Value of fructosamine measurement in pregnant women with abnormal glucose tolerance

Pregnant women with hyperglycemia are at high risk of early fetal loss.¹ And the one-year-old infants of diabetic mothers demonstrate less positive and more negative behaviors, which are correlated with abnormal maternal glucose tolerance than those of nondiabetic mothers.² So, early diagnosis and treatment of abnormal glucose tolerance will benefit both the mothers and babies. We intended to find a method that can diagnose impaired glucose tolerance at an early stage with high sensitivity and specificity.

　　The serum concentration of fructosamine, a product of nonenzymatic glycation, is correlated with the level of plasma glucose, reflecting the blood glucose control over the past 2－3 weeks. Some researchers suggested that measurement of fructosamine could be an alternative to the glucose challenge test (GCT), and be used to monitor glucose control.^3-8 The method can be more precise than glycosylated hemoglobin (HbA1c) measurement;^9,10 and can be used to predict the risk of gestational diabetes mellitus (GDM).¹¹ However, some scientists questioned if the method is sufficiently sensitive to screen GDM.^12,13 To answer the question, we designed a nested-case control study involving 161 pregnant women.

Case selection
A total of 161 pregnant women received prenatal care at the Peking University First Hospital from November 2004 to April 2005 were enrolled into this study. The blood samples were collected from the women after verbal consents were obtained. The study was approved by the Peking University First Hospital Institutional Review Board.

The exclusion criteria of the study included: (1) Women who were pregnant for more than once; (2) Who delivered before 34 weeks or after 42 weeks of gestation; (3) Who had not been screened for abnormal glucose tolerance.

Grouping
The women were divided into three groups according to gestational age (16－20 weeks, 28－34 weeks, and 37－41 weeks groups; Table 1). Each group was subdivided into normal and abnormal glucose tolerance subgroups. The glucose tolerance was evaluated through the GCT. The women with abnormal glucose tolerance were diagnosed with GDM or gestational impaired glucose tolerance (GIGT) based on the results of GCT and oral glucose tolerance test (OGTT). The cut-off values were set at GCT 7.8 mmol/L, and OGTT fasting 5.8 mmol/L, 1-hour 10.6 mmol/L, 2-hour 9.2 mmol/L, and 3-hour 8.1 mmol/L. Patients with abnormal fasting glucose level, or two or more abnormal OGTT values were diagnosed with GDM, and those who had one abnormal OGTT value was diagnosed with GIGT.

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Table 1. Age distribution of the women with normal or abnormal glucose tolerance (mean±SD, years)

Treatments
Diet control, insulin injection, or both were given to the patients with abnormal glucose tolerance to normalize their glucose level (preprandial below 5.6 mmol/L, postprandial below 6.7 mmol/L).

Samples collection
The blood samples from the 16－20 weeks group were collected at the outpatient clinic and stored at -80˚C. And those from the 28－34 weeks and 37－41 weeks groups were collected at inpatient department and stored at －20˚C. All the samples (3 ml) were collected without anticoagulant, and centrifuged at 2000 r/min for 10 minutes before being frozen.

Fructosamine detection
The serum level of fructosamine was measured using the Glypro^TM Assay (Genzyme Co., UK), by which the normal range in non-pregnant women was 122－236 µmol/L.

Statistical analysis
Data were expressed as mean±standard deviation (SD) and analyzed using SPSS 12.0. One way ANOVA and Student-Newman-Keuls test were used to compare the levels of serum fructosamine among the groups. Correlations between fructosamine level and results of GCT, OGTT, and HbA1c test, and infant's birth weight were analyzed by the Pearson correlation. The rate of macrosomia was compared using the Chi-square test. A P value less than 0.05 was considered statistically significant.

RESULTS

We found a trend that the mean level of serum fructosemine decreased with gestational age (Fig.). In the 28－34 weeks group, the mean level of fructosamine in women with abnormal glucose tolerance was significantly higher than that of those with normal glucose tolerance (P<0.05, Table 2). Because the results of OGTT and HbA1c test were not available in women with normal glucose tolerance, the only significant relationship was found between the serum level of fructosamine and the result of GCT in the 28－34 weeks group (P<0.05, Table 3).

