Maternal glycemic profiles during pregnancy and predelivery correlate with neonatal glucose homeostasis and jaundice risk: a prospective cohort study
Highlight box
Key findings
• This study reveals a significant correlation between maternal blood glucose levels during pregnancy and neonatal outcomes, particularly hypoglycemia and jaundice. Pregnant women with diabetes in pregnancy (DIP) had higher fasting blood glucose, glycated albumin, and hemoglobin A1c levels, which correlated with adverse neonatal outcomes like lower birth weight and higher neonatal bilirubin levels.
What is known and what is new?
• Previous research has established a link between maternal hyperglycemia and adverse pregnancy outcomes, including neonatal macrosomia and hypoglycemia.
• This study specifically highlights the impact of maternal glycemic levels on neonatal jaundice risk and provides evidence for the need of stringent glycemic control in DIP pregnancies to mitigate neonatal risks.
What is the implication, and what should change now?
• The findings emphasize the necessity for vigilant monitoring and management of maternal blood glucose, especially in DIP pregnancies. Healthcare providers should prioritize glycemic control and closely monitor neonatal glucose and bilirubin levels post-delivery.
• Future clinical practices should integrate these findings to improve neonatal health outcomes.
Introduction
Diabetes in pregnancy (DIP), including gestational diabetes mellitus (GDM) and pre-GDM (PGDM), are significant health problems during pregnancy. It affects 14% of pregnancies and is rapidly escalating in prevalence globally, posing challenges to the public health system (1). GDM, defined as glucose intolerance first identified during pregnancy (2), accounts for 90–95% of all patients with DIP (3). The pathogenesis of GDM mainly consists of insulin resistance and insufficient insulin secretion (4). GDM in advance (GDMA), a high-risk subtype of GDM, occurs when GDM women exhibit elevated blood glucose levels early in pregnancy (5). It may indicate a demand for insulin therapy and a more severe risk of maternal and infant complications (6). Different from GDM, PGDM is diagnosed prior to pregnancy, comprising type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and diabetes mellitus due to other causes (7,8).
These pregnancy-associated diabetes mellitus pose additional risks to maternal and infant health (9). It has been demonstrated that abnormally elevated blood glucose levels during pregnancy are implicated in multiple adverse pregnancy outcomes. Pregnancy complications associated with elevated blood glucose levels include gestational hypertension, preeclampsia, and spontaneous abortion, as well as preterm delivery. These maternal conditions can further impact neonatal health, resulting in outcomes such as congenital malformations, hyperinsulinemia, macrosomia, shoulder dystocia, and hypoglycemia. Additionally, neonates may experience respiratory distress syndrome. The long-term implications for these children extend beyond infancy, with an increased risk of obesity and the development of T2DM later in life (10). Neonatal hypoglycemia and neonatal jaundice are common complications after delivery in DIP pregnant women. Therefore, early identification and management of these patients are essential to improve pregnancy outcomes.
Since the human fetus is highly dependent on glucose from the maternal circulation, glucose homeostasis transferred from the mother to the placenta is thought to be a major determinant of fetal development (11). Consequently, maternal glycemic management has a direct impact on neonatal metabolic status. It has been demonstrated that maternal prenatal hemoglobin A1c (HbA1c) levels are negatively correlated with neonatal glucose level, indicating an increased risk of neonatal postnatal hypoglycemia and large for gestational age (LGA) in DIP (12). This heightened risk is attributed to factors such as insufficient glycogen or fat tissue reserves and increased glucose utilization due to excessive insulin production of the intra-uterine diabetic environment (13,14). Consequently, when blood sugar levels drop intensively, the brain does not receive adequate glucose, potentially contributing to various neurological symptoms, including an elevated rate of seizures observed in these infants (15). Therefore, adequate glycemic management during pregnancy influences the occurrence of neonatal hypoglycemia and is essential to improve the relevant adverse outcomes. On the other hand, maternal glucose may also cause disturbances in bilirubin metabolism, which may be relevant to the occurrence of neonatal jaundice. Neonatal jaundice poses a threat to neonatal health and intellectual development (16,17). It may pertain to the metabolic adaptation of the fetus in a hyperglycemic intrauterine environment, but there is a lack of direct report of this phenomenon in previous studies.
In this study, we delineate the intricate correlations that emerge throughout pregnancy and the perinatal period. Our investigation uncovers vital scientific insights and offer clinical guidance for the management of diabetic pregnancies, with the ultimate goal of reducing the prevalence of neonatal hypoglycemia and jaundice. The implications of our findings extend beyond immediate patient care, offering direction for future clinical practices. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-356/rc).
Methods
Study design and participants
As a prospective cohort study, it aimed to analyze the correlation between maternal blood glucose during pregnancy and predelivery with neonatal blood glucose and jaundice. The study included 710 pregnant women maintaining a pregnancy card and delivered in our obstetrics department between May 1, 2021 and October 31, 2022. All participants provided informed consent before inclusion and the study protocol was approved by the hospital ethics committee. Ethical approval for this study was obtained from the Ethics Committee of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (No. 2020KY239). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
Inclusion and exclusion criteria
Inclusion criteria included pregnant women aged between 18 and 45 years old, maintaining a pregnancy card between 12 and 18 gestational weeks, and with good compliance and voluntary participation in the study. Exclusion criteria included pregnant women younger than 18 or older than 45 years old, more than 18 or less than 37 gestational weeks at delivery, and with less than 2,500 grams birth weight or severe asphyxia (Apgar score 0–3) neonates.
Sample size determination
The sample size for our study was determined using standard statistical methods to ensure adequate power to detect a clinically significant effect while maintaining feasibility and cost-effectiveness. We utilized the formula for sample size calculation in randomized controlled trials, which takes into account the desired power of the study (usually set at 80%), the significance level (commonly set at α=0.05), and the expected effect size. In addition to the basic sample size calculation, we recognized the potential for subject dropout and loss to follow-up, which are common in long-term studies. To account for this, we adjusted our sample size. We aimed to maintain the integrity and robustness of our study design, ensuring that we would have an adequate number of participants to analyze for our primary and secondary outcome measures.
