EAL

GDM: Pharmacologic Therapy (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To determine whether the use of insulin glargine during pregnancy is associated with an increase in the incidence of fetal macrosomia or adverse neonatal outcome.

Inclusion Criteria:

Women with singleton pregnancies who had been treated with insulin glargine between 2003 and 2005
Women with singleton pregnancies who had been treated with an intermediate-acting human insulin (human isophane or insulin zinc suspension) during pregnancy between 2002 and 2005

Exclusion Criteria:

Women with coexisting medical problems, such as renal or cardiac disease were excluded.

Description of Study Protocol:

Recruitment

32 women with singleton pregnancies who had been treated with insulin glargine between 2003 and 2005 were identified using the obstetric database of the John Radcliffe Hospital, Oxford. 32 women with singleton pregnancies who had been treated with an intermediate-acting human insulin (human isophane or insulin zinc suspension) during pregnancy were selected retrospectively from the same database between 2002 and 2005.

Design: Matched case-control study

Blinding used (if applicable): not applicable

Intervention (if applicable)

32 pregnant women were treated with insulin glargine during their pregnancy and a control group of 32 pregnant women were treated with an intermediate-acting human insulin (isophane or insulin zinc suspension)
Insulin glargine treatment was commenced in women with GDM if prebreakfast home blood glucose measurements consistently exceeded 6 mmol/l
Premeal insulin aspart or insulin lispro was added if premeal or presnack home blood glucose measurements exceeeded 6 mmol/l despite dietary compliance
All women in study were treated with single bedtime injection of intermediate-acting human insulin or insulin glargine, combined with either insulin lispro, insulin aspart or short-acting human insulin before meals
The goal for all women was to maintain all 6 daily premeal and pre-snack blood glucose measurements between 4 and 6 mmol/l

Statistical Analysis

Analyses used were the t test for independent samples, the Mann-Whitney U test for nonparametric data and the Fisher's exact test. Post hoc power calculations were also performed.

Data Collection Summary:

Timing of Measurements

Measurements compared between cases and controls.

Dependent Variables

Birthweight
Centile birthweight, calculated from published Oxford data and corrected for gestational age and fetal sex
Mode of delivery
Apgar scores at 1 and 5 minutes
Incidence of fetal macrosomia (birthweight > 90th percentile)
Neonatal morbidity
Neonatal blood glucose measurements

Independent Variables

Treatment with insulin glargine or an intermediate-acting human insulin (isophane or insulin zinc suspension)

Control Variables

Mean blood glucose concentration was calculated using 6 home blood glucose measurements made each day throughout the third trimester
Gestational age at delivery was calculated from last certain menstrual period and confirmed by ultrasound measurement of the fetal crown rump length at 10 - 12 weeks

Description of Actual Data Sample:

Initial N: 64 pregnant women, 20 with type I diabetes, 44 with gestational diabetes

Attrition (final N): as above

Age: mean age control group with type I: 34.4 +/- 4.3 years, mean age glargine group with type I: 28.4 +/- 5.8 years (P = 0.02); mean age control group with GDM: 34.6 +/- 4.8 years, mean age glargine group with GDM: 32.0 +/- 5.5 years (P = 0.10)

Ethnicity: not mentioned

Other relevant demographics: see Results

Anthropometrics: Women were matched for type and duration of diabetes, weight at booking, height, gestation at delivery, parity, fetal sex, duration of insulin use in pregnancy, and glycemic control during the third trimester of pregnancy (glycosylated hemoglobin concentration and mean blood glucose concentration).

Location: Women's Centre, John Radcliffe Hospital, Oxford, United Kingdom

Summary of Results:

	Type I Controls (n=10)	Type I Glargine (n=10)	P value	GDM Controls (n=22)	GDM Glargine (n=22)	P value
Gestation at delivery (week)	37.0 +/- 1.6	37.0 +/- 1.6	1.00	38.1 +/- 0.52	38.1 +/- 0.47	0.76
Birthweight (g)	3325 +/- 356	3443 +/- 782	0.67	3594 +/- 429	3537 +/- 520	0.69
Percentile birthweight	79.3 (range 48 - 97)	80.8 (range 23 - 99)	0.85	85.2 (range 11 - 99)	77.7 (range 5 - 99)	0.63
Apgar Score at 1 minute	8.9 +/- 0.7	8.3 +/- 1.5	0.27	8.5 +/- 1.5	8.6 +/- 1.1	0.81
Apgar Score at 5 minutes	10.0 +/- 0.0	9.8 +/- 0.4	0.15	9.9 +/- 0.3	10.0 +/- 0.0	0.15
Macrosomia (birthweight > 90th centile)	3	4	0.67	10	8	0.76
Hypoglycemia	6	6	1.00	3	6	0.45
Respiratory distress	0	2	0.47	0	1	1.00
Admission to special care baby unit	3	5	0.65	2	2	0.60
Talipes	0	0	--	1	1	--
Hypospadias	1	0	1.00	1	0	1.00
Cleft lip	0	1	--	0	0	--

Other Findings

There was no significant difference between the birthweight or centile birthweight of babies born to the women treated with insulin glargine during pregnancy and that of the babies born to those in the control group treated with intermediate-acting human insulin.

The overall incidence of fetal macrosomia was 12/32 (37.5%) in the insulin glargine group and 13/32 (40.6%) in the control group.

There was no significant difference in neonatal morbidity between the groups.

Author Conclusion:

When good glycemic control is achieved in pregnant women with type I and gestational diabetes using insulin glargine, there does not appear to be any significant increase in mean birthweight, incidence of fetal macrosomia, or adverse neonatal outcome compared with that in women using human intermediate-acting insulins.

Funding Source:

University/Hospital:

John Radcliff Hospital

Reviewer Comments:

Groups with type 1 diabetes had statistically significant differences in age. Authors note limitations of small sample sizes limiting the power of the study to detect a significant difference in the birthweight of the 2 study groups to 11%. To achieve 80% power, a study of approximately 500 women with type I diabetes and 1660 with GDM would be required.

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?		???
	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?		No
	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?	No
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	No
	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.)	No
	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?	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?		Yes
	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?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	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?	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?		???
	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?	No
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