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Nicholson WK, Wilson LM, Witkop CT, et al. Therapeutic Management, Delivery, and Postpartum Risk Assessment and Screening in Gestational Diabetes. Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Mar. (Evidence Reports/Technology Assessments, No. 162.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Therapeutic Management, Delivery, and Postpartum Risk Assessment and Screening in Gestational Diabetes

Therapeutic Management, Delivery, and Postpartum Risk Assessment and Screening in Gestational Diabetes.

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4Discussion

Given the increase in obesity and sedentary lifestyles in the United States, the prevalence of gestational and type 2 diabetes among reproductive-aged women is expected to rise over the next decade. Both obstetrical and primary care physicians care for a growing number of women with gestational diabetes who are at increased risk of developing type 2 diabetes. For decades, obstetricians and primary care physicians have debated the optimal labor management and postpartum followup of women with gestational diabetes. Clinicians, public health advocates, and health policymakers have identified the need for evidenced-based practice guidelines for labor and postpartum management of women with gestational diabetes.

To identify the evidence on labor and postpartum management of gestational diabetes, the AHRQ, in conjunction with the ACOG, requested an evidence report on four distinct questions. We applied rigorous selection criteria and assessed the quality of each study, using a clinical and public health framework to guide our review. Our report is limited to gestational diabetes in which the diagnosis was confirmed by an OGTT, thereby ensuring that our review includes women with a definitive diagnosis of gestational diabetes. This evidence report outlines a comprehensive review of all the available research. In this final chapter, we first review the major findings pertaining to each question and the strength of the overall evidence; we then present our conclusions, make recommendations for future research, and offer clinical and public health perspectives.

Summary of the Key Findings

Key Question 1

What is the evidence for the risks and benefits of oral diabetes agents (e.g., second-generation sulfonylureas and metformin), as compared to all types of insulin, for both the mother and neonate in the treatment of women with gestational diabetes?

Relatively few studies have examined the effect of oral agents or insulin analogues, as compared to insulin, on a number of significant maternal and neonatal outcomes in women with gestational diabetes. Only three RCTs assessing the efficacy of glyburide and insulin met our inclusion criteria,32 33 37 and only two maternal outcomes were evaluated in more than one RCT: cesarean delivery and maternal glycemic control. There was little difference in maternal outcomes between those treated with glyburide and those receiving insulin. In the largest trial (n = 404) comparing glyburide and insulin, 49 percent of the women on insulin underwent cesarean delivery, as compared to 46 percent of those on glyburide.32 A second trial37 reported no difference in cesarean delivery rates for 51 women on glyburide, insulin, or acarbose. Three trials found no statistically significant differences in glucose control between women treated with insulin and those receiving glyburide.32 32 33 There was one study that considered pre-eclampsia, two studies that included maternal weight, and two studies that included information on maternal hypoglycemia. There were no available data with regard to perineal tears, operative vaginal delivery, or postpartum hemorrhage. Because of the small number of RCTs and the lack of consistency in the maternal outcomes measured across studies, we graded the overall strength of evidence as very low.

Only four neonatal outcomes were evaluated by more than one RCT: birth weight, LGA, macrosomia, and neonatal hypoglycemia. We conducted a meta-analysis of three RCTs with a total of 478 pregnancies. There was a lower average infant birth weight in the insulin group as compared to the glyburide group (-93 gm; 95 percent CI: -119 to 5). This difference was not statistically significant and is unlikely to have substantial clinical influence. We were unable to draw any definitive conclusions regarding neonatal hypoglycemia, given the limited data available. Langer et al.32 reported no significant difference between glyburide and insulin in the percentage of infants with hypoglycemia (9 percent versus 6 percent, p = 0.25), but Bertini et al.37 reported a higher percentage of infants with hypoglycemia in the glyburide group than in the insulin or acarbose groups (33 percent compared to 4 percent and 5 percent, respectively; p = 0.006). Several of our neonatal outcomes of interest were not included in the RCTs reviewed. Therefore, we were unable to draw conclusions about anoxia, birth trauma, respiratory distress syndrome, or shoulder dystocia.

We extended our review of the literature on insulin and glyburide to include four observational studies.4548 None of the observational studies were strong enough to justify a modification of the conclusions drawn from the RCTs.

Two RCTs compared the effect of insulin lispro and regular insulin on maternal and neonatal outcomes in women with gestational diabetes.34 36 We concluded that there was little difference in maternal glucose control (glycosylated hemoglobin or 1-hr glucose levels) between the women treated with insulin lispro and those treated with regular insulin. Neither Jovanoic36 nor Mecacci34 reported significant differences in mean infant birth weight between the insulin lispro and regular insulin groups. We concluded that no evidence exists to suggest that neonatal outcomes differ between those treated with regular insulin and those receiving insulin lispro. The limited number of trials, limited sample size, and paucity of information on neonatal outcomes made it difficult to draw any firm conclusions.