Data collection
Data were collected including general information (age, education, height, pre-pregnancy weight, delivery weight, maternal history, gestational week of delivery), maternal blood glucose data (pre-pregnancy diabetes, insulin use, fasting blood glucose (FBG), and glycated HbA1c, HbA1c at pregnancy card creation, oral glucose tolerance test (OGTT), OGTT and HbA1c in mid-pregnancy, HbA1c and blood glucose during predelivery), as well as neonatal gender, birth weight, Apgar score (1/5 minutes), neonatal postnatal blood glucose (0.5, 1, and 3 hours), and neonatal bilirubin levels (days 0, 1, 2, 3, and 4 after delivery). HbA1c reflects the percentage of hemoglobin molecules in red blood cells that have glucose bound to them, while OGTT is a test used to determine how well your body is processing glucose.
Relevant definition
DIP was defined either by an appropriate diagnosis in the patient’s medical record or an abnormal result in glucose tolerance test using the “two-step” method. Women with a fasting plasma glucose concentration of ≥140 mg/dL at the glucose challenge test (GCT), or with other risk factors for DIP and a result of ≥ 130 mg/dL at the GCT, were referred to undergo the OGTT. GCT is a screening test with a 50 g glucose load for pregnant women, while OGTT is a diagnostic test using a 75 g glucose load for both pregnant and non-pregnant individuals. A diagnosis of DIP was made if the woman meets specific criteria, which include fasting 3 h 100 g OGTT values [two or more of the following values: fasting ≥95 mg/dL, 1 h ≥180 mg/dL, 2 h ≥155 mg/dL, and/or 3 h ≥140 mg/dL (18)] or GCT result ≥200 mg/dL (19).
Management of neonatal hypoglycemia and jaundice
Neonatal hypoglycemia was defined based on plasma glucose concentrations, with hypoglycemia being present if plasma glucose levels were less than 2.2 mmol/L. For plasma glucose levels less than 2.2 mmol/L, intravenous administration of a 10% glucose injection was used. For levels between 2.2 and 2.6 mmol/L, oral administration of a 10% glucose solution was provided. For plasma glucose levels above 3 mmol/L, further monitoring of blood glucose fluctuations was conducted to ensure stable glucose homeostasis in the neonates. Neonatal jaundice is classified into physiologic and pathologic types. Physiologic jaundice typically appears 2–3 days after birth, with total serum bilirubin levels expected to rise during this period. At birth, the normal range is 34–103 µmol/L, increasing to 103–171 µmol/L by day 1. By day 2, levels may exceed the 95th percentile on the Bhutani curve, indicating a need for intervention. To manage high bilirubin levels, phototherapy is commonly used to break down bilirubin in the skin for excretion. If phototherapy is insufficient or bilirubin levels are extremely high, exchange transfusion may be necessary to prevent kernicterus, a serious complication that can lead to brain damage. In contrast, pathologic jaundice appears within the first day of life, with bilirubin levels exceeding normal for age, requiring immediate medical attention to identify and treat underlying causes, such as hemolytic diseases or infections.
Statistical analysis
Data were organized and analyzed with SPSS statistical software. Analysis methods included descriptive statistical analysis (maternal general information, blood glucose indicators, and neonatal data). Pearson correlation analysis was utilized to explore the association of maternal blood glucose during pregnancy and predelivery with neonatal blood glucose and jaundice. Additionally, multiple regression analysis was utilized to determine the independent influences of maternal delivery indicators on neonatal blood glucose and neonatal jaundice. Data were presented as mean ± standard deviation (SD) for continuous variables and as numbers (%) for categorical variables; 95% confidence intervals (CIs) were reported to measure the strength of the association. All statistical tests were two-sided. A P value of less than 0.05 was considered statistically significant.
Results
Participant characteristics
In this prospective cohort study, we found significant correlations between maternal blood glucose levels during pregnancy and neonatal outcomes, particularly hypoglycemia and jaundice. A total of 542 normoglycemic pregnant women and 168 DIP women were included in this study, consisting of 111 GDM and 57 PGDM (Figure 1). Demographic and obstetric characteristics of the study population are presented in Table 1.
Table 1
| Demographic and obstetric characteristics | Normal glycemic status (n=542) | Diabetes in pregnancy (n=168) |
|---|---|---|
| Maternal age (years) | 29±4.2 | 34.5±7.8 |
| Gravidity | 1.5±0.7 | 2.5±0.7 |
| Parity | 1.5±0.7 | 1.5±0.7 |
| Primipara | 385 (71.0) | 111 (66.1) |
| Gestational week | 38.4±0.5 | 38.6±1.2 |
| Cesarean delivery | 251 (46.3) | 113 (67.3) |
| Scarred uterus | 61 (11.3) | 46 (27.4) |
| Obesity (BMI >30 kg/m2) | 14 (2.6) | 70 (41.7) |
| Predelivery blood glucose (mmol/L) | 6±0.8 | 6.3±2.3 |
| FBG in first trimester (mmol/L) | 4.8±0.5 | 5.5±0.4 |
| HbA1c in first trimester (%) | 5.4±0.1 | 5.8±0.1 |
| HbA1c in second trimester (%) | 4.9±0.1 | 5.9±0.9 |
| HbA1c in third trimester (%) | 5.4±0.3 | 5.9±0.4 |
| GA in third trimester (%) | 12±1.1 | 12.4±1.2 |
| SF in third trimester (ng/mL) | 14.9±5.4 | 22.5±4 |
| OGTT-0H (mmol/L) | 3.9±0.6 | 5.9±1.8 |
| OGTT-1H (mmol/L) | 4.6±2.2 | 12.8±2.6 |
| OGTT-2H (mmol/L) | 5.3±0.1 | 9.9±1.7 |
Data are mean ± standard deviation or number (%). Diabetes in pregnancy: 111 GDMA and 57 PGDM. BMI, body mass index; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; GA, glycated albumin; SF, serum ferritin; OGTT-0H, 0-hour oral glucose tolerance test; OGTT-1H, 1-hour oral glucose tolerance test; OGTT-2H, 2-hour oral glucose tolerance test; GDMA, gestational diabetes mellitus in advance; PGDM, pre-gestational diabetes mellitus.
