to as GDM, although there is ongoing debate regarding diagnostic criteria. The development of GDM is likely influenced by a combination of genetic, epigenetic, and environmental factors, and the underlying mechanisms are complex and evolve over an extended period. However, in the majority of the cases, the pancreatic β-cells are unable to adequately compensate for prolonged excessive fuel intake, leading to insulin resistance, elevated plasma glucose levels, and increased glucose supply to the developing fetus. Additionally, adipose tissue expandability, chronic low-grade inflammation, gluconeogenesis, oxidative stress, and placental factors are implicated in the pathology of GDM.

6. Diagnosis

The ongoing debate surrounding the diagnosis of GDM has focused on two key issues: whether to include all pregnant women or only those with risk factors, and whether to use one- or two-stage diagnostic procedures. It is important to note that a GDM diagnosis can only be made after excluding previous diagnoses of diabetes (type I or type II) early in pregnancy. Screening only high-risk groups may result in the underdiagnosis of GDM in as many as 35–47% of pregnant women, which undoubtedly impacts obstetric outcomes [38].

The results of the Hyperglycemia Adverse Pregnancy Outcome (HAPO) study, which involved 23,316 women, provided clear evidence of the relationship between elevated glycemia (below the threshold for overt diabetes mellitus) and maternal and neonatal complications. These complications included large-for-gestational-age (LGA) infants, higher rates of cesarean sections, neonatal hypoglycemia, and increased umbilical C-peptide concentrations [39]. Based on the HAPO study findings, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) introduced current diagnostic criteria for GDM, leading to a threefold increase in GDM diagnoses and suggesting previous underestimation. The aim was to identify screening values that better identify pregnancies at risk of perinatal complications. The study demonstrated a positive linear relationship between screening glucose values and adverse perinatal outcomes, showing that perinatal risks began to increase even in women with glucose values considered “normal” in the past. Consequently, the current basis for GDM diagnosis involves administering 75 g of glucose between 24 and 28 weeks of pregnancy to all pregnant women without previously diagnosed diabetes [40, 41].

Treating even mild forms of glucose intolerance in GDM has proven beneficial, as demonstrated by studies such as the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) and the Maternal-Fetal Medicine Units Network (MFMU) study. These studies showed reduced rates of obstetric complications associated with hyperglycemia and pregnancy weight gain [42]. The ACHOIS study revealed a significant reduction in the composite endpoint (including neonatal death, perinatal injury, hyperbilirubinemia, neonatal hypoglycemia, and hyperinsulinemia) with antihyperglycemic interventions, along with lower weight gain and a decreased incidence of LGA. Most scientific societies have incorporated the recommendations of the IADPSG (2010) and the World Health Organization (WHO) (2013) into their daily practice.

The introduction of IADPSG criteria for GDM screening led to a threefold increase in prevalence without significant improvements in GDM-related events for women without risk factors, except for reduced risks of LGA, neonatal hypoglycemia, and preterm birth [40]. This prompted further research into GDM management. In a large randomized trial involving 23,792 pregnant women, Hillier et al. found that one-step screening, compared to two-step screening, doubled the incidence of GDM diagnosis but did not affect the risks of LGA, adverse perinatal outcomes, primary cesarean section, or gestational hypertension or pre-eclampsia [41]. Table 1 presents the criteria for the diagnosis of GDM according to different societies.

	Fasting (mg/dL); mmol/L	1 h (mg/dL); mmol/L	2 h (mg/dL); mmol/L	3 h (mg/dL); mmol/L	Values for diagnosis
ADA/ACOG	95; 5.3	180; 10	155; 8.6	140; 7.8	2
ADIPS	92; 5.1	180; 10	153; 8.5	—	1
DIPSI	—	—	140; 7.8	—	1
FIGO	92; 5.1	180; 10	153; 8.5	—	1
WHO	92; 5.1	180; 10	153; 8.5	—	1
IADPSG	92; 5.1	180; 10	153; 8.5	—	1
NICE	—; 5.6	—	—; 7.8	—	—

Table 1.

Criteria for GDM diagnosis according to different societies [4, 38, 43, 44, 45].

