GDM: Abnormal Glucose Tolerance During Pregnancy (2008)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To evaluate whether there is increased maternal or neonatal morbidity in connection with impaired glucose tolerance (IGT) during pregnancy when the condition is not treated.

Inclusion Criteria:
  • Only singleton pregnancies were included.
  • The Ethical Committees of the Medical Faculty at the Karolinski Hospital and Orebro University Hospital approved the study.
  • For each woman with untreated IGT, four control subjects were picked from the same delivery department, two before and two after. Information on these individuals came from the diaries of deliveries or attendance at the department. 
Exclusion Criteria:
Exclusion criteria was not detailed.
Description of Study Protocol:

Recruitment Method not described

Design Historical cohort

Blinding used:  not applicable 

Intervention

  • Women diagnosed with GDM or diabetes were referred to special antenatal clinics.
  • Women with OGTT results below the diagnostic criteria for diabetes were considered normal (non-GDM) and were treated in the routine antenatal clinics by midwives.
  • No extra control subjects were suggested.

Statistical Analysis

  • Statistical analyses were performed using the SPSS statistical software package (SPSS, Chicago, IL).
  • Mann-Whitney U or X2 tests were used for group comparisons between the IGT patients and the control subjects.
  • Results from women in whom GDM or diabetes was diagnosed are shown as reference group.
  • Multivariate logistic regression was used to analyze whether there was an independent association between different outcome measurements and untreated IGT.
  • To detect a difference of 5% concerning infants who were large for gestational age (LGA), defined as birth weight > 2 SDs greater than the mean for gestational age and sex.
  • 156 case subjects and 4 x 156 control subjects were calculated for statistical power (alpha=0.05, Beta =0.20). 
Data Collection Summary:

Timing of Measurements

  • All antenatal care clinics used a two-step screening program for GDM
  • All pregnant women were offered random blood glucose tests performed 4-6 times during the pregnancy.
  • If a random blood glucose level was > 8.0 mmol/L, a 75-g 2-h oral glucose tolerance test (OGTT) was performed, in accordance with World Health Organization guidelines, within the next few days.
  • If it was early in the pregnancy and the OGTT was repeated during gestational weeks 28-32.
  • An OGTT during weeks 28-32 was also proposed for women with prior GDM or a prior macrosomic infant > g or greater  than or equal to mean + SD).

Dependent Variables

Diagnostic criteria:

  • Blood samples, both random and in OGTT, were 5 µl capillary whole blood collected in microcurvet and immediately analyzed in Hemocue (hemocue AB, Angelholm, Sweden).
  • The diagnostic criteria for GDM was fasting blood glucose> 6.7 mmol/L and /or 2-h blood glucose > 11.1 mmol/L, which is the diagnostic criteria for diabetes.
  • IGT was diagnosed if the fasting blood glucose level was <6.7 mmol/L and the 2-h blood glucose level was 9.0-11.0 mmol/L (this definition of IGT during pregnancy, that is used in several European countries, was a modification of Lind’s definition)
  • Data about the woman, pregnancy, delivery, and child was collected from the records after delivery

Maternal Outcomes

  • IGT
  • BMI: < 25 kg/m2 ; 25-30 kg/m2 ; > 30 kg/m2
  • Parity
  • Preexisting hypertension - Prepregnancy hypertension (%) was defined as hypertension before pregnancy, which was noted by the midwife in the Special Antenal record with a mark in a check box during the first visit to antenatal care.
  • Pregnancy Induced Hypertension (%) was defined as blood pressure >140/90 mmHg measured twice with at least 6 h. 
  • Preeclampsia (%) was defined as blood pressure > 140 mmHg combined with proteinuria at least 1+ or more on dipstick test of two samples 6 h apart or >0.3 g in a 24-h urine collection.
  • Nordic origin
  • Prematurity
  • LGA

Neonatal Outcomes:

  • Apgar score: <7 at 5 min; <5 at 5 min
  • Erb’s palsy
  • Transient tachypnea
  • Hypoglycemia
  • Hyperbilirubinemia requiring treatment
  • Polycytemi requiring treatment
  • Admission to NICU 2 days or longer
  • No neonatal complications