The DIP group had a significantly higher mean maternal age and greater rates of pregnancies, deliveries, cesarean sections, scarred uterus, and obesity compared to the normoglycemic group. Additionally, predelivery glucose levels, including FBG, glycated albumin (GA), HbA1c, and serum ferritin (SF) levels in first trimester, as well as 0-, 1-, and 2-hour OGTT (OGTT-0H, OGTT-1H, and OGTT-2H) results, were all significantly elevated in the DIP group.
Comparative analysis of neonatal outcomes
In the comparison of neonatal outcomes, we observed significant differences between DIP and normoglycemic groups on several indicators (Table 2). Neonates born to mothers with DIP had a higher mean birth weight (3.9 vs. 3.5 kg, P<0.01) and higher rates of 1-minute Apgar scores below 7 (0.6% vs. 0.2%, P<0.01) compared to those born to normoglycemic mothers. Furthermore, the incidence of neonatal hypoglycemia (3.6%) was also significantly higher (P<0.01). Additionally, neonatal bilirubin levels were significantly higher in DIP group on the third and fourth day after birth (TB3 and TB4) (P<0.01), suggesting that DIP may be implicated in an enhanced risk of neonatal jaundice.
Table 2
| Neonatal outcomes | Normal glycemic status (n=542) | Diabetes in pregnancy (n=168) | P value |
|---|---|---|---|
| Birthweight (kg) | 3.5±0.3 | 3.9±0.7 | <0.01 |
| 1 min Apgar score <7 | 1 (0.2) | 1 (0.6) | <0.01 |
| Hypoglycemia | 5 (0.9) | 6 (3.6) | <0.01 |
| BGLU0.5 (mmol/L) | 4.5±0.2 | 3.2±0.3 | 0.21 |
| BGLU1 (mmol/L) | 3.6±0.3 | 5.3±0.9 | 0.51 |
| BGLU3 (mmol/L) | 3.9±0.4 | 6±1.1 | 0.73 |
| TB0 (mg/dL) | 1±0.1 | 1±0.3 | 0.84 |
| TB1 (mg/dL) | 6.4±2 | 5.5±2.2 | 0.99 |
| TB2 (mg/dL) | 9±1.2 | 8.9±0.2 | 0.13 |
| TB3 (mg/dL) | 10.4±1.1 | 11.9±1.6 | < 0.01 |
| TB4 (mg/dL) | 10.3±0.1 | 12±0.1 | < 0.01 |
Data are mean ± standard deviation or number (%). BGLU0.5, blood glucose levels at 0.5 hours after delivery; BGLU1, blood glucose levels at 1 hour after delivery; BGLU3, blood glucose levels at 3 hours after delivery; TB0, bilirubin levels on the day of birth; TB1, bilirubin levels on the first day after birth; TB2, bilirubin levels on the second day after birth; TB3, bilirubin levels on the third day after birth; TB4, bilirubin levels on the fourth day after birth.
Association of maternal blood glucose with neonatal blood glucose
Maternal blood glucose levels during pregnancy and immediately before delivery were analyzed for their association with neonatal blood glucose levels (Table 3). Data illustrated that there existed a correlation between predelivery blood glucose levels and neonatal blood glucose levels. We found no significant association between first-trimester FBG levels and neonatal blood glucose levels at 0.5, 1, or 3 hours after delivery (BGLU0.5, BGLU1, or BGLU3). However, as to predelivery blood glucose levels, BGLU0.5 was significantly lower in the hyperglycemic group (3.8±0.5 mmol/L) than the normoglycemic group (4±1 mmol/L, P<0.01). While this difference is statistically significant, it’s important to note that the actual glucose levels are still within the normal range and do not fall below the threshold considered to be neonatal hypoglycemia. Later BGLU1 and BGLU3 displayed a certain tendency but did not reach statistical significance (P=0.07, P=0.52). These results demonstrated that elevated predelivery blood glucose levels are implicated in neonatal hypoglycemia 0.5 hours after delivery.
Table 3
| Neonatal blood glucose | FBG in first trimester | Predelivery blood glucose | |||||
|---|---|---|---|---|---|---|---|
| ≥6 mmol/L | <6 mmol/L | P value | ≥6 mmol/L | <6 mmol/L | P value | ||
| BGLU0.5 (mmol/L) | 4±0.6 | 3.9±1 | 0.12 | 3.8±0.5 | 4±1 | <0.01 | |
| BGLU1 (mmol/L) | 5.2±0.3 | 3.3±0.7 | 0.94 | 5.1±0.2 | 3.5±0.5 | 0.07 | |
| BGLU3 (mmol/L) | 4±0.5 | 4.5±0.4 | 0.94 | 4.1±0.4 | 4.6±0.3 | 0.52 | |
Data are mean ± standard deviation. FBG, fasting blood glucose; BGLU0.5, blood glucose levels at 0.5 hours after delivery; BGLU1, blood glucose levels at 1 hour after delivery; BGLU3, blood glucose levels at 3 hours after delivery.
Predelivery blood glucose levels directly affected neonatal blood glucose levels
A multivariate analysis revealed that predelivery blood glucose levels significantly influence neonatal blood glucose concentrations shortly after birth. Specifically, as illustrated in Table 4, every 1 mmol/L increase in predelivery blood glucose levels corresponded to a decrease in neonatal BGLU0.5 levels [95% CI: (−0.1285, −0.2698), P<0.01]. This effect was not observed for BGLU1 and BGLU3 after delivery. Notably, first-trimester HbA1c and OGTT-1H results also predicted lower BGLU0.5 levels [95% CI: (−0.1505, −0.004214), P<0.05; and 95% CI: (−0.1698, −0.02407), P<0.01, respectively]. Later trimester HbA1c and other glycemic indicators did not significantly affect neonatal glucose levels. These findings underscore the importance of maternal glycemic control immediately prior to delivery for maintaining optimal neonatal glucose homeostasis.
