Abstract
Aims and introduction
It is helpful for both diabetologists and obstetricians to identify patients with gestational diabetes who require insulin therapy for glycemic control during pregnancy. The aim of the present study was to assess potential predictors of insulin requirement in patients with gestational diabetes.
Materials and methods
One hundred thirteen patients with gestational diabetes [mean age 34.2 ± 4.5 years; pre-gestational body mass index (BMI), 23.6 ± 6.0 kg/m2] were included in this study. The associations between insulin requirement and the following factors were analyzed: clinical maternal characteristics, number of abnormal oral glucose tolerance test (OGTT) values, gestational age at diagnosis, plasma glucose levels measured during the OGTT, glycated hemoglobin (HbA1c) and glycated albumin levels, and serum C-peptide level before breakfast and 1 and 2 h after breakfast.
Results
Thirty-six patients (32 %) required insulin during pregnancy (“insulin group”); the remaining patients were treated with nutrition therapy (“nutrition group”). The insulin group had a higher pre-gestational BMI, higher fasting glucose level, higher area under the curve (AUC) for serum C-peptide level, higher HbA1c level, and a younger gestational age at diagnosis than the nutrition group (p < 0.05, all). Logistic regression analysis showed that the pre-gestational BMI, AUC for serum C-peptide level, and the HbA1c level were independent predictors for the insulin group (p < 0.05, all).
Conclusions
The results suggest that a high insulin resistance and HbA1c level may be associated with insulin requirement in patients with gestational diabetes.
Keywords: Gestational diabetes, Insulin therapy, BMI, HbA1c, Glycated albumin, C-peptide
Introduction
Gestational diabetes poses risks to the mother and the neonate. The Hyperglycemia and Adverse Pregnancy Outcome study demonstrated an increased risk of macrosomia and maternal and neonatal complications in pregnant women with mild hyperglycemia [1]. Treatment for gestational diabetes improves perinatal outcomes [2–4]. Gestational diabetes is first managed with nutritional therapy and exercise; insulin therapy should be added if necessary.
In Japan, until 2010, gestational diabetes was diagnosed according to criteria defined by the Japan Society of Obstetrics and Gynecology [5]. The diagnosis of gestational diabetes required any two of the three plasma glucose values obtained during a 75-g oral glucose tolerance test (OGTT) to meet or exceed predefined values (fasting plasma glucose level, 100 mg/dL; 1-h plasma glucose level, 180 mg/dL; and 2-h plasma glucose level, 150 mg/dL). In 2010, new diagnostic criteria were used, based on the guidelines set by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) [6]. According to the IADPSG criteria, the diagnosis of gestational diabetes is made when any of the following three values are met or exceeded: fasting plasma glucose level, 92 mg/dL; 1-h plasma glucose level, 180 mg/dL; and 2-h plasma glucose level, 153 mg/dL. After using the new criteria, the number of patients with gestational diabetes increased from 2.4 to 6.6 % due to the lowering of the fasting glucose threshold value and the need to meet only one threshold value instead of at least two threshold values [7].
It is helpful for both diabetologists and obstetricians to identify patients who require insulin therapy for glycemic control during pregnancy. However, only one study has reported indicators for insulin therapy in patients with gestational diabetes diagnosed according to the IADPSG criteria [8]. The aim of the present study was to assess potential predictors of insulin requirement in patients with gestational diabetes diagnosed according to the new criteria.
Methods
Subjects
One hundred thirteen patients with gestational diabetes who were diagnosed using the IADPSG criteria and managed at Tokyo Women’s Medical University, Medical Center East, from April 2012 to October 2014 were included in this study. Their mean age was 34.2 ± 4.5 years, and their pre-gestational body mass index (BMI) was 23.6 ± 6.0 kg/m [2]. All patients had a singleton pregnancy. Patients who received intravenous ritodrine hydrochloride were excluded from this study.
