GDM: Prevention of GDM Diagnosis (2008)

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

To examine whether low maternal dietary intake of vitamin C and low maternal plasma ascorbic acid (AA) concentrations were associated with an increased risk of gestational diabetes mellitus (GDM).

Inclusion Criteria:

 

  • Subjects for this analysis were recruited between April 1998 and February 2000 as part of a case-control study design primarily to examine the epidemiology of preeclampsia. During the enrollment period,women were identified as having GDM with the then-current diagnostic criteria described by the National Diabetes Data Group(NDDG). Women were classified as having GDM if >= 2 of the following plasma glucose concentrations obtained during the 100-g, 3-hour oral glucose tolerance test were abnormal according to the NDDG criteria: fasting>=105 mg/dL, 1 hour >=190 mg/dL , 2 hour >= 165 mg/dL, 3 hour >=145 mg/dL. (n=67). Provided written informed consent.
  • Controls: were women who remained normotensive and who did not meet the NDDG criteria for GDM. Controls were frequently matched on maternal age and parity. Among 772 eligible controls were invited to participate, 50% agreed to provide written informed consent. Reasons for nonparticipation included not having time for the interview, having no interest in the goals of the study and missed appointments.
Exclusion Criteria:
The criteria was not delineated.
Description of Study Protocol:

Recruitment :Subjects for this analysis were recruited between April 1998 and February 2000 as part of a case-control study design primarily to examine the epidemiology of preeclampsia. During the study period, while recruiting preeclampsia patients from the labor and delivery wards at Swedish Medical Center, Seattle and Tacoma General Hospital, Tacoma, patients with diagnosis of GDM were also recruited.

Design : Case control

Blinding used -all assays were performed without knowledge of pregnancy outcome.

Intervention (if applicable):  not applicable

Statistical Analysis :

  • Examined the frequency distributions of maternal sociodemographic characteristics and for medical and reproductive history according to case-control status.
  • Examined the distribution of continuous variables and found them to be appropriately normal; hence the Student’s t test was used to evaluate unadjusted mean differences according to case or control status.
  • To estimate the relative association between GDM and levels of maternal vitamin C intake or plasma AA status, each subject was categorized according to quartiles determined by the distribution of each exposure measure. The highest quartile was used as the reference group and estimated odds ratios (Ors) and 95% CIs) for the lower 3 quartiles.
  • In the univariate analysis, the Mantel extension test to assess the linear component of trend in risk between GDM and dietary vitamin C intake or plasma AA status.
  • Examined potential effect modification by prepregnancy overweight status (prepregnancy BMI>=25kg/m2; yes/no) by using stratified analyses and multivariate logistic regression procedures
  • Dietary vitamin C was adjusted for total energy intake
  • To assess confounding, variables were entered into a generalized linear model. Final generalized linear models included covariates that altered unadjusted risk ratios by at least 10%, as well as those covariates of a priori interest (eg, advanced maternal age and prepregnancy adiposity).
  • Multivariate anlaysis-evaluated linear trends in risk by treating 4 quartiles of plasma ascorbic acid concentrations as a continuous variable after assigning a score [1 (high), 2, 3, and 4 (low)] as its value. 
  • Reported P values are 2 tailed. 
  • Continuous variables were presented as means ± standard error of mean (SE)
Data Collection Summary:

Timing of Measurements

  • During participants’ postpartum hospital stay, trained interviewers administered a structured interview questionnaire to collect information on maternal sociodemographic, medical, reproductive and lifestyle characteristics and on the use of prenatal vitamins during pregnancy.
  • Participants were also asked to report their attained height and their weight 3 months prior to the index pregnancy.
  • Maternal age was determined at the time of the interview.
  • Nonfasting blood samples were collected in EDTA 10-ml Vacutainer tubes at 13 weeks gestation, on average (interquartile range =11-16 weeks gestation). 
  • Maternal and infant medical records were reviewed  approximately 7-9 months after participants were enrolled in the study to collect detailed information concerning antepartum, labor and delivery characteristics, and conditions of the newborn.
  • Maternal plasma AA were determined on specimens collected during the intrapartum period.