7. Fetal and maternal effects

Gestational diabetes mellitus raises the likelihood of various short-term and long-term health complications for mothers. Apart from the typical stress associated with pregnancy, GDM is linked to antenatal depression. Furthermore, it increases the chances of additional pregnancy complications such as preterm birth and preeclampsia, often necessitating surgical delivery [46]. Around 60% of women with a history of GDM develop type II diabetes mellitus later in life. Each subsequent pregnancy also amplifies the risk of T2D threefold in women with a GDM history. Additionally, women who previously had GDM face an annual conversion risk of approximately 2–3% to T2D. Recent evidence suggests that women with prior GDM may have permanently altered blood vessels, making them more susceptible to cardiovascular disease (CVD). A recent study revealed a 63% increased risk of CVD in women with a history of GDM, which can only partially be attributed to BMI [13]. This is a significant concern, considering that CVD is the leading cause of death worldwide.

The increased transfer of glucose, amino acids, and fatty acids across the placenta, as mentioned earlier, stimulates the fetus’s production of insulin and insulin-like growth factor 1 (IGF-1). This can lead to fetal overgrowth, often resulting in macrosomia or excessive birth weight [47]. Furthermore, the excessive production of fetal insulin can exert stress on the developing pancreatic β-cells, contributing to their dysfunction and insulin resistance, even before birth. Macrosomia also increases the risk of shoulder dystocia, a type of obstructed labour, necessitating cesarean section delivery for babies in GDM pregnancies. Once born, these babies face an increased risk of hypoglycemia due to their dependency on maternal hyperglycemia (fetal hyperinsulinemia), which, if not properly managed, can lead to brain injury [48].

Epidemiological studies have consistently demonstrated that exposure to maternal diabetes in utero increases the risk of cardiovascular disease in the offspring and cardiovascular changes appear from fetal life and extent to adolescence and adulthood [49, 50]. Fetuses of mothers with GDM have more globular hearts with an increase in right and left ventricular sphericity index and subclinical systolic cardiac dysfunction which persists in infancy. These changes are not present at mid-gestation supporting the idea that exposure to glycemia could lead to increased secretion of fetal insulin [51]. Higher systolic and mean arterial blood pressure has also been reported in children and adolescents in association with exposure to maternal diabetes and higher rates of premature cardiovascular heart disease have been shown in offspring of mothers with diabetes in a 40-year follow-up study in Denmark [50].

The mechanisms of programming cardiovascular alterations by maternal diabetes remain speculative. It is possible that exposure to glycemia could lead to increased secretion of fetal insulin which can have adverse effects on fetal vascular gene expression and result in vascular and cardiac changes. Inflammatory and oxidative processes may also be involved to modify both gene expression and the vasculature. However, apart from glycemia, offspring of mothers with diabetes tend to be at increased risk of in-utero exposure to many other classical cardiovascular risk factors, such as obesity and higher maternal blood pressure which are commonly prevalent in mothers at risk of GDM and these may also contribute to fetal cardiovascular remodeling (Figure 3).

Figure 3.

GDM effects on offspring and mother.

8. Preconception care in women with diabetes

Preconceptional education for women with diabetes is an essential step toward achieving optimal maternal and fetal outcomes. By providing comprehensive information on glycemic control, nutrition, lifestyle, medication management, and psychosocial support, healthcare professionals can empower women to make informed decisions and take proactive steps to ensure a healthy pregnancy.

A cornerstone of preconception care for women with diabetes is achieving and maintaining optimal glycemic control. Insulin therapy, dietary management, or a combination of both are employed to target specific glucose levels. Aiming for fasting plasma glucose levels ≤5.7 mmol/l and postprandial blood glucose levels ≤7.8 mmol/l, along with a glycosylated hemoglobin A (HbA1c) level of less than 53 mmol/mol (<7.0%), helps minimize the risk of complications during pregnancy [52].

Preconception screening for diabetes-related complications, such as retinopathy, nephropathy, and cardiovascular issues, is pivotal. Addressing any identified complications before conception allows for timely intervention and optimization of health. This comprehensive screening approach is vital in reducing the risk of maternal and fetal complications.

Until optimal glycemic control is achieved, the use of contraception is recommended to prevent unplanned pregnancies. This strategy ensures that pregnancy occurs in the most favorable metabolic environment, minimizing potential risks to both mother and fetus [52].