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Fig. The mean level of fructosamine in the three groups. Group 1: 16－20 weeks group; Group 2: 28－34 weeks group; Group 3: 37－41 weeks group.

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Table 2. The level of fructosamine of the women with normal or abnormal glucose tolerance (mean±SD, μmol/L)

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Table 3. Relations between the level of fructosamine and other clinical characteristics

Among the 94 women with abnormal glucose tolerance, 9 lost to follow-up or gave birth between34 and 37 weeks gestation, 10 of the rest 85 (11.76%) delivered infants weighing ≥ 4000 g. In the 67 women with normal glucose tolerance, 5 gave birth between 34 and 37 weeks gestation, the rate of macrosomia was 8.3%. The Chi-square test did not show significant difference in the rate of macrosomia between the women with normal and abnormal glucose tolerance (χ²=0.447, P=0.588). No significant differences was detected in the mean level of serum fructosamine among the three groups (P>0.05, Table 4).

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Table 4. Comparison of mean fructosamine level between the mothers of macrosomic and non-macrosomic infants

DISCUSSION

Some researches have shown that no difference exists in the glucose metabolism between patients with GIGT and GDM.¹⁴ The incidences of macrosomia and other complications in women with GIGT are higher than those in normal pregnant women.^14,15As the early phase of GDM or DM, GIGT should be treated in the same way as GDM. In this study, because ANOVA showed no significant difference in the level of fructosamine between the women with GIGT and GDM at the three gestational stages, the two diseases were analyzed together.

Staley and colleagues¹⁶ found that the level of plasma fructosamine varies interindividually and is constant individually during pregnancy. In this study, however, the level of serum fructosamine decreased progressively during pregnancy that is consistent with the results of several studies.^5,17,18 We consider that the decrease is due to the physiological hemodilution in pregnancy. Because the sample size was small, no difference was found in the level of fructosamine in the 16－20 and 37－41 weeks groups.

We found that the level of fructosamine in normal pregnant women was the same as that of the women with GIGT of GDM in the 16－20 weeks group, because the insulin resistance is weak during that period of pregnancy. After that, the insulin resistance increases fast with the duration of pregnancy, that is the reason why the levels of fructosamine were different between the normal and abnormal women at 28－34 gestational weeks. The same result was also shown in the Roberts' research.⁶ In our hospital, as long as the abnormal glucose tolerance is diagnosed, diet control, insulin injection, or both were prescribed to decrease the level of glucose to a normal level (preprandial below 5.6 mmol/L, postprandial below 6.7 mmol/L). Therefore, no significant difference was found in the level of fructosamine between the normal and abnormal women during 37－41 weeks gestation. The above results suggest that pregnant woman with high level of fructosamine are at high risk of developing GDM or GIGT, and the level of fructosamine partly reflects the change of glucose level. We should further investigate the relationship between the levels of fructosamine and fasting glucose to determine whether the fructosamine level can be used as a monitoring index in blood glucose control.

In this study, the level of fructosamine was positively related to GCT during 28－34 weeks gestation, and unrelated to other factors, implying that the level of fructosamine can be used to screen GDM during the 28－34 weeks gestation. However, the cut-off value for the screening test should be further determined. Furthermore, the fructosamine level can not be used to diagnose GDM in early pregnancy, because there was no correlation between the fructosamine level and the results of GCT and OGTT during that period, and it also can not be used as the golden criterion to make a final diagnosis.

Wahid and colleagues¹⁹ had suggested that the level of serum fructosamine was correlated with neonatal macrosomia. In our study, nevertheless, because all the patients with abnormal glucose tolerance were treated as soon as they were diagnosed, no correlation was detected between the fructosamine level and the birth-weight of the newborn, and the incidence of macrosomia in the patients with GDM or GIGT were similar to that of the normal women. None of the women in this study had a stillbirth. So, we suggest timely treatment to improve the outcome of the infants. Moreover, we found that the fructosamine level of the women who delivered macrosomic infants was similar to that of the women had normal infants, suggesting that the birth of macrosomia is not caused by abnormal glucose tolerance.

In conclusion, the level of serum fructosamine partly reflects the change of blood glucose. Therefore, it can be used to monitor glucose level, and to identify the pregnant women with high risk of GDM or GIGT. However, it can not be used to predict the abnormal glucose tolerance in early stage of pregnancy.

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