Table 4
| Maternal blood glucose | BGLU0.5 | BGLU1 | BGLU3 | |||||
|---|---|---|---|---|---|---|---|---|
| 95% CI | P value | 95% CI | P value | 95% CI | P value | |||
| Predelivery blood glucose (mmol/L) | (−0.1285, −0.2698) | <0.01 | (−0.05142, 0.09566) | 0.55 | (−0.05626, 0.09086) | 0.64 | ||
| FBG in first trimester (mmol/L) | (−0.1248, 0.02198) | 0.17 | (−0.07741, 0.06974) | 0.92 | (−0.04614, 0.1009) | 0.46 | ||
| HbA1c in first trimester (%) | (−0.1505, −0.004214) | <0.05 | (−0.1164, 0.03053) | 0.25 | (−0.07698, 0.07017) | 0.93 | ||
| HbA1c in second trimester (%) | (−0.1291, 0.01757) | 0.14 | (−0.09181, 0.05530) | 0.63 | (−0.07530, 0.07186) | 0.96 | ||
| HbA1c in third trimester (%) | (−0.1463, 0.0001108) | 0.05 | (−0.1013, 0.04573) | 0.46 | (−0.09165, 0.05546) | 0.63 | ||
| GA in third trimester (%) | (−0.02462, 0.1222) | 0.19 | (−0.06091, 0.08623) | 0.74 | (−0.08261, 0.06454) | 0.8 | ||
| SF in third trimester (ng/mL) | (−0.02760, 0.1192) | 0.22 | (−0.03682, 0.1101) | 0.33 | (−0.07945, 0.06770) | 0.88 | ||
| OGTT-0H (mmol/L) | (−0.1418, 0.004650) | 0.07 | (−0.1302, 0.01644) | 0.13 | (−0.06403, 0.08311) | 0.8 | ||
| OGTT-1H (mmol/L) | (−0.1698, −0.02407) | <0.01 | (−0.09672, 0.05036) | 0.54 | (−0.03550, 0.1114) | 0.31 | ||
| OGTT-2H (mmol/L) | (−0.08360, 0.06354) | 0.79 | (−0.08547, 0.06167) | 0.75 | (−0.05416, 0.09294) | 0.6 | ||
BGLU0.5, blood glucose levels at 0.5 hours after delivery; BGLU1, blood glucose levels at 1 hour after delivery; BGLU3, blood glucose levels at 3 hours after delivery; CI, confidence interval; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; GA, glycated albumin; SF, serum ferritin; OGTT-0H, 0-hour oral glucose tolerance test; OGTT-1H, 1-hour oral glucose tolerance test; OGTT-2H, 2-hour oral glucose tolerance test.
Natural delivery had a greater impact on fetal blood glucose levels than cesarean section
The management of diabetic pregnant women differs between natural and cesarean deliveries, affecting neonatal blood glucose levels. In cases of natural delivery without fasting, subcutaneous insulin therapy is discontinued, and intravenous insulin management is initiated to stabilize blood glucose levels during labor. This approach allows for more flexible and immediate adjustments to insulin dosing based on frequent blood glucose monitoring. On the other hand, pregnant women undergoing cesarean section are typically fasted, and their blood glucose levels are managed through intravenous insulin infusions before and after the surgery. Special care is taken to monitor and adjust insulin doses to maintain euglycemia and prevent hypoglycemia, especially in the postoperative period.
As illustrated in Table 5, in cesarean section delivery, every 1 mmol/L increase in predelivery blood glucose levels corresponded to an increase in neonatal BGLU1 levels [95% CI: (0.08262, 0.2816), P<0.01]. Furthermore, every 1% increase in HbA1c in first trimester correlated with elevated BGLU1 levels [95% CI: (0.08757, 0.2862), P<0.01].
Table 5
| Multivariate analysis | Delivery mode | BGLU0.5 | BGLU1 | BGLU3 | |||||
|---|---|---|---|---|---|---|---|---|---|
| 95% CI | P value | 95% CI | P value | 95% CI | P value | ||||
| Predelivery blood glucose (mmol/L) | Cesarean section | (−0.05066, 0.1546) | 0.31 | (0.08262, 0.2816) | <0.01 | (−0.07621, 0.1295) | 0.61 | ||
| Natural birth | (−0.02850, 0.1762) | 0.16 | (−0.02977, 0.1796) | 0.16 | (−0.05004, 0.1599) | 0.3 | |||
| FBG in first trimester (mmol/L) | Cesarean section | (−0.1087, 0.09719) | 0.91 | (−0.01720, 0.1872) | 0.1 | (−0.07096, 0.1347) | 0.54 | ||
| Natural birth | (0.1634, 0.3553) | <0.01 | (0.02706, 0.2340) | <0.05 | (−0.1371, 0.07324) | 0.55 | |||
| HbA1c in first trimester (%) | Cesarean section | (−0.1611, 0.04407) | 0.26 | (0.08757, 0.2862) | <0.01 | (−0.1080, 0.09785) | 0.92 | ||
| Natural birth | (0.01091, 0.2141) | <0.05 | (−0.04386, 0.1659) | 0.25 | (−0.1438, 0.06640) | 0.47 | |||
| HbA1c in second trimester (%) | Cesarean section | (−0.1494, 0.05600) | 0.37 | (−0.07389, 0.1318) | 0.58 | (−0.1115, 0.09437) | 0.87 | ||
| Natural birth | (0.07289, 0.2726) | <0.01 | (−0.06334, 0.1469) | 0.43 | (−0.1153, 0.09520) | 0.85 | |||
| HbA1c in third trimester (%) | Cesarean section | (−0.1684, 0.03651) | 0.21 | (−0.07105, 0.1346) | 0.54 | (−0.1319, 0.07381) | 0.58 | ||