Dependent Variables

Maternal plasma ascorbic acid

  • Nonfasting blood samples were collected in EDTA 10-ml Vacutainer tubes at 13 weeks gestation, on average (interquartile range =11-16 weeks gestation. 
  • The samples were protected from ultraviolet light , kept on wet ice, and processed within 30 minutes of phlebotomy.
  • Plasma decanted into cryovials was preserved with metaphosphoric acid/dithiothreitol solution frozen at -70 degrees until analysis.
  • Blood samples were available for 92% (63 of 67) of cases and 79% of controls(205 of 260). Ascorbic acid concentrations have been shown to be stable for more than 57 months under these storage conditions.
  • Plasma ascorbic acid (ie, total ascorbate) was determined on a Roche Cobas(Branchburg,NJ) Mira Plus Chemistry analyzer using a colorimetric procedure.
  • The intra-and interassay coefficients of variation for the assay used were both less than 10%.

Dietary Vitamin C

  • The food frequency questionnaire (FFQ) included fruits, vegetables and other food items.  A standard unit or portion sizes was specified, and participants were asked how often, on average, during the 12-month reporting period (9 months of pregnancy and the 3 preconception months), they had consumed that amount. Vitamin C intake was computed by multiplying the frequency of consumption of each unit of food by the vitamin C content of the specified portion. Food composition values for vitamin C and other nutrients were  obtained from the University of Minnesota Nutrition Coding Center nutrient data base (Nutrition Coordinating Center, Minneapolis). Approximately 90% of GDM cases and 90% of controls returned completed food frequency questionnaires.  

Independent Variables

  • maternal age
  • height
  • reproductive and medical history
  • race*
  • age
  • education*
  • no prenatal vitamins
  • marital status
  • smoking during pregnancy*
  • worked during pregnancy
  • first degree family history of type 2 diabetes*
  • prepregnancy adiposity* -prepregnancy body mass index (BMI), used as a measure of overall maternal adiposity, was calculated as weight (kg) divided by height (m) squared. All participants reported their maximum height and weight 3 months before the index pregnancy
  • annnual household income*
  • parity-was reported as the number of previous pregnancies lasting beyond 20 weeks of pregnancy.
  • Maternal habitual dietary intake during the peri period and early pregnancy were ascertained at 12 weeks gestation, on average, using the self-administered , 121 item semiquantitative food frequency questionnaire developed for the Women's Health Initiative Clinical Trial. Food composition values for vitamin C and other nutrients were obtained from the University of Minnesota Nutrition Coding Center nutrient data base(Nutrition Coordinating Center), Minneapolis, MN. 

 *possible confounders

Control Variables

 

Description of Actual Data Sample:

Initial N: 67 cases; 260 controls

Attrition (final N): 327

Age: See Table I

Ethnicity: not mentioned

Other relevant demographics:

Anthropometrics

Location: Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, Washington.

 

Summary of Results:

 

As compared with controls, GDM cases tended to be older and heavier. Over 97% of cases and controls reported taking multivitamins during pregnancy (Table 1).

Table I Distribution of GDM Cases and Controls According to Selected Characteristics, Seattle and Tacoma, 1998-2000.

  GDM cases> (n=67) Controls> (n=260)
Characteristic

n

%

n

%

Maternal age(yr)

-

-

-

-

<=19

0

0.0

7

2.7

20-34

34

50.7

160

61.3

35-39

 21

 31.3

 77

 29.6

>=40

 12

 18.0

 16

 6.4

 Maternal race/ethnicity

 -

 -

 -

 -

 European ancestry

 43

 64.2

 198

 76.2

 African ancestry

 5

 7.5

 20

 7.7

 Asian ancestry

 9

 13.5

 27

 10.3

 Other

 10

 14.8

 13

 5.1

 Missing

 0

 0.0

 2

 0.8

 Unmarried

 14

 20.9

 46

 17.7

 <12 year's education

 3

 4.5

 5

 1.9

 Nulliparous

 29

 43.3

 91

 35.1

 No prenatal vitamins

 2

 3.0

 3

 1.2

 Smoked during pregnancy

 12

 17.9

 23

 8.8

 Annual household income

 -

 -

 -

 -

<30,000

12

17.9

29

11.2

 30,000-69,999

 29

 43.3

 89

 34.2

>=70,000

22

32.8

127

48.8

Not reported

4

6.0

15

5.8

Prepregnancy BMI

_

-

-

-

<20.0

4

4.5

64

25.5

20.00-24.9

18

28.4

143

54.8

25.0-29.9

21

31.3

38

14.6

>=30

23

34.3

13

5.0

Missing

1

1.5

2

0.8

First-degree family history of diabetes

21

31.3

34

13.1

Worked during pregnancy

59

88.1

232

89.2

After adjusting for total energy intake, maternal age, race, parity, family history of type 2 diabetes and the preprergnancy adiposity, women with the lowest quartile of the control distribution of daily vitamin C intake, as compared with those with those with the highest quartile, experienced a 2.3-fold increase in risk of GDM (Table II).

