JRSM >
Volume 95, Number 9 >
Pp. 435-439
Department of Clinical Biochemistry, Hospital General de Riotinto,
Huelva, Spain
1 Department Obstetrics and Gynaecology, Hospital General de Riotinto, Huelva,
Spain
Correspondence to: Rafael Perea-Carrasco MD, Department of Clinical Biochemistry, Hospital Riotinto, C/Los Cantos s/n, Minas de Riotinto 21660 (Huelva), SpainE-mail: rperea{at}hrt.sas.junta_andalucia.es
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 TOP SUMMARY INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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4000 g). With a cut-off value of I=27.2, sensitivity was 98%, specificity 89%, diagnostic efficiency 90%, positive likelihood ratio 8.76. Application of the index would have avoided 42% of the OGTTs demanded by the standard screening test, reducing false positives from about 24% to 10%. Predictive efficacy for macrosomia was 10.3% versus 7.9%.
Our index offers an efficient screening test for gestational diabetes, and with more stringent cut-off points may be applicable as a single-step diagnostic procedure.
| INTRODUCTION |
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TOPSUMMARYINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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According to the published work the ST has a sensitivity of about 78% and a specificity of 83%5,6. In the present study we sought to devise an index that would improve on these figures, offering better screening capability and possibly greater ease of diagnosis.
| PATIENTS AND METHODS |
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TOPSUMMARYINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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7.8 mmol/L. Irrespective of whether the ST was positive or negative,
all women had a full OGTT. For this, 100g glucose was given after a fast of
8-14 hours. The women were advised to take a carbohydrate-rich diet ( 150
g/d) and be moderately active during the three days before the test. During
the test they rested and refrained from eating or smoking. The concentrations
of glucose were measured at baseline (fasting) and 1, 2 and 3 hours. As
recommended by the third
Workshop4, GDM was
diagnosed when at least two of the following glucose concentrations were
observed: 5.8 mmol/L at baseline; 10.5 mmol/L at 1 hour, 9.1
mmol/L at 2 hours and 8.0 mmol/L at 3 hours. From this initial study we generated an index (I) that statistically discriminated between those women who were subsequently identified (on the results of the OGTT) as having GDM and those who did not. The index was then prospectively applied to a further 642 women attending the antenatal clinic. These women fulfilled the same criteria as those taking part in the preliminary study. Out of the initial 642, we were able to obtain outcome information—birthweight, caesarean sections, dystocia scores, and complications—in 578.
Methods
The oral glucose load (50 g or 100 g) was a commercial preparation
(Biomedics SL, Spain), administered chilled to minimize nausea, vomiting and
abdominal
discomfort7,8.
Plasma glucose was determined by the hexokinase method with UV absorbance at
340 nm. The imprecision of the glucose measurement was 1.1% at a concentration
of 3 mmol/L and 1.2% at a concentration of 16.6 mmol/L. These values were
obtained on 30 replicate measurements on quality control sera Precinorm and
Precipath (Roche Diagnostics, USA) performed over 30 consecutive days.
Fructosamien was measured by the tetrazolium blue colorimetric method at an
absorbance of 552 nm and with a calibrator normalized with glycosylated
poly-L-lysine. The imprecision of the fructosamine measurements was 3.0% at a
concentration of 268 µmol/L and was derived from 30 replicate measurements
of control sera (Precinorm) measured over 30 consecutive days. Total proteins
were measured by the biuret method. The imprecision was 1.4% at a
concentration of 5.14 g/dL and 1.2% at a concentration of 5.12 g/dL. The
values were derived from 30 replicate measurements on control sera (Precinorm
and Precipath) performed over 30 consecutive days.
All the measurements were made in a Hitachi 717 auto-analyzer (Hitachi, Japan) with commercial reagents from Roche Diagnostics. The blood samples were taken in the hospital's outpatient antenatal clinic or at the primary healthcare centre if that was the patient's choice. In the latter case, the samples were immediately centrifuged on site and transported on ice to the hospital laboratory.
The index ‘I’ derived from the analyte measurements
conducted on the 1 hour post-load blood sample was defined as:
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Statistical analyses
The ST measurements of glucose, fructosamine, total proteins, albumin,
HbA1c, together with birthweight, type of birth, Apgar score,
I index and the OGTT definitive GDM diagnosis were entered into a data
spreadsheet (Excel, Microsoft). To obtain the cut-off point of I, we
initially applied the Shapiro-Wilk test to the calculated values of I
generated from the preliminary study, to assess the normality of distribution.
The distribution was found to be non-Gaussian; therefore non-parametric
methods (2.5th percentile) were used to select the cut-off point.
To assess the diagnostic value of I we used the GraphROC 2.0 program for Windows to calculate sensitivity, specificity, positive predictive value, negative predictive value, diagnostic efficiency, positive likelihood ratio and negative likelihood ratio. The exact 95% confidence intervals (95% CI) were calculated from the standard error of proportions or according to Miettinen's test.
| RESULTS |
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TOPSUMMARYINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Assessment of I as a screening tool
A value of I < 27.2 (index negative) was used to reject the
diagnosis of GDM, and I 27.2 (index positive) was used to indicate
the requirement for definitive diagnosis. Of the 642 women studied, 524 were
index negative. Of the 118 who were index positive, 52 had GDM according to
the OGTT. Just one women had a false-negative result with the I index.