There was insufficient evidence to draw meaningful conclusions about the effect of long-acting versus short-acting insulin, twice-daily versus four-times-daily use of regular insulin, or diet alone versus diet plus insulin. In one study comparing long-acting to short-acting insulin, there was a higher percentage of infants with macrosomia in the long-acting insulin group than in the short-acting insulin group.31 Limited data from one RCT35 suggested that twice-daily insulin may be associated with worse neonatal outcomes (neonatal hypoglycemia, macrosomia, LGA, and SGA) than four-times-daily use of insulin. We found no evidence to suggest a difference in maternal outcomes between twice-daily and four-times-daily use of regular insulin. In the study by Thompson,30 women were randomized to diet alone or diet plus a fixed insulin regimen that included 20 units of NPH insulin and 10 units of regular insulin. There was no reported difference in maternal glucose control or the proportion of women undergoing cesarean delivery in the two groups. In terms of neonatal outcomes, infant birth weight was higher in the diet-alone group than in the diet and insulin group. Similarly, there was a higher proportion of infants with macrosomia in the diet-alone group. These findings must be viewed with caution because the overall strength of the evidence for diet compared to insulin and dietary management was very low.

We did not identify any studies that compared metformin with other diabetes medications in women with gestational diabetes. Also, we found no evidence regarding maternal or neonatal outcomes as related to the level of glucose at the initiation of a medication.

Key Question 2

What is the evidence that elective cesarean delivery or the choice of timing of induction in gestational diabetes results in beneficial or harmful maternal and neonatal outcomes?

There is little evidence on the effect of gestational age or EFW on the timing of labor induction or performance of elective cesarean delivery in women with gestational diabetes. The findings from one experimental study55 suggested that active induction of labor at 38 weeks of gestation reduced infant birth weight (3,672 gm versus 3,446 gm; p < 0.01) and rates of macrosomia (27 percent versus 15 percent; p = 0.05) when compared to expectant management, with no concomitant increase in the rate of cesarean delivery (25 percent in the active induction group versus 31 percent in the expectant management group; p = 0.43). While these results suggested that maternal outcomes might be better in women who undergo elective induction, we were unable to draw firm conclusions based on this one trial.

Observational studies5254 5659 provided some additional evidence of a reduction in macrosomia and shoulder dystocia with elective labor induction or cesarean delivery, when compared to expectant management. For example, in the study by Conway,53 women with diabetes underwent ultrasonographic estimates of fetal weight between 37 and 38 weeks of gestation. Women whose EFW was greater than or equal to 4,250 gm underwent cesarean delivery; those whose EFW was estimated at less than 4,250 gm but LGA (defined as ≥ 90th percentile for the gestational age in their population) underwent labor induction. Fewer infants were macrosomic (weighing 4,000 gm or more) in the group undergoing elective cesarean or labor induction than in the expectant management group (8.9 percent versus 11.6 percent; p = 0.04). In addition, the incidence of shoulder dystocia was higher in the expectant management group (OR = 1.9, 95 percent CI: 1.0 to 3.5) than in the group undergoing elective cesarean or labor induction. The overall strength of evidence on this comparison was graded as very low. Only one of the observational studies adjusted for potential confounders,56 so any measures of association may have been biased. Second, there may have been selection bias in the recruitment of women to participate in the studies. Third, there was substantial heterogeneity in terms of the comparison groups, length of followup, and outcome measures included in the analysis. Fourth, the four primary observational studies were conducted over a wide timeframe. It would be difficult to adequately adjust for changes in practice patterns and treatment modalities that occurred over the long time periods of the studies.

Key Question 3

What risk factors, including but not limited to family history, physical activity, pre-pregnancy weight, and gestational weight gain, are associated with short-term and long-term development of type 2 diabetes following a pregnancy with gestational diabetes?

Several factors were associated with the development of type 2 diabetes in women with previous gestational diabetes. Anthropometric measures before, during, and after pregnancy were found to be positively associated with the development of type 2 diabetes in 10 of 11 cohort studies. Waist circumference and BMI were the strongest anthropometric measures associated with type 2 diabetes in gestational diabetic women. Early gestational age at diagnosis of gestational diabetes (primarily less than 24 weeks) and use of insulin versus diet for glucose control were key pregnancy-related clinical factors that were positively associated with type 2 diabetes. Physiologic measures, including FBG and 2-hr plasma glucose levels during the diagnostic OGTT, were also associated with development of type 2 diabetes. Higher blood glucose following a screening 50-gm GCT, prior gestational diabetes, and OGTT area under the curve during both the antepartum and postpartum periods were positively associated with development of type 2 diabetes, but the strength of the associations was not consistent across studies. There is conflicting data on progesterone-only contraceptive use and the risk for developing type 2 diabetes. Elevated postpartum homocysteine levels were positively associated with type 2 diabetes in one study. Surprisingly, there were no studies of lifestyle factors in women with gestational diabetes that met our review criteria.