Table II   ORs and 95% CIs for GDM According to Varying Levels of Maternal Dietary Intake of Vittamin C and Maternal Plasma AA

      OR(95% CI)

>>>

Exposure status

Cases (n)

Controls (n)

Unadjusted

Adjusted

Dietary vitamin C (mg/d) a - -  -  -
<90.8

22

59

1.5(.7-3.2)

2.3(.8-6.7)

90.8-131.1

 12

 59

.8(.3-1.8)

1.2(.4-3.4)

 131.2-184.4

 12

 59

 .8(.3-1.8)

 .7(.2-2.1)

 >184.4

 15

 58

 1.0 Referent

 1.0 Referentc

 -

 -

Adjusted c >

P values for>

linear trend=0.46

 Dietary vitamin C (mg/dl)a

 -

 -

 -

 -

 <70

 18

 31

 2.8(1.4-5.4)

 3.7(1.7-8.2)

 >=70

 43

 204

 1.0 Referent

 1.0 Referent c

 Plasma AA (µmol/L)b

 -

 -

 -

 -

<42.6

47

51

9.4(3.5-25.7)

12.8 (3.5-46.2)

 42.6-53.6

 5

 51

 1.0(0.3-3.7)

 1.0(.2-4.7)

53.7-63.3

6

52

1.2(0.3-4.1)

1.7(.4-7.9)

>63.3

5

51

1.0 Referent

1.0 Referentd

 -

 -

Adjusted >

P values for >

linear trends <.001

Plasma AA (µmol/L)b

-

-

-

-

<35.0(lowest decile)

29

20

1.48 (5.0-43.6)

18.6(4.8-72.9)

>63.3 (highest quartile)

5

51

1.0 Referent

1.0 Referent d

a Based on 61 cases and 235 controls

b  Based on 63 cases and 205 controls

c Adjusted for maternal age(continous) , race (Asian ancestry /other), parity (nulliparous, multiparous), prepregnancy adiposity (grouped linear), annual household income (grouped linear), total energy intake (continous), and family history of Type 2 diabetes. 

dAdjusted for maternal age(continous) , race (Asian ancestry /other), parity (nulliparous, multiparous), prepregnancy adiposity (grouped linear), annual household income(grouped linear), total energy intake (continous), and family history of Type 2 diabetes. 

The excess risk of GDM associated with being overweight and consuming a diet inadequate in vitamin C was 32.5, which is much greater than the sum of the excess risk of each actor considered independently (i.e. 9.6+ 4.8=15.6) (Table 3).

Table III Evaluation of the Joint Association Between Maternal Prepregnancy Overweight Status, Low Dietary Vitamin C Intake and Low Plasma AA Concentrations in Relationship to the Risk of GDM, Seattle and Tacoma, 1998-2000.

Exposure group

Overweight c

Cases(n) Controls(n) Unadjusted OR Adjusted OR(95% CI)
Inadequate dietary vitamin C intake a,d

 -

 -

 -

 -

 -

No

 No

 11

 163

 1.0 referent

 1.0 Referentf

No

 yes

 7

 25

 11.5

 9.6(4.0-23.0)

Yes

 No

 31

 40

 4.1

 4.8(1.6-14.7)

Yes

 Yes

 11

 6

 27.2

 32.5(8.8-120.8)

 -

Missing

1

6

-

-

Low plasma AA concentrationb,e

 -

 -

 -

 -

 -

No

No

4

123

1.0 Referent

1.0 Referentg

No

Yes

12

30

12.3

10.3(3.0-35.6)

Yes

No

16

40

12.3

13.2 (3.9-44.4)

yes

Yes

30

11

83.3

75.2                        (21.6- 262.1)            

 

Missing

1

1

-

-

a Based on 61 cases and 235 controls

b  Based on 63 cases and 205 controls

c   Overweight defined as prepregnancy BMI>=25 kg/m2 .

d  Inadequate dietary vitamin C intake defined as reported intake <70 mg/d.

e Low plasma AA defined as concentrations <42.6 µmol/L (i.e lowest quartile)

f Adjusted for maternal age (continous) , race (Asian ancestry /other), parity (nulliparous,multiparous), prepregnancy adiposity (grouped linear), annual household income(grouped linear), total energy intake (continous), and family history of Type 2 diabetes.

 gAdjusted for maternal age(continous) , race (Asian ancestry /other), parity (nulliparous, multiparous), prepregnancy adiposity (grouped linear), annual household income(grouped linear) and family history of Type 2 diabetes.