9. Prognosis factors in GDM

It is important to recognize that not all cases of GDM carry the same level of risk for adverse outcomes. While the diagnostic criteria for GDM primarily focus on identifying glucose metabolism dysregulations, GDM is increasingly acknowledged as a heterogeneous disorder affecting all metabolic fuels. Various factors that contribute to metabolic health are considered risk factors for developing GDM, including higher BMI and sociocultural influences. The clinical and metabolic variations among individuals with GDM can modify the impact of the condition on both maternal and fetal well-being. Within the GDM population, individuals with elevated triglyceride levels or markers indicating insulin sensitivity impairment face a greater likelihood of delivering a larger-than-average newborn or a macrosomic one. The simultaneous presence of excess adiposity and GDM is linked to an elevated risk of delivering a larger-than-average newborn or a macrosomic one, as well as complications related to pregnancy [3, 4].

10. Pregnancy management in GDM

10.1 Lifestyle intervention

Gestational diabetes mellitus (GDM) is a condition that requires careful management to achieve normoglycemia, optimal weight gain, and proper fetal development. While pharmacological treatments can be essential, they do not replace the significance of following a tailored diet plan. This chapter explores the importance of individualized nutritional recommendations for women with GDM, taking into account glycemic self-control, pre-pregnancy BMI, energy requirements, macronutrient proportions, and maternal preferences, as well as lifestyle factors such as work, rest, and exercise.

Chao et al. emphasize the effectiveness of personalized dietary recommendations for women with GDM compared to generalized guidelines. A well-designed nutritional plan includes three main meals and 2–3 snacks per day, with a late-night snack around 9:30 pm to safeguard against nocturnal hypoglycemia and morning ketosis [53, 54].

Carbohydrates play a pivotal role in the diet of women with GDM. While excessive consumption may lead to hyperglycemia, glucose remains a vital energy source for the placenta and fetus. The American Thyroid Association (ATA) recommends that saccharides constitute 40–50% of energy intake, with at least 180 g/day, mainly derived from low glycemic index (GI) starchy foods. Adequate dietary fiber intake of 25–28 g per day, primarily from fruits, vegetables, whole grain bread, pasta, and rice, is also recommended [54, 55].

Protein intake should account for about 30% of caloric intake, equivalent to approximately 1.3 g/kg of body weight per day, with a minimum daily intake of 71 g. Favoring plant proteins, lean meat, and fish over red and processed meats can enhance insulin sensitivity and support the treatment of GDM [56].

A high-fat diet is contraindicated for women with GDM, as it may lead to placental dysfunction, infant obesity, and other complications. Recommended fat intake should be 20–30% of the total caloric value, with less than 10% of saturated fat. Instead, emphasis should be placed on consuming polyunsaturated fatty acids (PUFA) n-3 (linolenic acid) and n-6 (linoleic acid) to support fetal growth and development [53].

The recommended weight gain during pregnancy varies depending on the initial body mass index, with an average of 8–12 kg. Excessive weight gain, especially over 18 kg, increases the risk of macrosomia (Table 2). Women with GDM may require additional supplementation of vitamins and minerals, particularly folic acid, vitamin D, calcium, and iron, to meet their increased needs during pregnancy [59, 60].

BMI (kg/m^2)	Weight gain in pregnancy (kg)
<18.5	12.5–18
18.5–24.9	11.5–16
25–29.9	7–11.5
>30	5–9

Table 2.

Weight gain in relation to baseline body mass index (BMI) [57, 58].

Personalized nutritional recommendations play a pivotal role in the management of gestational diabetes mellitus. By emphasizing balanced carbohydrate, protein, and fat intake, along with appropriate weight gain and micronutrient supplementation, healthcare providers can help women with GDM achieve optimal health outcomes for both themselves and their unborn children. Further research into emerging therapies and the impact of gut microbiota may shed light on future advancements in GDM management. A comprehensive and individualized approach to nutrition during pregnancy can pave the way for healthier pregnancies and better long-term maternal and fetal health.

The role of exercise and physical activity in improving glycemic control among women with GDM has been a topic of ongoing research. Exercise recommendations for women with GDM have been a subject of ambiguity in terms of their quantitativeness and qualitativeness. It is crucial to consider obstetric indications and contraindications while incorporating physical activity into the management of GDM. Observational studies suggest that physical activity can be safe during pregnancy, but the specific types and intensities need careful evaluation. Certain activities have been deemed safe and beneficial for pregnant women, including walking, cycling, swimming, selected pilates, and low-intensity fitness exercises. Pregnant individuals can continue with activities like yoga, running, tennis, badminton, and strength exercises after consulting with their obstetrician. However, caution is necessary when it comes to contact sports, horse riding, surfing, skiing, and diving [61].