Diagnosis and treatment of gestational diabetes
At our hospital, a two-step screening test for gestational diabetes was performed for each patient. Patients with random plasma glucose levels of over 100 mg/dL in early pregnancy or whose plasma glucose levels exceeded 140 mg/dL after a 50-g glucose challenge test in mid-pregnancy underwent a diagnostic OGTT.
All patients were diagnosed with gestational diabetes based on the results of the OGTT at 25.8 ± 5.8 (range 8.1–37.4) weeks of pregnancy, and their glycated hemoglobin (HbA1c) and glycated albumin levels were measured at diagnosis, or at the first visit if the patient was referred to our hospital after diagnosis. First, they received dietary instructions (30 kcal/kg ideal body weight + 200 kcal) from a nutritionist. Second, to assess their glycemic control and endogenous insulin secretion, all patients underwent a meal tolerance test (MTT) in which they ate their usual breakfast and had their plasma glucose levels and serum C-peptide levels measured before breakfast and at 1 and 2 h after breakfast. Their plasma glucose levels were obtained from the measurements taken during the MTT, at 1–3 weekly visits at the outpatient clinic, and by self-monitoring blood glucose. If they had elevated fasting plasma glucose levels (>100 mg/dL) or 2-h postprandial glucose levels that exceeded 120 mg/dL despite nutritional therapy and exercise, insulin treatment was started.
Study methods
Subjects were divided into the following two groups: those who required insulin therapy during pregnancy (“insulin group”) and those treated with nutritional therapy only (“nutrition group”). We evaluated the associations between insulin requirement and the following parameters: maternal age, pre-gestational BMI, maternal weight gain at the time of diagnosis of gestational diabetes, family history of diabetes, number of parity, prior gestational diabetes, prior fetal macrosomia, smoking status, number of abnormal OGTT values, gestational age at diagnosis, plasma glucose levels measured during the OGTT, serum C-peptide level measured during the MTT, and HbA1c and glycated albumin levels. Furthermore, the pregnancy outcome included weight gain during pregnancy, gestational age at delivery, preterm delivery, cesarean section, pregnancy-induced hypertension, birth weight, sex of the baby, and placental weight; neonatal complications such as respiratory problems, hypoglycemia, hyperbilirubinemia, congenital malformation, and neonatal intensive care unit (NICU) admission were analyzed to evaluate the appropriateness of our therapeutic intervention. BMI was calculated by the following formula: body weight (kg) divided by height squared (m2). Macrosomia was defined as a birth weight of >4000 g.
At our hospital, plasma glucose was determined by the hexokinase UV method (Labospect 7700, Hitachi, Tokyo, Japan) using the Serotec GLU-HL (Serotec Co., Ltd., Sapporo, Japan). The HbA1c level was analyzed by high-performance liquid chromatography assay (HLC ®-723G9 automated glycohemoglobin analyzer, Tosoh Corp., Tokyo, Japan). Glycated albumin was measured by an enzymatic method using a Lucica GA-L kit (Asahi Kasei Pharma, Tokyo, Japan). Serum C-peptide was determined by CLEIA (Lumipulse Presto II, Fujirebio, Inc., Tokyo, Japan) using the Lumipulse Presto C-peptide reagent.
This study was approved by the Tokyo Women’s Medical University Ethics Committee (project no.: 3514).
Statistical analysis
All data were reported as the mean ± standard deviation or as a percentage for frequencies. The area under the curve (AUC) was calculated using the trapezoidal rule. We used the Student t test and the chi-square test to examine differences in continuous and categorical variables between the two groups. In logistic regression analyses, the backward elimination method was used to determine significant predictors of insulin requirement. All analyses were conducted using SPSS Statistics version 22 for Windows (IBM Corp., Armonk, NY, USA). A probability of <0.05 was considered significant.