| Natural birth | (−0.06479, 0.1408) | 0.47 | (−0.08342, 0.1270) | 0.68 | (−0.1089, 0.1016) | 0.95 | |||
| GA in third trimester (%) | Cesarean section | (0.02751, 0.2299) | <0.05 | (−0.1018, 0.1041) | 0.99 | (−0.1077, 0.09817) | 0.93 | ||
| Natural birth | (−0.4500, −0.2711) | <0.01 | (−0.09941, 0.1111) | 0.91 | (−0.1873, 0.02176) | 0.12 | |||
| SF in third trimester (ng/mL) | Cesarean section | (−0.1115, 0.09436) | 0.87 | (−0.04544, 0.1597) | 0.27 | (−0.1164, 0.08939) | 0.8 | ||
| Natural birth | (−0.1295, 0.07625) | 0.61 | (−0.02503, 0.1842) | 0.13 | (−0.09046, 0.1201) | 0.78 | |||
| OGTT-0H (mmol/L) | Cesarean section | (−0.1509, 0.05450) | 0.35 | (−0.08206, 0.1237) | 0.69 | (−0.07869, 0.1271) | 0.64 | ||
| Natural birth | (0.1552, 0.3479) | <0.01 | (−0.1103, 0.1003) | 0.92 | (−0.1780, 0.03138) | 0.17 | |||
| OGTT-1H (mmol/L) | Cesarean section | (−0.1420, 0.06350) | 0.45 | (−0.07841, 0.1273) | 0.64 | (−0.06422, 0.1413) | 0.46 | ||
| Natural birth | (−0.1844, 0.02009) | 0.11 | (−0.04088, 0.1688) | 0.23 | (−0.1007, 0.1099) | 0.93 | |||
| OGTT-2H (mmol/L) | Cesarean section | (−0.06348, 0.1421) | 0.45 | (−0.1247, 0.08105) | 0.68 | (−0.08365, 0.1221) | 0.71 | ||
| Natural birth | (−0.1108, 0.09504) | 0.88 | (−0.04771, 0.1622) | 0.28 | (−0.1624, 0.04750) | 0.28 | |||
BGLU0.5, blood glucose levels at 0.5 hours after delivery; BGLU1, blood glucose levels at 1 hour after delivery; BGLU3, blood glucose levels at 3 hours after delivery; CI, confidence interval; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; GA, glycated albumin; SF, serum ferritin; OGTT-0H, 0-hour oral glucose tolerance test; OGTT-1H, 1-hour oral glucose tolerance test; OGTT-2H, 2-hour oral glucose tolerance test.
For natural deliveries, significant correlations were observed between FBG levels and neonatal BGLU0.5 and BGLU1 [95% CI: (0.01614, 0.1631), P<0.01; 95% CI: (0.02706, 0.2340), P<0.05]. Furthermore, each 1% increase in HbA1c during the first and second trimesters, as well as each 1 mmol/L increase in OGTT-0H results, corresponded to higher BGLU0.5 levels [95% CI: (0.01091, 0.2141), P<0.05; 95% CI: (0.07289, 0.2726), P<0.01; 95% CI: (0.1552, 0.3479), P<0.01]. Both delivery methods showed significant correlations between GA in the third trimester and BGLU0.5 [95% CI: (0.02751, 0.2299), P<0.05; 95% CI: (−0.4500, −0.2711), P<0.05]. Collectively, these results indicate that natural delivery has a more pronounced impact on fetal blood glucose levels compared to cesarean section.
Maternal hyperglycemia elevated the risk of neonatal jaundice
We further analyzed the relevance of different maternal blood glucose levels and neonatal jaundice (Table 6). Results showed that there existed a significant association between maternal blood glucose levels and neonatal bilirubin levels. Although first-trimester FBG levels did not significantly affect bilirubin levels on the day of birth (TB0) or the first day after birth (TB1), neonates of mothers with hyperglycemia exhibited significantly higher bilirubin levels on the second, third, and fourth days after birth (TB2, TB3, and TB4) (P<0.05, P<0.01, P<0.05). This trend was also observed with predelivery blood glucose levels, where TB2, TB3, and TB4 were significantly elevated (P<0.01). These results suggested that elevated blood glucose levels during pregnancy and predelivery were associated with an elevated risk of neonatal jaundice, especially on the second, third and fourth days after birth.
Table 6
| Neonatal jaundice | FBG in first trimester | Predelivery blood glucose | |||||
|---|---|---|---|---|---|---|---|
| ≥6 mmol/L | <6 mmol/L | P value | ≥6 mmol/L | <6 mmol/L | P value | ||
| TB0 (mg/dL) | 0.6±0.8 | 0.6±0.6 | 0.88 | 0.7±0.6 | 0.5±0.5 | 0.08 | |
| TB1 (mg/dL) | 3.8±1.3 | 3.7±1.9 | 0.25 | 3.9±1 | 3.6±2.1 | 0.21 | |
| TB2 (mg/dL) | 8±0.9 | 6.4±2.5 | <0.05 | 8.2±1.1 | 6±2.3 | <0.01 | |
| TB3 (mg/dL) | 10±0.5 | 7.5±3 | <0.01 | 10.2±0.4 | 7.3±2.2 | <0.01 | |
| TB4 (mg/dL) | 10.6±4 | 9±2 | <0.05 | 10±3.2 | 7.6±2 | <0.01 | |
Data are mean ± standard deviation. FBG, fasting blood glucose; TB0, bilirubin levels on the day of birth; TB1, bilirubin levels on the first day after birth; TB2, bilirubin levels on the second day after birth; TB3, bilirubin levels on the third day after birth; TB4, bilirubin levels on the fourth day after birth.