Research indicates that engaging in regular physical activity can significantly reduce the risk of developing GDM. A meta-analysis by Aune et al. revealed a 38% reduction in GDM risk among physically active women. Nasiri-Amiri et al. conducted an intervention study among overweight patients, showing a 24% risk reduction in GDM for women exercising no more than three times a week. Furthermore, in women with normal body weight, increased physical activity was associated with lower weight gain during pregnancy without affecting the child’s weight or the frequency of cesarean sections. Ming et al. reported a substantial 42% reduction in GDM risk with increased physical activity [62]. A meta-analysis by Harrison et al. reviewed eight randomized trials, highlighting the positive impact of regular physical activity on fasting and postprandial glucose levels in women with GDM. Engaging in 20–30 min of activity 3–4 times a week showed significant improvements in glycemic control [61, 63, 64].

Exercise and physical activity play a vital role in the management of GDM. Although recommendations may be ambiguous, focusing on safe and beneficial activities tailored to individual needs can yield positive outcomes. Regular physical activity has been associated with a reduced risk of GDM and improved glycemic control in pregnant women. Healthcare providers should encourage and guide pregnant individuals in incorporating suitable exercise routines into their daily lives to promote better maternal and fetal health outcomes. However, caution should be exercised, and obstetric guidance sought to ensure the safety and effectiveness of the chosen physical activities during pregnancy. As more research emerges, a deeper understanding of the link between exercise and GDM can be harnessed to optimize care for expectant mothers and their unborn child.

10.2 Pharmacological treatment

When glycemic targets cannot be achieved through a well-balanced diet and dietary corrections, pharmacological interventions become essential in managing GDM. This chapter delves into the various pharmacological treatment options available for GDM, with a focus on insulin therapy, oral medications, and emerging agents. The safety and efficacy of these treatments are critically evaluated, along with the importance of evidence-based decisions to optimize maternal and neonatal outcomes.

Numerous studies strongly support insulin therapy as the safest and most effective treatment for GDM. Extensive research has demonstrated the safety of human insulin use during pregnancy, with no passage of insulin analogues across the placenta [62, 63, 64, 65]. Oral administration drugs should only be considered when insulin therapy is unsuitable due to patient consent or unavailability [65]. There is no generally accepted treatment plan but we can either use regular insulin, prandial types of insulin or a combination of these [66]. To limit the postprandial spikes, we can either use human insulin or rapid-acting insulin analogues (lispro, aspart, glulisine, and fast-acting aspart) [65]. To control the fasting levels long-lasting analogues (detemir) or human insulin can be used [67]. Plasma glucose levels should be used to adjust insulin dosage.

Metformin and glibenclamide are utilized as oral medications in specific cases of GDM. Although they do cross the placenta, research suggests they are unlikely to be teratogenic. The landmark Metformin in Gestational Diabetes trial, one of the largest randomized controlled trials, provided valuable insights into the safety and efficacy of metformin use in GDM. The results indicated that metformin, with or without supplemental insulin, did not lead to increased perinatal complications. Some studies have indicated potential long-term effects of metformin use on offspring, including higher body mass index, increased visceral and subcutaneous tissue, and elevated blood glucose levels when the offspring reached nine years of age. On the other hand, despite its effectiveness, the use of glibenclamide may lead to a higher percentage of intrauterine deaths and neonatal complications such as hypoglycemia, macrosomia, and fetal growth restriction (FGR) [68, 69]. Therefore, careful consideration of the benefits and potential risks of oral medications is essential [70].

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agents are being explored as potential treatments for GDM. While SGLT2 inhibitors have shown promise in reducing plasma glucose concentration, their use during pregnancy is not recommended due to adverse effects noted in animal reproductive studies. GLP-1 agents, including dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists, have demonstrated benefits in treating type 2 diabetes but have not yet become a common choice for GDM [71]. Rigorous clinical trials are needed to establish their safety and efficacy in the context of GDM.