Results
Maternal characteristics
Thirty-six (32 %) patients required insulin during pregnancy (insulin group); the remaining patients were treated with nutrition therapy (nutrition group). The maximum daily insulin dose prescribed during pregnancy was 28 ± 24 (range 2–102) units. Maternal age at delivery was similar in the insulin group and the nutrition group (Table 1). The insulin group had a higher pre-gestational BMI than the nutrition group. The weight gain at the time of diagnosis was lower in the insulin group than in the nutrition group. There was no difference between the two groups in terms of family history of diabetes or smoking status.
Table 1.
Maternal characteristics
| Insulin group (n = 36) | Nutrition group (n = 77) | P value | |
|---|---|---|---|
| Age (years) | 34.2 ± 5.1 | 34.2 ± 4.2 | ns |
| Pre-gestational BMI (kg/m2) | 26.4 ± 3.2 | 22.2 ± 5.5 | 0.001 |
| Weight gain at the time of diagnosis (kg) | 3.5 ± 3.7 | 5.6 ± 3.5 | 0.018 |
| Nulliparous, n (%) | 18 (50) | 46 (60) | ns |
| Family history of DM, n (%) | 15 (42) | 41 (53) | ns |
| Prior gestational diabetes, n (%) | 3 (8) | 1 (1) | ns |
| Prior fetal macrosomia, n (%) | 1 (3) | 2 (3) | ns |
| Smoking, n (%) | 9 (25) | 10 (13) | ns |
Data are shown as the mean ± standard deviation
BMI body mass index, DM diabetes mellitus
Status of glucose metabolism
Results of the diagnostic OGTT are shown in Table 2. The gestational age at diagnosis of gestational diabetes was younger in the insulin group than in the nutrition group. The fasting blood glucose level was higher in the insulin group than in the nutrition group. There were no significant differences between both groups in terms of the 1-h glucose level, 2-h glucose level, AUC for blood glucose levels, and number of abnormal OGTT values. The HbA1c level was higher in the insulin group than in the nutrition group (5.4 ± 0.5 and 5.2 ± 0.4 %; p < 0.05), whereas there was no significant difference between the two groups in the glycated albumin levels.
Table 2.
Status of glucose metabolism
| Insulin group (n = 36) | Nutrition group (n = 77) | P value | |
|---|---|---|---|
| Gestational age at diagnosis (weeks) | 23.3 ± 6.4 | 27.0 ± 5.1 | 0.001 |
| OGTT | |||
| Plasma glucose | |||
| Fasting (mg/dL) | 88 ± 11 | 83 ± 9 | 0.013 |
| 1-h (mg/dL) | 177 ± 29 | 173 ± 28 | ns |
| 2-h (mg/dL) | 161 ± 22 | 157 ± 25 | ns |
| AUC (mg/dL min) | 18053 ± 2051 | 19310 ± 1558 | ns |
| Number of abnormal values | 1.5 ± 0.7 | 1.4 ± 0.7 | ns |
| HbA1c (NGSP) (%) | 5.4 ± 0.5 | 5.2 ± 0.4 | 0.001 |
| Glycated albumin (%) | 12.9 ± 1.1 | 13.0 ± 1.1 | ns |
| Meal tolerance test | |||
| Gestational age | 27.6 ± 5.4 | 30.4 ± 4.6 | 0.006 |
| Plasma glucose | |||
| Fasting (mg/dL) | 92 ± 16 | 84 ± 7 | 0.014 |
| 1-h (mg/dL) | 147 ± 32 | 121 ± 20 | <0.001 |
| 2-h (mg/dL) | 128 ± 32 | 104 ± 18 | <0.001 |
| AUC (mg/dL min) | 15383 ± 2988 | 12903 ± 1602 | <0.001 |
| Serum C-peptide | |||
| Fasting (ng/mL) | 1.96 ± 0.94 | 1.49 ± 0.68 | 0.003 |
| 1-h (ng/mL) | 6.83 ± 2.91 | 5.54 ± 2.67 | 0.022 |
| 2-h (ng/mL) | 7.53 ± 3.76 | 4.87 ± 2.39 | <0.001 |
| AUC (ng/mL min) | 695 ± 288 | 523 ± 233 | 0.001 |
Data are shown as the mean ± standard deviation
OGTT oral glucose tolerance test, AUC area under the curve, HbA1c glycated hemoglobin, NGSP National Glycohemoglobin Standardization Program
Regarding insulin secretion, the serum C-peptide level before breakfast and at 1 h and 2 h after breakfast and the AUC for serum C-peptide level were higher in the insulin group than in the nutrition group.