After a review of the available evidence, we concluded that the strongest epidemiological risk factors were anthropometric measures prior to pregnancy and during both the antepartum and postpartum periods. Taking into consideration the quantity, quality, and consistency of the studies evaluating the association of risk factors for type 2 diabetes following a pregnancy with gestational diabetes, we graded the strength of the evidence as very low. While there was substantial consistency in the direction of association across studies for many of the risk factors, there was considerable variation in the covariates adjusted for in multivariate models across studies.

Key Question 4

What are the performance characteristics (sensitivity, specificity, and reproducibility) of tests for diagnosing type 2 diabetes after pregnancy in patients with a history of gestational diabetes? Are there differences in the performance characteristics of the test results based on subgroup analysis?

Several studies have pointed to poor physician compliance with postpartum glucose screening for type 2 diabetes among women with a history of gestational diabetes.19 20 We reviewed the available studies of the diagnostic accuracy of screening for type 2 diabetes in this population. We identified 8 studies and 10 evaluations of screening tests, with three types of comparisons:

1.

two different diagnostic fasting value thresholds applied to the 75-gm OGTT (the WHO 1985 criteria compared to the WHO 1999 criteria);

2.

single FBG level greater than 7.0 mmol/L (126 mg/dL) (ADA 1997) compared to the 75-gm OGTT (WHO 1999); and

3.

single FBG greater than 7.0 mmol/L (126 mg/dL) (ADA 1997) compared to the 75-gm OGTT (WHO 1985).

For the first comparison, we concluded that there was acceptable specificity (98 percent) for the OGTT using either a FBG value greater than 7.0 mmol/L (126 mg/dL) or greater than 7.8 mmol/L (140 mg/dL). For the second comparison, we were unable to draw meaningful conclusions. The sensitivities for a single FBG greater than 7.0 mmol/L (126 mg/dL), as compared to a complete OGTT using the same FBG threshold, ranged from 46 to 89 percent in the three studies. For the third comparison, there were five studies, which reported a high specificity of the FBG greater than 7.0 mmol/L (126 mg/dL). However, there was a wide range of sensitivity, from 14 to 100 percent.

The six studies9598 100 101 that used an FBG threshold greater than 7.8 mmol/L (140 mg/dL) in the reference test may be obsolete, since current guidelines recommend an FBG greater than 7.0 mmol/L (126mg/dL)17 93 105 The wide variation in the reported sensitivities for studies that compared the OGTT as the reference test to a single FBG greater than 7.0 mmol/L (126 mg/dL) may reflect differences in the study samples' risk for type 2 diabetes, based on heterogeneity of study design and population. The overall strength of evidence was very low because of the high loss-to-followup rates (22 to 82 percent) for studies using clinic convenience samples.

Conclusions

Based on the available data outlined in Chapter 3, we have made the following conclusions:

Key Question 1: Little evidence exists to guide patients, health care providers, or policymakers in the choice of treatment for gestational diabetes. We were unable to draw firm conclusions from any of the five treatment comparisons in Key Question 1 because of the availability of only a limited number of studies within each category of comparison, a lack of consistency in the outcomes measured across studies, and heterogeneity in the definition of outcome measures. Limited evidence demonstrated no substantial clinical differences in maternal or neonatal outcomes with the use of glyburide or insulin lispro as compared to insulin in women with gestational diabetes. Our meta-analysis of three studies showed a small difference in infant birth weight. We expect little clinical relevance for the weighted mean difference of 93 gm. The results of our meta-analysis provide additional information for clinicians to incorporate into their discussions with patients about their choice of treatment but are unlikely to affect current clinical practice.

We did not identify any available evidence on variations in maternal or neonatal outcomes based on the level of glucose at the initiation of a medication. Each of the clinical trials and observational studies reviewed specified threshold glucose levels for the initiation of medical treatment as part of the study protocol. However, none of the studies compared outcomes based on glucose thresholds in their evaluation of maternal or neonatal outcomes. Findings from the HAPO study may provide further insights. Therefore, we were unable to provide evidence for this portion of Key Question 1. We were also unable to identify any published studies comparing metformin to diet, insulin, or insulin analogues in women with gestational diabetes. However, the ongoing MiG trial will likely provide evidence regarding the comparative effects of metformin and insulin on maternal and neonatal outcomes.

