EAL

GDM: Pharmacologic Therapy (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this study was to evaluate the side-effects of oral anti-diabetic treatment in a cohort of pregnant women with gestational diabetes.

Inclusion Criteria:

All women with gestational diabetes mellitus or type 2 diabetes mellitus treated during the years 1966-1991 at the diabetes center at the obstetrical department, Rigshospital, Copenhagen.

Exclusion Criteria:

None specified.

Description of Study Protocol:

Recruitment

All women with gestational diabetes mellitus or type 2 diabetes mellitus treated with oral hypoglycemic agents at the Rigshospitalet obstetrical department from 1966-1991.

Design Retrospective Cohort Study. Upon diagosis of GDM (based on results of an oral glucose tolerance test), women were started either on tolbutamide (normal weight women) or metformin (overweight as defined by prepregnancy weight >120% ideal weight). Oral hypoglycemic agents were replaced by insulin if proper control could not be reached by 3-4 days. Oral agents were initiated after 20 weeks gestation and stopped 24 hr prior to delivery.

Blinding used (if applicable): Not applicable

Intervention (if applicable)

Metformin treatment versus Tolbutamide versus insulin therapy

Statistical Analysis

Chi squared test, Fisher's exact test, Mann-Whitney test or the Mantel-Haenszel test were applied to analyze the differences between groups. Statistical signficance was accepted at P <0.05

Data Collection Summary:

Timing of Measurements

Maternal and neonatal characteristics at delivery.

Dependent Variables

Maternal characteristics
Neonatal characteristics

Independent Variables

Treatment with metformin, tolbutamide or insulin therapy for gestational diabetes or type 2 diabetes during pregnancy

Control Variables

None

Description of Actual Data Sample:

Initial N: Women: Metformin group n = 50, tolbutamide group n = 68, insulin therapy (reference group) n=42

Attrition (final N): Infants: Metformin group n = 50, tolbutamide group n = 69, insulin therapy (reference group) n=43

Age:

	Metformin	Tolbutamide	Insulin
Caucasians no (%)	38 (76)	57 (83)	30 (71)
Age at delivery (years) median (range)	32 (21-46)	28 (16-41)	29 (20-45)
Pre-pregnancy BMI median (range)	31.2 (19.2- 54.1)	22.8 (16.3 - 37.6)	24.8 (17.0-33.7)

Ethnicity: see table

Other relevant demographics:

Anthropometrics : see table

Location: Copenhagen, Denmark

Summary of Results:

Variables	Metformin group	Tolbutamide group	Insulin reference group	P value
Maternal pre-eclampsia no (%)	16 (32)	5 (7)	4 (10)	<0.001
Gestational age median (range)	38 (33-39)	37 (29-39)	37 (31-39)	NS
Birthweight g (range)	3700 (1700-5470)	3437 (1710-4460)	3400 (1440 - 4600)	NS
Birthweight > 90th %ile no (%)	19(38)	20 (29)	19(44)	NS
Stillborn infants no (%)	4 (8)	0	1 (2.3)	0.042

Other Findings

Infants of women who had metformin their third trimester (n=43) had an increased perinatal mortality compared to infants of orally treated women who had tolbutamide in their third trimester or in whom insulin treatment was instituted before the beginning of the third trimester (11.6 vs. 1.3%, p <0.02).

Author Conclusion:

Treatment with metformin during pregnancy was associated with an increased prevalence of pre-eclampsia and a high perinatal mortality.

Funding Source:

University/Hospital:

University of Texas Health Science Center

Reviewer Comments:

BMI ranges were so wide despite the statement in the paper that tolbutamide was used in normal weight women and metformin was given to overweight women.

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?	???
3.	Were study groups comparable?		???
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	???
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	No
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	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?	No
	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?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	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%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	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.)	Yes
	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?		???
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	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?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	???
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	No
	6.6.	Were extra or unplanned treatments described?	No
	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?	Yes
	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?	???
	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)?	???
	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?	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