Predictive factors for insulin requirement
To investigate the independent predictive factors for the requirement for insulin therapy in patients with gestational diabetes, logistic regression analyses were performed for associated variables, including the pre-gestational BMI, gestational age at diagnosis, fasting plasma glucose level, HbA1c level, and AUC for serum C-peptide level. Results showed that the pre-gestational BMI, AUC for serum C-peptide level, and HbA1c level were independent predictors in the insulin group (Table 3). However, the accuracy of the AUC for serum C-peptide level and the HbA1c level as predictors of insulin requirement was low. Sensitivity for insulin requirement was 72.2 % and specificity was 70.1 % with a BMI of 22.29 kg/m2 (Fig. 1).
Table 3.
Logistic regression analysis of predictive factors for insulin requirement
| Odds ratio (95 % confidence interval) | P value | |
|---|---|---|
| AUC for serum C-peptide | 1.002 (1.000–1.004) | 0.021 |
| Pre-gestational BMI | 1.089 (1.008–1.175) | 0.030 |
| HbA1c | 3.311 (1.013–10.821) | 0.048 |
Excluded: fasting glucose level, gestational age at diagnosis of gestational diabetes
AUC area under the curve, BMI body mass index, HbA1c glycated hemoglobin
Fig. 1.
a Receiver operating characteristic (ROC) curve of the area under the curve (AUC) for serum C-peptide for insulin requirement. AUC 0.677, 95 % confidence interval 0.574–0.781, p < 0.05. b ROC curve of the pre-gestational body mass index (BMI) for insulin requirement. AUC 0.736, 95 % confidence interval 0.631–0.841, p < 0.05. c ROC curve of glycated hemoglobin (HbA1c) levels for insulin requirement. AUC 0.673, 95 % confidence interval 0.561–0.786, p < 0.05
Pregnancy outcomes
Gestational age at delivery was younger in the insulin group than in the nutrition group (Table 4). There was no difference between the two groups in terms of the rate of cesarean section and the birth weight of the baby. The NICU admission rate was higher in the insulin group than in the nutrition group (Table 5).
Table 4.
Pregnancy outcome
| Insulin group (n = 36) | Nutrition group (n = 77) | P value | |
|---|---|---|---|
| Gestational age at delivery (weeks) | 38.3 ± 1.2 | 39.0 ± 1.2 | 0.002 |
| Weight gain during pregnancy (kg) | 6.9 ± 5.6 | 8.2 ± 4.0 | ns |
| Preterm delivery, n (%) | 2 (6) | 2 (3) | ns |
| Cesarean section, n (%) | 17 (47) | 23 (30) | ns |
| Pregnancy-induced hypertension, n (%) | 3 (8) | 6 (8) | ns |
| Birth weight (g) | 2970 ± 445 | 2995 ± 449 | ns |
| Male sex, n (%) | 17 (47) | 43 (56) | ns |
| Placental weight (g) | 575 ± 114 | 550 ± 87 | ns |
Data are shown as the mean ± standard deviation
Table 5.