The overall positive association between low vitamin C intake and increased GDM risk persisted in each subgroup and was not modified by any of the covariates listed in Table 4. Tests for interaction were not statistically significant.

Table IV Associations Between Inadequate Dietary Vitamin C Intake and Risk of GDM Startified by Selected Risk Factors, Seattle and Tacoma,1998-2000.

 

 

Dietary vitamin C

intake(mg/d)

Characteristic

>=70

<70

All

1.0 Referent

3.7(1.7-8.2)2
Any recreational physical activity during pregnancy?

 -

 -

 Yes

1.0 Referent

 3.1(1.1-9.2)2
 No

1.0 Referent 

 6.3(1.5-25.7)2
First-degree family history of diabetes

 -

 -

 Yes

1.0 Referent

 1.3(0.2-9.8)3
 No

1.0 Referent

 4.9(2.0-11.8)3
Dietary intake (g/d)

 -

 -

 Total fat 1

 -

 -

 Low (<75.1)

 1.0 Referent

 4.6(1.4-15.1)2
 High (>75.1)

 1.0 Referent

 4.0 (1.0-15.6)2
 Carbohydrate1

 -

 -

 Low (<251.5)

 1.0 Referent

 3.4(1.3-8.6)2
High (> 251.5)

1.0 Referent

 4.1(0.5-33.0)2
Total fiber1

 -

 -

Low( <19.0)

1.0 Referent

 3.5(1.4-8.2)2
High (>=19.0)

1.0 Referent

 2.1(0.2-26.1)2
Vegetable protein1

 -

 -

Low (< 23.6)

1.0 Referent

 4.4(1.6-12.2)2
High (> 23.6)

1.0 Referent

 4.1(0.7-22.6)2

1 Median values among the controls were used as the cutoff point.

2  Adjusted for maternal age(continous) , race (Asian ancestry /other), parity (nulliparous, multiparous), prepregnancy adiposity (grouped linear), annual household income(grouped linear), total energy intake (continous), and family history of diabetes.

3Adjusted for maternal age(continous) , race (Asian ancestry /other), parity (nulliparous, multiparous), prepregnancy adiposity (grouped linear), annual household income(grouped linear), total energy intake (continous).

Other Findings

 

 

Author Conclusion:

Low maternal dietary vitamin C intake and plasma AA concentrations were associated with an increased risk of GDM.

Although a potential beneficial role of vitamin C was suggested by this study, larger, prospective studies are needed that allow careful assessment of glucose tolerance in pregnancy in relation to: (1) other nutrients, including other antioxidants; (2) foods; and (3) dietary intake patterns.

Limitations

  • Could not exclude the possibility of selection bias. The control participation rate 50% and the case participation rate was 81%.
  • Potential for misclassification of maternal daily dietary vitamin C intake because food frequency questionnaires were completed at the end of pregnancy, could not exclude the possibility that that differential recall and reporting of habitual diet are likely to have occurred.
  • Could not determine with certainty whether the observed case control differences in plasma AA concentration preceded GDM or could be attributed to physiological alterations.
  • Could not conclude with certainty that the ORs reported were not affected by residual confounding.
  • Unable to assess the independent effect of maternal dietary supplements versus supplement use on the risk of GDM.
  • The diagnostic criteria for GDM used in the present study were changed in 2002.
  • If the new criteria had been used the study, the authors reported that some women who were classified as controls would have been classified as having GDM. 
Funding Source:
Reviewer Comments:

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

Case control studies are studies in which patients who already have a certain condition are compared with people who do not. Case control studies are less reliable than cohort studies. Just because there is a statistical relationship between two conditions does not mean that one condition actually caused the other.

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) N/A
  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) N/A
 
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? ???
  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? ???
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) Yes
  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? N/A
  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.) Yes
  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? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? Yes
  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? N/A
  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? N/A
  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? ???
  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? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? ???
  7.5. Was the measurement of effect at an appropriate level of precision? ???
  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)? Yes
  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? N/A
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
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