Independent Variables

  • Age (years)
  • Weight (kg)
  • Length (cm)
  • BMI (kg/m2 )
  • Primipara (%)
  • Non-Nordic origin (%)
  • Cesarean section total (%)
  • Emergency
  • VE/Forceps (%)
  • Gestational age (weeks)
  • Prematurity < 37 weeks (%)
  • Birthweight (g)
  • Macrosomic > 4,000 g (%) ;> 4,500 g (%) ;> 5,000 g (%)
  • SGA (%)

Control Variables

 

 

Description of Actual Data Sample:

Initial N: 812 controls, 213 untreated IGT; 116 GDM/DM subjects

Attrition (final N):  as above

Age: See Table 1

Ethnicity:

Other relevant demographics:

Anthropometrics

Location: Department of Women's and Children's Health, Upsala, Sweden, Department of Obstetrics and Gynecology, Orebro University Hospital, Orbero, Sweden. 

Summary of Results:

The women with IGT were significantly older, had higher BMI, more often had prepregnancy hypertension, and were more often of non-Nordic origins than in the control subjects (Table 1).

Table 1 Maternal characteristics and complications in the untreated IGT group, control subjects, and women with treated GDM/diabetes

 

Control group(n=812)

Untreated IGT(n=213)

P*

GDM/DM (n=116)

Age (years)

30.0 + 5.0

32.5+ 5.0

<0.001

31.4+ 5.3

Weight (kg)

66.2 +11.7

73.4 + 16.0

<0.001

77.9+ 16.8

Length (cm)

166+ 6

163 + 7

<0.001

163 + 6

BMI (kg/m2)

24.1 + 4.0

27.5 + 5.4

<0.001

29.4 + 5.8

Primipara (%)

42.9

33.8

0.02

33.9

Non-Nordic origin (%)

18.8

48.3

<0.001

50.4

Prepregnancy hypertension (%)

0.9

3.8

0.002

6.1

PIH (%)

1.7

2.4

NS

2.6

Preeclampsia (%)

2.7

4.7

NS

6.9

Cesarean section total (%)

14.7

26.4

<0.001

26.7

Emergency

9.8

17.0

0.001

13.8

V/E/Forceps (%)

7.9

7.5

NS

6.2

Data are rates or means + SD. * For control vs. IGT subjects by x2 or Mann-Whitney U tests.

Prematurity was significantly higher in the group of IGT women. The only confounder that was significant in the multivariate analysis was PIH/preeclampsia (3.8, 1.6-9.0)(Table 2).

Table 2-Neonatal characteristics in the untreated IGT group, control subjects, and the women with treated GDM/diabetes 

 

Control group(n=810)

Untreated IGT(n=211)

     P*

GDM/DM

(n=116)

Gestational age(weeks)

39.2+ 1.9

38.6+1.8

<0. 001

38.3 +1.9

Prematurity<37 weeks (%)

5.4

11.4

0.005

13.9

Birth weight (g)

3,516+ 571

3,799+ 657

<0.001

3,733 + 681

Macrosomic

-

-

-

-

> 4,000 g (%)

16.4

33.0

<0.001

30.4

> 4,500 g (%)

3.3

12.4

<0.001

10.4

> 5,000 g (%)

0.2

4.3

<0.001

4.3

LGA (%)

4.2

24.9

<0.001

25.2

SGA (%)

2.2

0.5

NS

0.9

Data are rates or means + SD. * For control vs. IGT subjects by x2 or Mann-Whitney U tests. LGA, large for gestational age. SGA, small for gestational age.

LGA infants were independently significantly associated with untreated IGT during pregnancy(7.3, 4.1-12.7)( Table 3).

Table 3- Crude and adjusted Ors for LGA infants in IGT women 

 

Univariate >>>

model

Multivariate >>

Model

Control subjects

1.0

-

1.0

-

IGT

7.6

4.7-12.0

7.3

4.1-12.7

BMI

-

-

-

-

<25 kg/m2

-

-

1.0

-

25-30 kg/m2

-

-

3.4

1.8-6.5

>  30 kg/m2

-

-

5.0

2.5-10.0

Parity

-

-

-

 -

0

-

-

1.0

-

1-

-

-

2.1

1.2-3.8

Preexisting hypertension

-

-

-

-

No

-

-

1.0

-

Yes

-

-

3.5

0.9-13.2

PIH/Preeclampsia

-

-

-

-

No

-

-

1.0

-

Yes

-

-

0.7

0.2-2.1

Nordic origin

-

-

-

-

Yes

-

-

1.0

-

No

-

-

0.4

0.2-0.7

Table 4 shows neonatal morbidity , which was rare in all groups, with no significant difference except for Erb's palsy and hypoglycemia.