Increased risk of neonatal jaundice associated with elevated blood glucose levels during pregnancy and delivery
Subsequently, in multivariate analysis, elevated maternal blood glucose levels during pregnancy and immediately before delivery were associated with an increased risk of neonatal jaundice. Specifically, as illustrated in Table 7, for each 1 mmol/L increase in predelivery blood glucose, neonatal TB1, TB2, and TB3 levels showed a significant increase [95% CI: (0.003286, 0.1505), P<0.05], [95% CI: (0.09530, 0.2393), P<0.01], [95% CI: (0.1331, 0.2751), P<0.01], respectively. Similarly, FBG levels were significantly correlated with higher TB2 and TB3 levels [95% CI: (0.01614, 0.1631), P<0.05], [95% CI: (0.05447, 0.2003), P<0.01]. While GA and SF levels did not reach statistical significance, each 1% increase in HbA1c levels during the first and second trimesters was linked to higher TB2 and TB3 levels [95% CI: (0.009849, 0.1570), P<0.05], [95% CI: (0.05107, 0.1970), P<0.01], [95% CI: (0.03423, 0.1807), P<0.01], [95% CI: (0.05099, 0.1969), P<0.01], respectively. Additionally, TB3 also exhibited significant correlation with OGTT-0H and OGTT-1H results [95% CI: (0.03062, 0.1772), P<0.01], [95% CI: (0.007170, 0.1544), P<0.05]. These findings suggested that maternal glucose control during pregnancy, especially FBG and HbA1c, may exert a crucial consequence on neonatal jaundice.
Table 7
| Maternal blood glucose | TB0 | TB1 | TB2 | TB3 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 95% CI | P value | 95% CI | P value | 95% CI | P value | 95% CI | P value | ||||
| Predelivery blood glucose (mmol/L) | (−0.02437, 0.1234) | 0.19 | (0.003286, 0.1505) | <0.05 | (0.09530, 0.2393) | <0.01 | (0.1331, 0.2751) | <0.01 | |||
| FBG in first trimester (mmol/L) | (−0.09977, 0.04823) | 0.5 | (−0.06194, 0.08614) | 0.75 | (0.01614, 0.1631) | <0.05 | (0.05447, 0.2003) | <0.01 | |||
| HbA1c in first trimester (%) | (−0.09348, 0.05456) | 0.6 | (−0.06262, 0.08546) | 0.76 | (0.009849, 0.1570) | <0.05 | (0.05107, 0.1970) | <0.01 | |||
| HbA1c in second trimester (%) | (−0.1067, 0.04123) | 0.38 | (−0.06065, 0.08742) | 0.72 | (−0.03363, 0.1143) | 0.28 | (0.03563, 0.1821) | <0.01 | |||
| HbA1c in third trimester (%) | (−0.05390, 0.09414) | 0.59 | (−0.01327, 0.1343) | 0.11 | (0.03423, 0.1807) | <0.01 | (0.05099, 0.1969) | <0.01 | |||
| GA in third trimester (%) | (−0.03820, 0.1097) | 0.34 | (−0.05400, 0.09404) | 0.59 | (−0.06834, 0.07986) | 0.88 | (−0.01938, 0.1284) | 0.15 | |||
| SF in third trimester (ng/mL) | (−0.08816, 0.05991) | 0.7 | (−0.08691, 0.06116) | 0.73 | (−0.08307, 0.06512) | 0.81 | (−0.09225, 0.05590) | 0.63 | |||
| OGTT-0H (mmol/L) | (−0.1091, 0.03877) | 0.35 | (−0.05761, 0.09045) | 0.66 | (−0.008915, 0.1387) | 0.08 | (0.03062, 0.1772) | <0.01 | |||
| OGTT-1H (mmol/L) | (−0.09866, 0.04935) | 0.51 | (−0.08041, 0.06769) | 0.87 | (−0.02358, 0.1242) | 0.18 | (0.007170, 0.1544) | <0.05 | |||
| OGTT-2H (mmol/L) | (−0.01900, 0.1287) | 0.14 | (−0.1355, 0.01208) | 0.1 | (−0.1268, 0.02097) | 0.16 | (−0.1076, 0.04046) | 0.37 | |||
TB0, bilirubin levels on the day of birth; TB1, bilirubin levels on the first day after birth; TB2, bilirubin levels on the second day after birth; TB3, bilirubin levels on the third day after birth; TB4, bilirubin levels on the fourth day after birth; CI, confidence interval; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; GA, glycated albumin; SF, serum ferritin; OGTT-0H, 0-hour oral glucose tolerance test; OGTT-1H, 1-hour oral glucose tolerance test; OGTT-2H, 2-hour oral glucose tolerance test.
Cesarean section had a greater impact on fetal neonatal jaundice than natural delivery
As illustrated in Table 8, in cesarean section delivery, every 1 mmol/L increase in first-trimester FBG and OGTT-0H results, as well as every 1% increase in HbA1c in first, second, third trimester, corresponded to an increase in neonatal TB2 levels [95% CI: (0.05536, 0.2565), P<0.01], [95% CI: (0.03767, 0.2398), P<0.01], [95% CI: (0.03285, 0.2353), P<0.01], [95% CI: (0.0001557, 0.2041), P<0.05], [95% CI: (0.06032, 0.2611), P<0.01], respectively. Similarly, these factors, along with second and third trimester HbA1c increases, were also significantly associated with higher TB3 levels.