Pharmacological interventions are essential in cases where lifestyle modifications are insufficient to achieve glycemic control in GDM. Insulin therapy remains the preferred and safest option, while oral medications like metformin and glibenclamide require careful consideration of potential long-term effects. Emerging agents like SGLT2 inhibitors and GLP-1 agents hold promise but demand further investigation through well-designed clinical trials. The future of GDM management relies on evidence-based decisions that prioritize the safety and well-being of both mothers and their newborns.

10.3 Maternal care

In the context of GDM, fasting plasma glucose (FPG) measurement and glycated hemoglobin (HbA1c) investigation provide valuable insights into the management and control of blood glucose levels during pregnancy. These tests are crucial tools in diagnosing and monitoring GDM, as well as assessing overall glycemic control.

FPG is a blood test that measures the level of glucose in the blood after an overnight fast, typically of 8–12 h. FPG provides information about how well the body is able to regulate plasma glucose levels after a period of fasting. Elevated fasting glucose levels in GDM can indicate an increased risk of adverse pregnancy outcomes, including macrosomia (large birth weight), preeclampsia, and neonatal hypoglycemia. If FPG levels are consistently elevated, the treatment plan is to be adjusted by modifying the diet, increasing physical activity, or, in some cases, starting insulin therapy.

HbA1c serves as an accepted metric for the preliminary detection of pre-existing diabetes in early pregnancy, the confirmation of glycemic regulation among women employing self-monitoring of blood glucose (SMBG), and the evaluation of glycemic control when SMBG falls short. However, it is noteworthy that HbA1c measurements are influenced by factors affecting the lifespan of red blood cells (RBCs), a category that encompasses pregnancy. The physiological state of pregnancy engenders modified RBC kinetics typified by heightened erythropoiesis, hemodilution, and altered kinetics.

According to The American Diabetes Association (ADA) maintaining HbA1C levels below 6 in the early stages of pregnancy is associated with the lowest incidence of adverse fetal outcomes or maternal complications. Some research posits a connection between elevated HbA1C and adverse outcomes, such as spontaneous abortion and the likelihood of cesarean section. Certain studies suggest that heightened HbA1C in the initial trimester corresponds to severe maternal morbidity (SMM) and mortality risks [72].

The literature suggests a linkage between suboptimal HbA1C control and unfavorable pregnancy outcomes, advocating for improved HbA1C management to mitigate complications. However, challenges persist. Firstly, divergent cutoff values and conclusions arise among various ethnicities and experimental approaches. For instance.

Recognizing the significant influence of maternal blood glucose levels on adverse maternal and infant outcomes in gestational diabetes, meticulous blood glucose management is imperative. Existing studies highlight the association between HbA1C during pregnancy and glycemic levels among pregnant women. Notably, the dynamic values of HbA1C in pregnancy and non-pregnancy states warrant consideration. The ADA recommends utilizing HbA1C for glucose monitoring in gestational diabetes patients, with an optimal target of 42–53 mmol/mol (6–7%) in the initial trimester and below 42 mmol/mol (<6%) in the subsequent trimesters [72].

Glycosylated hemoglobin emerges as a valuable tool for blood glucose management in diabetic patients. The prevailing consensus among researchers affirms the utility of HbA1c for screening and managing gestational diabetes. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) suggests employing HbA1c for gestational diabetes screening, although it should not supplant an oral glucose tolerance test (OGTT) for definitive diagnosis. Current research underscores the feasibility of HbA1c as an indicator for screening and selecting pregnant women warranting further OGTT assessment, especially when used in conjunction with gestational age measurements. In conclusion, the aggregate evidence substantiates the relationship between HbA1c, pregnancy glycemia, and adverse pregnancy outcomes, thereby validating its application in gestational diabetes management to mitigate complications. However, the establishment of precise glycemic control targets demands continued research [72].

It’s important to note that while FPG and HbA1c provide valuable information, GDM management often involves multiple tests and considerations, including self-monitoring of blood glucose levels, postprandial glucose measurements, and close collaboration with healthcare providers. The ultimate goal is to achieve and maintain optimal glycemic control to ensure the well-being of both the mother and the developing fetus.

Self-monitoring of blood glucose (SMBG) levels through glucometers has gained increasing recognition as a critical component of diabetes management during pregnancy. Fluctuations in maternal plasma glucose levels can impact fetal development and increase the risk of complications for both mother and child.