Neonatal complications
| Insulin group (n = 36) | Nutrition group (n = 77) | P value | |
|---|---|---|---|
| Respiratory problems, n (%) | 8 (22) | 6 (8) | ns |
| Hypoglycemia, n (%) | 5 (14) | 2 (3) | ns |
| Hyperbilirubinemia, n (%) | 1 (3) | 1 (1) | ns |
| Congenital malformation, n (%) | 3 (8) | 1 (1) | ns |
| NICU admission, n (%) | 15 (42) | 14 (18) | 0.016 |
NICU neonatal intensive care unit
Discussion
This study showed that 32 % of patients with gestational diabetes who were diagnosed using the new criteria needed insulin therapy. Pre-gestational BMI, AUC for the serum C-peptide level, and HbA1c level were independent predictors for insulin requirement in patients with gestational diabetes. In our study, factors that were associated with insulin resistance, such as a high BMI and a high serum C-peptide level, were extracted as predictors. However, the accuracy of these predictors for insulin requirement was low.
Gestational diabetes is characterized by carbohydrate intolerance of varying severity, which has its onset or is first recognized during pregnancy. As pregnancy advances, the increasing insulin resistance creates a demand for more insulin. When insulin resistance becomes dominant due to impaired insulin secretion, hyperglycemia develops [9]. It was reported that a decreased insulin disposition index, i.e., the beta cell function in relation to insulin sensitivity, was found in Japanese patients with gestational diabetes [10]. The insulin group had a higher pre-gestational BMI, serum C-peptide level before breakfast and at 1 h and 2 h after breakfast, and AUC for serum C-peptide level than the nutrition group in the present study. These results suggest that patients with gestational diabetes who need insulin therapy may have more severe insulin resistance due to their higher BMI and other factors that were not determined in our study. Hormonal changes [11] and an imbalance between inflammatory and anti-inflammatory mediators [12] that are associated with pregnancy, which were associated with insulin resistance aside from BMI, affect the impaired suppression of hepatic glucose production and deficiency in muscle glucose uptake in the same manner as in type 2 diabetes [13].
The insulin group had a lower weight gain at the time of diagnosis of gestational diabetes than the nutrition group. This may be explained by the fact that the insulin group had a higher pre-gestational BMI and a younger gestational age at diagnosis.
A high fasting blood glucose level from a diagnostic OGTT was associated with insulin therapy, whereas the 1-h glucose level, the 2-h glucose level, and the number of abnormal OGTT values were not associated with insulin therapy. The insulin group had a younger gestational age at diagnosis of gestational diabetes. Some studies have demonstrated that the fasting glucose level on OGTT [14–17] and the gestational week at diagnosis [14–16, 18] are associated with the requirement for insulin therapy. The initial abnormality in glucose intolerance is postprandial hyperglycemia [13, 19]. Thus, a higher fasting glucose level and early diagnosis indicate that patients who have more advanced glucose intolerance need insulin therapy. Moreover, nutritional treatment alone may not improve their fasting glucose tolerance.
The HbA1c level was an independent predictor for insulin therapy in our patients, although the glycated albumin level was not related to the requirement for insulin therapy. HbA1c levels decreased in the second trimester and increased in the third trimester during pregnancy, and glycated albumin levels decreased toward the third trimester in healthy Japanese women [20]. Measuring the glycated albumin level is recommended in order to achieve strict glycemic control during pregnancy, because changes in this level are rapid and marked. Our patients who needed insulin therapy had a high fasting glucose level. HbA1c reflects the fasting glucose level more than the postprandial glucose level, and glycated albumin reflects the postprandial glucose level [21, 22]. This may be one of the reasons why HbA1c and not glycated albumin is a predictor of insulin therapy. The other possible reason is that patients who needed insulin therapy may have had high glucose levels since pre-pregnancy or early pregnancy. The glycated albumin level is negatively correlated with BMI [23]. Therefore, as the patients in the insulin group had higher BMIs, their glycated albumin levels may have been relatively low.