Table 8
| Multivariate analysis | Delivery mode | TB0 | TB1 | TB2 | TB3 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 95% CI | P value | 95% CI | P value | 95% CI | P value | 95% CI | P value | |||||
| Predelivery blood glucose (mmol/L) | Cesarean section | (−0.07433, 0.1314) | 0.58 | (−0.07814, 0.1276) | 0.64 | (−0.009322, 0.1950) | 0.07 | (0.08153, 0.2808) | <0.01 | |||
| Natural birth | (−0.09215, 0.1212) | 0.79 | (−0.03465, 0.1776) | 0.18 | (0.05215, 0.2602) | <0.01 | (0.07061, 0.2774) | <0.01 | ||||
| FBG in first trimester(mmol/L) | Cesarean section | (−0.05677, 0.1487) | 0.38 | (−0.03686, 0.1681) | 0.21 | (0.05536, 0.2565) | <0.01 | (0.06774, 0.2680) | <0.01 | |||
| Natural birth | (−0.1964, 0.01522) | 0.09 | (−0.1237, 0.08961) | 0.75 | (−0.02771, 0.1843) | 0.15 | (0.03259, 0.2419) | <0.05 | ||||
| HbA1c in first trimester (%) | Cesarean section | (−0.08531, 0.1205) | 0.74 | (−0.03924, 0.1658) | 0.22 | (0.03285, 0.2353) | <0.01 | (0.05291, 0.2542) | <0.01 | |||
| Natural birth | (−0.1364, 0.07677) | 0.58 | (−0.1228, 0.09047) | 0.76 | (−0.01190, 0.1996) | 0.08 | (0.04747, 0.2559) | <0.01 | ||||
| HbA1c in second trimester (%) | Cesarean section | (−0.08696, 0.1189) | 0.76 | (−0.007559, 0.1965) | 0.07 | (0.0001557, 0.2041) | <0.05 | (0.08139, 0.2807) | <0.01 | |||
| Natural birth | (−0.1691, 0.04337) | 0.24 | (−0.1563, 0.05652) | 0.36 | (−0.08420, 0.1290) | 0.68 | (−0.04681, 0.1658) | 0.27 | ||||
| HbA1c in third trimester (%) | Cesarean section | (−0.03159, 0.1732) | 0.17 | (0.07021, 0.2701) | <0.01 | (0.06032, 0.2611) | <0.01 | (0.08700, 0.2859) | <0.01 | |||
| Natural birth | (−0.1217, 0.09161) | 0.78 | (−0.1376, 0.07552) | 0.57 | (−0.01309, 0.1984) | 0.09 | (−0.02713, 0.1849) | 0.14 | ||||
| GA in third trimester (%) | Cesarean section | (−0.06357, 0.1420) | 0.45 | (−0.09845, 0.1074) | 0.93 | (−0.1117, 0.09447) | 0.87 | (−0.04807, 0.1575) | 0.29 | |||
| Natural birth | (−0.02298, 0.1889) | 0.12 | (0.01048, 0.2209) | <0.05 | (−0.005183, 0.2060) | 0.06 | (0.03084, 0.2402) | <0.05 | ||||
| SF in third trimester (ng/mL) | Cesarean section | (−0.07517, 0.1305) | 0.6 | (−0.1611, 0.04402) | 0.26 | (−0.1055, 0.1007) | 0.96 | (−0.1039, 0.1023) | 0.99 | |||
| Natural birth | (−0.1639, 0.04875) | 0.29 | (−0.07168, 0.1414) | 0.52 | (−0.1156, 0.09773) | 0.87 | (−0.1402, 0.07290) | 0.53 | ||||
| OGTT-0H (mmol/L) | Cesarean section | (−0.06366, 0.1419) | 0.45 | (−0.03084, 0.1740) | 0.17 | (0.03767, 0.2398) | <0.01 | (0.07307, 0.2730) | <0.01 | |||
| Natural birth | (−0.2012, 0.01018) | 0.08 | (−0.1200, 0.09329) | 0.8 | (−0.07529, 0.1378) | 0.56 | (−0.04753, 0.1651) | 0.28 | ||||
| OGTT-1H (mmol/L) | Cesarean section | (−0.07654, 0.1292) | 0.61 | (−0.08102, 0.1248) | 0.67 | (−0.01837, 0.1863) | 0.11 | (0.04156, 0.2435) | <0.01 | |||
| Natural birth | (−0.1356, 0.07754) | 0.59 | (−0.09914, 0.1142) | 0.89 | (−0.01257, 0.1989) | 0.08 | (−0.02896, 0.1831) | 0.15 | ||||
| OGTT-2H (mmol/L) | Cesarean section | (−0.002558, 0.2013) | 0.06 | (−0.1893, 0.01499) | 0.09 | (−0.1696, 0.03561) | 0.2 | (−0.1458, 0.05997) | 0.41 | |||
| Natural birth | (−0.1775, 0.03476) | 0.19 | (−0.1377, 0.07543) | 0.56 | (−0.08182, 0.1314) | 0.65 | (−0.02248, 0.1894) | 0.12 | ||||
TB0, bilirubin levels on the day of birth; TB1, bilirubin levels on the first day after birth; TB2, bilirubin levels on the second day after birth; TB3, bilirubin levels on the third day after birth; TB4, bilirubin levels on the fourth day after birth; CI, confidence interval; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; GA, glycated albumin; SF, serum ferritin; OGTT-0H, 0-hour oral glucose tolerance test; OGTT-1H, 1-hour oral glucose tolerance test; OGTT-2H, 2-hour oral glucose tolerance test.
As to natural delivery, TB1 and TB3 exhibited significant correlation with GA in third trimester [95% CI: (0.01048, 0.2209), P<0.05], [95% CI: (0.03084, 0.2402), P<0.05]. Every 1 mmol/L increase in Predelivery blood glucose also corresponded to an increase in TB2 levels [95% CI: (0.05215, 0.2602), P<0.01]. Both cesarean section and natural delivery exhibited significant correlation in TB3 with PREDELIVERY blood glucose, FBG in first trimester, and HbA1c in first trimester. Together, these results demonstrated that cesarean section has a greater impact on fetal neonatal jaundice than natural delivery.
Discussion
Substantial studies have demonstrated that elevated gestational blood glucose, whether during predelivery or pregnancy in each trimester, is associated with an increased risk of adverse birth outcomes, even in nondiabetic pregnancies (20). Previous research has primarily focused on outcomes of newborns born to patients with GDM, for instance, neonatal blood glucose and abnormal body size (6). Our study highlights the significant impact of maternal blood glucose levels on neonatal outcomes, specifically focusing on hypoglycemia and jaundice. The results underscore the intricate relationship between maternal glycemic control and the health of the newborn, with important implications for clinical practice and future research.