Table 1 summarizes the
results.
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Table 2 shows the number of false positives for I in relation to the standard ST. If the I index had been used for screening, this would have avoided about 42% of the OGTTs performed because of suspected GDM.
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Of the 642 women initially included in the study, we were able to assess
578 with respect to birthweight. 34 babies were macrosomic (4000g).
I27.2 detected 32% (11/34) and the standard test detected 44%
(15/34); however efficacy in detection of macrosomia was somewhat better with
I (Table 3). The
collective results for macrosomia detection are shown in
Table 4.
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Assessment of I as a diagnostic tool
Using three values (<27.2, 27.2-30.5, >30.5) we explored the value of
I for one-stage diagnosis.
Of 524 women with a value of I<27.2, only one was subsequently diagnosed as having GDM—i.e. the sensitivity was 98%.
Of 62 women with an I value of 27.2-30.5, 20 were diagnosed as having GDM, 34 were completely normal on OGTT criteria, while the other 8 were ‘indefinite’ in having only one abnormal glucose value on the OGTT.
56 women had an I value of >30.5, of whom 32 were positive for GDM; 4 had only one abnormal glucose value on OGTT and the other 20 had a completely normal result. Hence, the specificity of this cut-off value is 96% (Table 5).
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| DISCUSSION |
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TOPSUMMARYINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The specificity achieved for I as a screening tool is one of the strong points of our study: at 89% it substantially exceeded the 75% recorded for the standard ST. A negative index discounts GDM and a positive index indicates the need for an OGTT. The low specificity of the ST implies that many women with a positive result will prove to have normal glucose tolerance. This difficulty is well recognized, and the Toronto TriHospital9 study recommended confining the ST to women of medium-to-high risk, so as to reduce the number of false positives. This strategy, however, could mean that about 4% of cases were missed because the women seemed at low risk10. These recommendations have been adopted by the American Diabetic Association and are adhered to by several other countries including Spain. The selective policy is partly driven by cost, since the standard ST is inefficient and often demands repeated investigations which are not only costly but also unpleasant for the patient11,12,13,14,15.
The use of I reduced false-positive screening from about 24% to 10% in the current study. Discrepancies such as negative OGTT with strongly positive ST have been noted by several research groups14, 15. The data in Table 1 show that I is much superior to the ST. An I-positive woman has a nearly 8-fold risk of having GDM. A positive I was also somewhat superior to the ST for prediction of macrosomia. The number of macrosomias in non-diabetic patients who were positive for I or ST deserves attention. It raises doubt as to the value of the OGTT for predicting this complication. An alternative to universal screening16,17, recommended by the fourth Workshop on Gestational Diabetes Mellitus, is to perform an OGTT directly on women of medium-to-high risk, or to screen selectively. We do not think the 4% failure rate of selective screening is acceptable. An OGTT for women at medium-to-high risk (or the diagnostic strategy based on the 2-hour oral load18) does have its advocates, despite the inconvenience and discomfort.
It does not seem logical that, to achieve a diagnosis of GDM, the patient has to be diagnosed in two stages, and we propose that the I index could offer a single test—albeit with certain cautions. A value of I<27.2 definitely excludes the necessity for any further testing for GDM, and a value of I>30.5 indicates GDM with a specificity of 96%. A value of I between 27.2 and 30.5 is borderline with respect to GDM diagnosis. In this situation there are two options. One is to consider the patient as diabetic and to proceed with established protocols for its treatment; or, alternatively, perform the OGTT in all of these women (n=62 in our study) and await confirmation of the diagnosis. The present study indicates that if the I index was used as a diagnostic tool, only 62 OGTTs would be needed for diagnostic confirmation, compared with 203 with the standard ST or 118 with the I index used as a screening tool.
The measurement of fructosamine in screening for GDM is not new. It has its proponents6 and a greater number of detractors because of insensitivity19,20,21. The ratios of fructosamine to total protein or of fructosamine to albumin22 have been evaluated and rejected for the same reasons. However, if we multiply these ratios by the concentration of glucose, the product value differentiates reasonably well between diabetic and normal pregnant women.
The response to the glucose load in the diabetic patient is very variable. Therefore it is necessary, both in screening and in diagnosis, to incorporate a measure that is less susceptible to fluctuations. Fructosamine corrects for variability in response to the oral glucose load by representing the mean concentration of glucose over 1-3 weeks, while total proteins correct for the haemodilution associated with pregnancy. As a continuous variable, glucose cannot be used with much confidence for either screening or diagnosis. The calculated index I is likewise a continuous variable, but a positive has good sensitivity and specificity. Although there were 66 false positives in our study, we suspect that some of these gestations were abnormal with respect to carbohydrate metabolism. For screening purposes, the positive and negative predictive values for I>27.2 are highly acceptable.
As a single-stage diagnostic tool, the technique offers further attractions, not least convenience. However, more work with a greater number of patients is needed to confirm the validity of the index in relation to OGTT screening and to show how it compares with the ST in prediction of complications other than macrosomia.
| Acknowledgments |
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