In this study, the pre-gestational BMI, the AUC for serum C-peptide level, and the HbA1c level were independent predictors for insulin therapy. Some similar studies that evaluated clinical factors for insulin requirement in gestational diabetes demonstrated that pre-gestational BMI [15, 16, 24], a family history of diabetes mellitus [16, 24, 25], gestational age at diagnosis [15, 16, 18], plasma glucose levels measured during an OGTT [8, 14–18, 25], number of abnormal OGTT values [24, 25], and HbA1c level [14, 18, 24] were predictors. Some of those predictors were confirmed in our study. However, accurate predictors have not been determined yet, and it is difficult to identify the patients who need insulin therapy using these existing predictors. Currently, it is necessary to closely monitor the glucose level (e.g., by self-monitoring) to achieve glycemic management, which includes determining whether insulin therapy is needed.
A study reported that the 1-h glucose level from a diagnostic OGTT was an indicator for insulin therapy in patients with gestational diabetes diagnosed according to the IADPSG criteria [8], which was different from our study. There is a possibility that the subjects in our study had a higher BMI overall than the subjects in the former study, although pre-gestational BMI was not examined in the former study. Our study is the first to assess the associations of pre-gestational BMI, insulin secretion, and HbA1c level with insulin requirement in patients with gestational diabetes diagnosed according to the IADPSG criteria.
The gestational age at delivery was younger and the NICU admission rate was higher in the insulin group than in the nutrition group. As insulin therapy influenced the decision about the timing and mode of delivery, and labor was often induced in the insulin group, the insulin group had a higher frequency of early delivery and a higher rate of admission of infants to the NICU. However, the frequencies of other neonatal complications were not significantly different between the two groups. This means that our intervention for gestational diabetes is reasonable.
This study had some limitations. Firstly, the load inequality between a usual breakfast (which we used) and a standard test meal in MTT could be taken into account, but the patients received their dietary instructions before MTT and we assessed the contents of the meal in MTT. Secondly, the range of gestational ages at the time of diagnosis was wide. In further studies, clinical features including the need for insulin therapy should be investigated in patients with gestational diabetes diagnosed at different gestational ages.
In conclusion, 32 % of patients with gestational diabetes who were diagnosed using the new criteria needed insulin therapy to achieve strict glycemic control during pregnancy. Pre-gestational BMI, AUC for serum C-peptide level, and HbA1c level were independent predictors for insulin therapy. The requirement for insulin therapy in patients with gestational diabetes may be associated with insulin resistance due to a higher BMI and other factors. Further studies that are designed to clarify the other factors for insulin resistance during pregnancy are needed to precisely determine the predictors of insulin therapy in patients with gestational diabetes.
Conflict of interest
H. Sakura received lecture fees from Mitsubishi Tanabe Pharma Corp. and research grants from Astra Zeneca K.K., Chugai Pharma Manufacturing Co., Ltd., Takeda Pharma Ltd., and Ono Pharmaceutical Co., Ltd. Y. Uchigata received lecture fees from Novo Nordisk Pharma Ltd., Sanofi K.K., Takeda Pharma Ltd., Mitsubishi Tanabe Pharma Corp., Ono Pharmaceutical Co., Eli Lilly Japan K.K., MSD K.K., and research grants from Novartis Phama K.K., Astellas Pharma Inc., Pfizer Japan Inc., Chugai Pharma Manufacturing Co., Ltd., Boehringer Ingerheim, Astra Zeneca K.K., Kyowa Hakko Kirin Co., Ltd., Alcon, Otsuka Pharmacuetical Co., Ltd., Nipro, Eli Lilly Japan K.K., Kowa Shinyaku Co., Ltd., Eizai Co., Ltd., Takeda Pharma Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corp., MSD K.K., Ono Pharmaceutical Co., Novo Nordisk Phama Ltd., Terumo Corp., Sumitomo Dainippon Pharma Co., Ltd., and Diaiichu Sankyo Co., Ltd. The other authors declare that they have no conflict of interest.
Human rights statement and informed consent
All procedures conducted in this study were in accordance with the ethics committee of Tokyo Women’s Medical University and with the Declaration of Helsinki of 1964 and later revisions. Informed consent or a substitute for it was obtained from all patients before they were included in the study.
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