Maternal glycemic management has a direct impact on neonatal metabolic status. HbA1c levels is a stable indicator of long-term glycemic control during pregnancy, serving as a valuable tool when interpreted with caution and in conjunction with other glucose monitoring methods (21). Study has shown that early HbA1c levels are significantly associated with adverse fetal or neonatal events such as respiratory distress syndrome and pneumonia (22). This emphasizes the importance of early HbA1c testing as an auxiliary method for identifying potential respiratory distress syndrome in neonates. Our findings suggested that maternal blood glucose levels during pregnancy and predelivery were both significantly negatively correlated with neonatal blood glucose levels, consistent with previous studies that maternal hyperglycemia is implicated in elevated risks of neonatal macrosomia and neonatal hypoglycemia (12,23). It is further supported by the negative correlation between maternal predelivery HbA1c levels and neonatal blood glucose levels (12). Our research highlights a significant association between prenatal hyperglycemia and an elevated risk of neonatal hypoglycemia 0.5 hours after delivery, consistent with the “fuel-mediated hypothesis”. It is hypothesized that the fetus exposed to a hyperglycemic environment in utero promotes glucose absorption through enhanced insulin generation. After delivery, due to the sudden cessation of glucose supply, it may cause a rapid drop in blood glucose levels (4). Multivariate analysis further confirmed the direct effect of predelivery blood glucose levels on neonatal blood glucose levels, especially in the early neonatal period.
Different from previous research, the impact of maternal blood glucose levels on neonatal jaundice was also a major focus of this study. Results indicated a significant positive correlation between maternal blood glucose levels and neonatal bilirubin levels, being a crucial finding. Jaundice is characterized by elevated bilirubin levels and may have adverse effects on neonatal neurodevelopment if left untreated (24,25). Our study emphasized that maternal hyperglycemia during pregnancy and predelivery may disrupt fetal metabolic environment and make neonates more susceptible to jaundice after delivery, especially on the second and third day after birth.
Apart from neonatal hypoglycemia and jaundice, various theories have been proposed to explain the underlying mechanisms of DIP and its impact on fetal outcomes (26,27). DIP is recognized for causing damage to the endothelial cells, increasing the release of vasoactive substances and triggering oxidative stress, which can result in circulatory problems like thrombosis, hypertension, and atherosclerosis (27-29). The microangiopathy in the placenta impairsits capability to supply adequate nourishment and oxygen to the developing fetus, as well as disrupting lipid metabolism, the balance of crucial amino acids, and raising levels of inflammation. All these factors ultimately contribute to restriction of fetal growth. Therefore, appropriate glycemic management of pregnant women is essential to improve pregnancy outcomes. As stated in previous study (4), treatment of DIP improved pregnancy outcomes. Our findings align with the study of Karkia et al. (30) which observed an increased risk for adverse neonatal outcomes in DIP, including low Apgar scores, early thrombocytopenia, hypoxic-ischemic encephalopathy, hypoglycemia, and pulmonary hemorrhage. However, our findings further emphasized the clinical relevance of monitoring neonatal blood glucose and bilirubin levels immediately after delivery for DIP pregnant women, with important clinical implications for DIP management. It highlights the necessity of early recognition and aggressive management of maternal hyperglycemia to prevent adverse neonatal outcomes. Our findings support the standards established by American Diabetes Association (ADA), for the care of GDM, encompassing the importance of maintaining normoglycemic levels to reduce risks of complications (4,31), which should be strictly adhered to, especially in high-risk DIP population. In addition, previous study points out that economic subsidy programs can increase the rate of glycemic management in pregnant women, consequently decreasing the risk of adverse pregnancies for mothers and infants (32).
DIP is a significant health condition that not only affects immediate neonatal outcomes but also has profound implications for long-term health, making its evaluation and management crucial for both short-term and lifelong well-being (23). The long-term health consequences of neonatal hypoglycemia extend beyond the neonatal period, with potential adverse effects on neurodevelopment and future risk of cardiometabolic diseases, underscoring the importance of early identification and treatment (33). The findings of this study underscore the immediate neonatal impacts of maternal hyperglycemia, such as neonatal hypoglycemia and jaundice, and also highlight the potential for long-term health consequences, including an increased risk of neurodevelopmental delays and cardiometabolic disorders in later life. Early identification of DIP is crucial for early diagnosis and intervention of the disease as well as improvement of maternal and infant health. Currently, international guidelines recommend screening for DIP at 24–28 weeks of gestation (34), but some patients may already have pathological alterations such as insulin resistance or insufficient insulin secretion before that. Therefore, exploring early predictive molecules of DIP is of great value for disease early intervention. Recent years have witnessed much progress made in the study of DIP molecular prediction. For instance, predictive molecules such as adipokines, protein molecules, and metabolite molecules, are closely related to insulin resistance, obesity, inflammation, and so forth (35). Recent study has also proposed a novel classification method for DIP on the basis of OGTT results, in an attempt to better stratify the management of DIP risk and improve maternal and infant health (36).
Limitations of the study involve the relatively small sample size which may limit the generalizability of the findings. To further support our findings and hypotheses, future studies should include larger and more diverse populations to validate these results. Longitudinal studies are also required to assess the long-term effects of maternal blood glucose levels on neonatal health and development. Future research should continue to explore the long-term health outcomes associated with neonatal hypoglycemia, including the impact on cognitive development and the risk of chronic diseases in adulthood, to further inform prevention and treatment strategies. Furthermore, future research might include shed more light on the underlying mechanisms the use of Doppler ultrasound to evaluate placental issues, providing concrete evidence of the vascular irregularities linked to DIP and its effects on neonatal outcomes. Examining maternal blood indicators like placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and inflammatory cytokines could shed more light on the underlying mechanisms (37).
Conclusions
In conclusion, our study underscores the significant influence of maternal blood glucose levels on neonatal outcomes, particularly hypoglycemia and jaundice. These findings reinforce the necessity for stringent glycemic control throughout pregnancy to mitigate risks and improve neonatal health. Continued research and enhanced clinical practices are essential to address the challenges associated with diabetes in pregnancy and ensure the best possible outcomes for both mothers and their newborns.
Maternal blood glucose levels significantly influence neonatal blood glucose and bilirubin levels, thereby heightening the risk of hypoglycemia and jaundice in newborns. These findings highlight the critical need for stringent glycemic control in pregnant women with DIP.
Acknowledgments
Funding: None.
Footnote
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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-356/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethical approval for this study was obtained from the Ethics Committee of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (No. 2020KY239) and informed consent was obtained from all individual participants.
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