SMBG helps pregnant individuals to maintain tight control over their plasma glucose levels, reducing the risk of adverse outcomes such as macrosomia, preterm birth, and preeclampsia and personalize their diabetes management by providing immediate feedback on the effects of food choices, physical activity, and medication regimens.

SMBG aids in the early detection of hypo- and hyperglycemic episodes, allowing timely interventions to prevent complications for both mother and fetus.

Monitoring times during pregnancy include fasting, pre-meal, post-meal, and before bedtime to assess glucose control across different periods of the day. Maintaining a record of SMBG results allows for the tracking of trends and patterns over time. Data from glucometers is used to design tailored treatment plans, ensuring that blood glucose levels are kept within recommended ranges [73].

Self-monitoring of blood glucose levels through glucometers is a pivotal tool for managing diabetes during pregnancy. It empowers pregnant individuals to maintain optimal glycemic control, mitigating risks and enhancing maternal and fetal outcomes.

10.4 Fetal surveillance

The monitoring of fetal well-being in women with gestational diabetes mellitus remains an area with limited evidence and consensus regarding specific antepartum tests and their frequency. Determining the appropriate type and frequency of monitoring depends on one side on the fetal growth and wellbeing but it is also influenced by the presence of other pregnancy complications, such as preeclampsia or fetal growth restriction, as well as the severity of maternal hyperglycemia.

Fetal size and the amniotic fluid are important indicators in GDM management. Large-for-gestational age (LGA) infants can result from inadequately treated GDM, and studies have found that fetal overgrowth is associated with adverse perinatal outcomes including hypoglycemia, respiratory distress syndrome, shoulder dystocia, and Erb’s palsy [74]. Ultrasound-guided management may better identify which pregnancies are at risk for fetal overgrowth. In this management framework, fetal ultrasound measurements, specifically fetal abdominal circumference (AC), are used to risk-stratify pregnancies and alter glycemic targets accordingly. Fetal abdominal circumference (AC) measured on ultrasound, equal to or greater than the 75th percentile for gestational age, between 29 + 0- and 33 + 6-weeks’ gestation, is associated with evidence of excess fetal growth/adiposity and an increased risk of delivering a large-for-gestational-age (LGA) baby [4, 43]. In such cases, more intensive glucose-lowering therapy may be necessary. However, if fetal ultrasound shows that average growth is maintained, relaxation of glycemic targets may be considered. Longitudinal growth assessment is superior to a single late-pregnancy measurement, especially if abnormalities are detected on the initial scan. Accelerating AC growth, particularly if it exceeds the 95th percentile, holds clinical significance as well and it should not be ignored. Polyhydramnios, defined as the vertical measurement of the deepest pocket of amniotic fluid free of fetal parts more than 8 cm, is considered a consequence of poor glycemic control [43].

For women with unstable diabetes or those requiring pharmacological therapy, or having comorbid risk factors like obesity, hypertension, LGA or SGA, or a previous stillbirth, 2–4 weekly ultrasounds may be considered. Fetal wellbeing monitoring and growth assessment in gestational diabetes demand careful consideration and tailored approaches [4]. Regular ultrasound evaluations, involving fetal abdominal circumference, estimated fetal growth and amniotic fluid index play a crucial role in identifying potential risks and guiding management decisions.

11. Delivery and intrapartum treatment

The timing of delivery and intrapartum treatment in gestational diabetes mellitus (GDM) is a critical aspect of managing maternal and fetal health. Careful consideration of factors such as glycemic control, fetal weight, presence of the polyhydramnios and the need for insulin during labour helps optimize delivery outcomes while minimizing potential risks. This aspect should be discussed in the third trimester.

Timing the delivery in women with GDM is a delicate balance between ensuring adequate fetal lung maturity and reducing the risk of maternal and neonatal complications. Based on current guidelines and evidence, delivery is typically recommended at around 39–40 weeks of gestation. Delivering at around 39–40 weeks helps prevent potential complications associated with prolonged pregnancies, which are common in GDM [4, 43].