Table 4 Neonatal morbidity (%) in the untreated IGT group, control subjects, and the women with treated GDM/diabetes 

 

Control group(n=810)

Untreated IGT (n=211)

P*

GDM (n=117)

Apgar score < 7 at 5 min

1.4

2.9

NS

0.9

Apgar score< 5 at 5 min

0.5

1.0

NS

0.9

Erb’s palsy

0.1

1.9

0.007

0.9

Transient tachypnea

1.8

1.4

NS

6.1

Hypolglycemia¶

2.5

7.1

0.001

20.9

Hyperbilirubinemia requiring treatment

4.1

5.7

NS

6.1

Polycytemi requiring treatment

0.2

1.0

NS

--

Admission to NICU 2 days or longer

6.3

18.6

<0.001

28.7

No neonatal complication

87.3

71.3

<0.001

64.7

Data are rates or means + SD. * For control vs. IGT subjects by x2 test.  ¶The glucose cut point for hypoglycemia was recommended to be <2.2 mmol/L.

Prematurity was a strong mediating factor for NICU admission, but after introduction into the model. IGT still had an OR of 2.0 (1.1-3.8)(Table 5).

Table 5 Crude and adjusted OR for transfer to NICU for 2 days or longer

-

Model 1

Model 1

Model II

Model II

Model III

Model III

-

OR

95% CI

OR

95% CI

OR

95% CI

Control subjects

1.0

-

1.0

-

1.0

-

IGT

3.4

2.2-5.3

 2.3

 1.3-4.0

 2.0

 1.1-3.8

Chronic hypertension

-

-

-

-

-

-

No

-

-

 1.0

 -

 1.0

 -

Yes

-

-

 1.4

 0.4-5.6

 1.1

 0.2-4.9

PIH/preeclampsia

-

-

-

-

-

-

No

 

 

 1.0

 -

 1.0

 -

Yes

-

-

 1.9

 0.7-4.6

 1.4

0.5-3.6 

BMI

-

-

-

-

-

-

<25 kg/m2

-

-

 1.0

 -

 1.0

 -

<25-30 kg/m2

-

-

 1.7

 1.0-3.0

 1.7

 0.9-3.1

>  30kg/m2

-

-

 1.8

 0.9-3.5

 2.2

 1.0-4.6

LGA

-

-

-

-

-

-

No

-

-

 1.0

 -

 1.0

 -

Yes

-

-

 2.3

1.2-4.4 

 2.4

1.1-4.9 

Nordic origin

-

-

-

-

-

-

Yes

-

-

 1.0

 -

 1.0

 -

No

 

 

 0.8

0.5-1.5 

 0.8

0.4-1.5 

Prematurity

-

-

-

-

-

-

No

-

-

 -

 -

 1.0

 -

Yes

-

-

 -

 -

 16.3

 8.7-31

Other Findings

 

 

Author Conclusion:
  • There was an increased independent association between cesarean section rate, prematurity, LGA, and macrosomic infants born to mothers with untreated IGT.
  • A significantly higher number of children in IGT group were admitted to and treated for 2 days or longer at a NICU.

Limitations:

Recommendation of randomized study is needed because:

  • Most of the children were healthy, but there was still increased morbidity.
  • The outcome in the diabetes group could be due to either difficulties to influence the  outcome by treatment, or the fact that treatment could have stopped the increased  complications noted in this group with greater deterioration in glucose tolerance.
Funding Source:
Reviewer Comments:

In a historical cohort study, data on exposure and occurrence of disease are collected after the events have taken place—the cohorts of exposed and non-exposed subjects are assembled from existing records, or health care registries. Studies of this kind provide a better opportunity than one time cross sectional studies to examine whether certain behaviors do in fact lead to (or cause) the disease.

The limitations and critique of the study, as stated by the authors appear to be very appropriate.

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? N/A
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? N/A
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? N/A
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? N/A
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes