Gestational diabetes mellitus (GDM) is a special type of diabetes that commonly occurs in women during pregnancy and involves impaired glucose tolerance and abnormal glucose metabolism; GDM is diagnosed for the first time during pregnancy and can affect fetal growth and development.

To investigate the associations of serum D-dimer (D-D) and glycosylated hemoglobin (HbA1c) levels with third-trimester fetal growth restriction (FGR) in GDM patients.

The clinical data of 164 pregnant women who were diagnosed with GDM and delivered at the Obstetrics and Gynecology Hospital of Fudan University from January 2021 to January 2023 were analyzed retrospectively. Among these women, 63 whose fetuses had FGR were included in the FGR group, and 101 women whose fetuses had normal body weights were included in the normal body weight group (normal group). Fasting venous blood samples were collected from the elbow at 28-30 wk gestation and 1-3 d before delivery to measure serum D-D and HbA1c levels for comparative analysis. The diagnostic value of serum D-D and HbA1c levels for FGR was evaluated by receiver operating characteristic analysis, and the influencing factors of third-trimester FGR in GDM patients were analyzed by logistic regression.

Serum fasting blood glucose, fasting insulin, D-D and HbA1c levels were significantly greater in the FGR group than in the normal group, while the homeostasis model assessment of insulin resistance values were lower (P < 0.05). Regarding the diagnosis of FGR based on serum D-D and HbA1c levels, the areas under the curves (AUCs) were 0.826 and 0.848, the cutoff values were 3.04 mg/L and 5.80%, the sensitivities were 81.0% and 79.4%, and the specificities were 88.1% and 87.1%, respectively. The AUC of serum D-D plus HbA1c levels for diagnosing FGR was 0.928, and the sensitivity and specificity were 84.1% and 91.1%, respectively. High D-D and HbA1c levels were risk factors for third-trimester FGR in GDM patients (P < 0.05).

D-D and HbA1c levels can indicate the occurrence of FGR in GDM patients in the third trimester of pregnancy to some extent, and their combination can be used as an important index for the early prediction of FGR.

Pregnancy causes metabolic and immune changes, characterized by insulin resistance (IR) and increased immune tolerance to the fetus and placenta. In susceptible women, these physiological changes may contribute to the development of gestational diabetes mellitus (GDM)[1,2]. GDM involves abnormal glucose tolerance of varying degrees that is detected or occurs for the first time during pregnancy as a result of IR and impaired compensatory insulin secretion. GDM has become a growing health problem, affecting approximately 15% of pregnancies worldwide[3,4]. Its occurrence not only increases the risk of short-term complications in mothers and babies (macrosomia, fetal intrauterine growth ab-normalities, maternal predisposition to preeclampsia, etc.) but also affects their long-term health[5,6]. Studies have shown that even though GDM is a transient state in which glycemic regulation usually returns to normal shortly after delivery, it leads to a 40% increase in the risk of developing type 2 diabetes within 10-15 years[7]. Fetal growth restriction (FGR), a common pregnancy complication, is a condition in which the fetus does not develop according to its expected biological potential in the uterus[8]. FGR, in contrast to a small constitution, is a pathological condition (known as placental insufficiency) in which the placenta undersupply nutrients and oxygen to the developing fetus[9]. GDM combined with FGR may lead to adverse perinatal outcomes, such as very low birth weight, seriously endangering perinatal life[10].

D-dimer (D-D) is produced through the specific degradation of cross-linked fibrin and is generally considered to be related to hyperfibrinolysis and hypercoagulability in vivo. D-D levels are directly related to the intensity of fibrinolytic activity, which is typically greater in pregnant women than in nonpregnant women and tends to increase in the third trimester as gestation progresses[11]. Although 78% and 99%-100% of pregnant women have D-D levels above the standard cutoff during the second and third trimesters, respectively, severe elevation can lead to disseminated intravascular coagulation and thrombosis; hence, monitoring and prediction are needed for effective prevention[12,13]. Glycosylated hemoglobin (HbA1c), a sensitive indicator of glucose metabolism during pregnancy, is not directly affected by maternal emotions, drugs or diet and is an ideal clinical blood glucose monitoring index[14,15]. Poor glycemic control has been associated with large-for-gestational-age infants among mothers with GDM[16]. Poor blood sugar control during pregnancy may cause complications such as macrosomia, FGR, premature delivery, and spontaneous abortion[17]. Conversely, good glycemic control is the main means to reducing maternal and infant complications and is highly important for improving maternal and infant outcomes in GDM patients[18].

However, the associations of serum D-D and HbA1c levels with third-trimester FGR in GDM patients have rarely been studied. Based on these findings, in this study, we preliminarily investigated the serum D-D and HbA1c levels in GDM patients in the third trimester of pregnancy, analyzed their correlations with neonatal body weight, and determined their diagnostic value for third-trimester FGR to provide a reference for the early diagnosis and treatment of FGR in GDM patients in the third trimester of pregnancy.

GDM is a common maternal complication with a global standardized total prevalence of 14.0%[21]. Zhu et al[22] reported that the incidence of GDM among generally screened urban women in China increased significantly from 4% in 2010 to 21% in 2020. Although the increase in the prevalence of GDM has slowed since the implementation of China's universal two-child policy, it remains high. GDM can cause female reproductive tract infection, pregnancy-induced hypertension, preterm birth, fetal distress, FGR and other adverse outcomes, while FGR can lead to perinatal death or metabolic syndrome, mental retardation and short stature, seriously threatening the health of infants[23]. However, the occurrence of FGR is influenced by many factors, such as fetal, maternal, and placental factors, with no effective clinical predictors at present[24]. Therefore, exploring biological targets that can be used to effectively diagnose and treat FGR and improve maternal and infant quality of life is highly important.