Cesarean section may be necessary in cases with an estimated fetal weight equal to or greater than 4500 g (approximately 7.7 pounds) [4, 43]. A cesarean section may be preferred to prevent birth-related complications associated with macrosomia (large birth weight) such as shoulder dystocia. Ultrasound measurements are used to estimate fetal weight and determine if it meets the criteria for considering a cesarean section [4, 43]. This assessment helps healthcare providers make informed decisions regarding the safest delivery method for both the mother and the baby.

During labour, insulin infusion is rarely needed, especially in insulin-depend cases, to maintain stable glycemic control. Monitoring maternal plasma glucose, using capillary plasma glucose every 4 h during labour to determine the appropriate insulin dosage is essential. Frequent checks help avoid fluctuations and ensure a steady balance throughout the delivery process [4].

12. Postpartum management

In the majority of cases GDM will resolve after delivery, but up to one-third of the affected women will have diabetes or impaired glucose metabolism at postpartum screening. The patients should be counseled to stop the insulin treatment if they had it, start breastfeeding, lose weight and have an OGTT at 6–12 weeks postpartum. It is estimated that between 15 and 70% of women with GDM will develop DM later in life. Although the fasting plasma glucose test is easier to perform, it lacks sensitivity for detecting other forms of abnormal glucose metabolism, whereas the results of the OGTT can confirm an impaired fasting glucose level and impaired glucose tolerance. If the results of the OGGT test are normal (fasting glucose <100 mg/dL, 2 h glucose <140 mg/dL) you should recommend screening for DM at 3 years for the rest of her life. Abnormal results showing impaired fasting glucose, impaired tolerance (fasting glucose 100–125 mg/Dl, 2 h glucose 140–199 mg/dL) or diabetes (fasting glucose >125 mg/dL, 2 h glucose >199 mg/dL) require referral for diabetes management [4]. GDM can increase the risk of postpartum thyroiditis, therefore the assessment of the thyroid function has to be recommended [20].

The recurrence risk for a future pregnancy is estimated at 40–60%. It is recommended to screen for GDM earlier in the pregnancy, providing an opportunity to ensure good glucose control [22].

13. Conclusions

Gestational diabetes is a significant health concern that affects pregnant women worldwide. The prevalence of gestational diabetes has been on the rise in recent years, paralleling the increasing rates of obesity and sedentary lifestyles. Moreover, the condition poses potential risks not only to the mother but also to the unborn child, with adverse effects on fetal development and long-term health outcomes. Identifying the risk factors for gestational diabetes is crucial in early detection and intervention. This includes a family history of diabetes, obesity, previous gestational diabetes, advanced maternal age, and certain ethnic backgrounds. Health professionals should remain vigilant in screening pregnant women for the condition during prenatal care to ensure timely diagnosis and appropriate management.

The management of gestational diabetes typically involves dietary modifications, regular physical activity, and monitoring plasma glucose levels. In some cases, insulin or other medications may be required to maintain optimal plasma glucose levels. Close collaboration between the healthcare team and the expectant mother is essential to achieve successful outcomes for both the mother and the baby. Women diagnosed with gestational diabetes should be educated about the condition and its potential consequences. Empowering them to make informed decisions regarding lifestyle changes and treatment options can significantly improve their ability to manage the condition effectively. Furthermore, long-term follow-up and postpartum care are essential to monitor the mother’s health and reduce the risk of developing type 2 diabetes in the future. Encouraging postpartum screenings and lifestyle modifications can help women prevent or delay the onset of diabetes beyond pregnancy.

Prevention is a crucial aspect of combating gestational diabetes. Public health initiatives should focus on promoting healthy lifestyles, emphasizing the importance of balanced nutrition and regular physical activity for all women, especially those planning to conceive or are already pregnant. By addressing modifiable risk factors, we can make significant strides in reducing the burden of gestational diabetes and its associated complications.

In conclusion, gestational diabetes is a complex condition that requires a multi-faceted approach from healthcare providers, policymakers, and individuals alike. By raising awareness, facilitating early diagnosis, promoting healthy behaviors, and offering comprehensive care, we can work toward ensuring a healthier future for both mothers and their children. With continued research and collective efforts, we can make a positive impact on the lives of countless women and prevent the potential long-term consequences of gestational diabetes.

Acknowledgments

We would like to express our sincere gratitude to all the individuals who assisted, whether directly or indirectly. Their contributions, no matter how small, have played a significant role in the successful completion of this chapter.

Conflict of interest

The authors declare no conflict of interest.