As a specific thrombus marker, D-D levels can be used to detect hypercoagulability in vivo. The blood of pregnant women is usually physiologically hypercoagulable. During pregnancy, D-D levels tend to increase during endometrial growth along with trophoblasts, which in turn erode venous sinuses and spiral arteries, leading to the constant activation of the coagulation and fibrinolysis system to remove thrombi[25]. The results of this study revealed a significant di-fference in D-D expression between the FGR and normal groups at 28-30 wk of pregnancy and 1-3 d before delivery. It is suggested that sustained hyperglycemia in patients with FGR may damage vascular endothelial cells, disrupting the balance among fibrinolysis, coagulation and anticoagulation. With increasing gestational age, vascular endothelial damage and placental villus necrosis worsen, leading to the release of a large amount of tissue thromboplastin and causing widespread microthrombosis, further affecting the placental blood supply and causing FGR and increased obstetric infections that exacerbate the impact on the fetus. In addition, several studies have shown that the endothelial decompensation severity determines the formation of a local "catastrophe" in the fetal-placental unit in the form of FGR[26].

Clinically, the traditional evaluation of glycemic control is usually achieved by blood sugar monitoring, but blood sugar is often affected by many interfering factors and great fluctuations. The concentration of HbA1c, formed by hemoglobin and glucose in red blood cells in human blood, is directly proportional to the blood sugar concentration and is maintained for approximately 120 d, which means that the blood sugar concentration before 120 d can be measured by detecting HbA1c[27]. The characteristics of HbA1c are highly important for diabetes monitoring. The higher the blood sugar level is, the greater the HbA1c level is. Due to its slow formation, HbA1c is quite stable and not easily decomposed. Therefore, although it cannot reflect short-term blood sugar fluctuations, it can well reflect the degree of glycemic control over a longer period of time[28]. Related studies have shown that good control of HbA1c levels can greatly reduce the possibility of microvascular complications in diabetic patients[29]. In this study, HbA1c levels were significantly different between the FGR group and the normal group at 28-30 wk of pregnancy and 1-3 d before delivery. It was also found that the mean HbA1c level in the FGR group was greater than 6%, compared with that of 4%-6% in the general population[30]. Therefore, controlling HbA1c to below 6% can reduce the incidence of FDR in GDM patients.

The AUCs of the serum D-D and HbA1c levels for the diagnosis of FGR were determined to be 0.826 and 0.848, respectively. When the serum D-D level was greater than 3.04 mg/L or the HbA1c level was above 5.80%, the probability of developing third-trimester FGR was increased in pregnant women with GDM, suggesting that D-D and HbA1c levels have certain diagnostic value for FGR. The AUC of the diagnosis of FGR based on the combination of serum D-D and HbA1c levels was 0.928, and the sensitivity and specificity were 84.1% and 91.1%, respectively. It is suggested that the combination of D-D and HbA1c levels can effectively improve the specificity and diagnostic efficiency for FGR, which is helpful for predicting the occurrence of third-trimester FGR in pregnant women with GDM. Further study revealed that high D-D and HbA1c levels were risk factors for third-trimester FGR in GDM patients, suggesting that increased serum D-D and HbA1c levels may increase the risk of FGR. Timely monitoring of D-D and HbA1c levels is therefore conducive to the early diagnosis of FGR and the control of disease progression. We believe that the relationship between D-D and HbA1c levels and FGR lies in the fact that high levels of D-D and HbA1c can predict the occurrence of FGR to a certain extent and that HbA1c is not easily decomposed, has fewer interfering factors, has a high degree of stability, and can be tested instantly at any time without the need for fasting blood sampling; these characteristics enable us to more accurately assess the overall blood glucose level at certain times. A high HbA1c level indicates that a patient is hyperglycemic, and persistent hyperglycemia leads to damage to vascular endothelial cells, worsens the necrosis of placental villi, leads to the release of a large amount of tissue thromboplastin, and causes extensive microthrombosis, which in turn affects the blood supply of the placenta. D-D levels can indicate a hypercoagulable state in vivo. Therefore, we believe that the com-bination of the two parameters can better predict the occurrence of FGR.

Several limitations of our study should be acknowledged. Our results should be considered in light of certain limitations of our design. First, the limited samples included and the fact that maternal serum biomarkers were measured only during the late third trimester but not earlier trimesters may lead to discrepancies compared to other research. Second, although the study design revealed that D-D and HbA1c levels could be somewhat suggestive of the development of FGR in patients with GDM in late pregnancy, it was not possible to draw conclusions about the potential dynamics of changes throughout pregnancy, as relevant indicators were quantified only during late pregnancy. Another limitation of the study was the use of self-reported prepregnancy BMI data. In our area, all women trying to conceive utilize community health services and learn how to measure their weight and height. These women only visit obstetric clinics after becoming pregnant. Although we were unable to personally check the prenatal BMI of the participants, the self-reported data under the supervision of community caregivers were generally reliable. In addition, we were not able to test this hypothesis across BMI categories because of the small sample size. Additionally, there were inevitably some unmeasured confounders in this study, including household income and smoking status, as they were not captured in the electronic medical records system. Thus, the inclusion of large sample sizes and large amounts of data for these categories to replicate our findings is essential.

Taken together, D-D and HbA1c levels are closely associated with the occurrence of FGR in GDM patients in the third trimester of pregnancy. The combined detection of the two parameters in GDM patients can be used as an important index for the early prediction of FGR.