Key Question 2: Little evidence exists to guide health care providers in the use of EFW or gestational age in making decisions about the timing of labor induction or elective cesarean delivery. We identified only one relevant RCT. The findings from the few available observational studies were difficult to interpret because of variations in clinical practice over the time period of the studies. Furthermore, serious methodological limitations made it difficult to draw firm conclusions. While our review does provide physicians and other health care providers with a summary of the gaps in the available evidence, further study involving clinical trials or well-designed observational studies is necessary to effect modifications in clinical management and inform development of clinical pathways.

Key Question 3: There was consistent evidence that anthropometric measures (i.e., weight, BMI, and waist circumference) prior to pregnancy and during both the antepartum and postpartum periods were positively associated with development of type 2 diabetes. These findings suggested similar risk factors for type 2 diabetes in reproductive and middle-aged women. Moreover, it appeared that weight and the distribution of weight were strong predictors of type 2 diabetes in this special population of women. Metabolic risk factors, including higher FBG at diagnosis of gestational diabetes, high glucose levels in oral glucose tolerance testing, insulin-requiring gestational diabetes, and glucose AUC for antepartum glucose tolerance testing, were consistently associated with an increased likelihood of type 2 diabetes. The relationship between progesterone-only contraception use and the risk of type 2 diabetes in women with a prior history of gestational diabetes, however, remains unclear. There was no evidence available regarding the potential effect of lifestyle factors (e.g., physical activity) on the development of type 2 diabetes in women with a prior history of gestational diabetes. Further investigation, ideally involving RCTs, would provide evidence for the primary prevention of type 2 diabetes in this high-risk group. Such evidence could then be incorporated into preconception and prenatal care education.

Key Question 4: We were unable to draw meaningful conclusions from the limited evidence available for our review. As compared to the 75-gm OGTT, the FBG had high specificity, but the sensitivity was variable across studies. As a result of heterogeneity in the study design, recruited population, and interval of followup testing, we were unable to draw firm conclusions about the performance characteristics of the FBG in women with a history of gestational diabetes. There was also insufficient evidence regarding test reproducibility. Until the appropriate intervals for followup testing are realized, further investigations would benefit from an interdisciplinary clinical approach. While obstetricians may provide immediate postpartum screening, general practitioners, internists, and other health care providers will likely provide long-term followup. With the increasing prevalence of childbearing among older women, pregnant women more commonly receive care from an obstetrician-gynecologist and either an internist or other primary care provider. Thus, an interdisciplinary dialogue among providers will be necessary to influence future care.

Future Research

While basic science research and investigations using animal models have helped us to better understand the underlying pathophysiology of gestational diabetes, there is a wide gap in our clinical knowledge with regard to how potential treatments and postpartum management can benefit both mothers and infants. Future research should be directed toward filling this gap by conducting studies that will lead to the development of evidenced-based guidelines for maternal glucose control and physician recommendations for labor induction, elective cesarean, and expectant management. In addition, future research should focus on risk factors for type 2 diabetes in this high-risk population and on developing effective screening modalities for identifying women who are at risk for developing type 2 diabetes.

Further RCTs are needed to better assess maternal and neonatal outcomes in women with gestational diabetes who are being treated with insulin, insulin analogues, metformin, or glyburide. Future trials should specify a priori hypotheses and conduct power analyses prior to recruitment to ensure the ability to detect small differences in maternal glucose levels that can affect fetal weight and the risk of macrosomia, as well as common outcomes such as cesarean delivery. Power analyses will aid researchers in detecting differences in less common but critically important outcomes, such as shoulder dystocia and birth trauma. Clinical trials designed to capture these differences can offer important information and help us to draw reasonable and firm conclusions. Finally, intention-to-treat analysis will be essential to the ability to draw firm conclusions from the reported data. Consistency in the collection of outcome measures across studies is essential to our ability to draw confident conclusions. Furthermore, it would help to have more consistent definitions of clinical outcomes, including maternal and neonatal hypoglycemia, so that clinicians and investigators can better compare results across multiple studies. Observational studies in this area should be prospective, with protocols developed to minimize loss to followup. Adjustment for covariates will be of paramount importance for determining true estimates of the association of treatment choice with maternal and neonatal outcomes.

Well-designed RCTs comparing elective induction and cesarean delivery to expectant management would provide relevant, critical data to practitioners. These trials should incorporate appropriate methods of randomization and an intention-to-treat analysis, as well as power calculations with estimated effect sizes for mothers and infants. We acknowledge the potential barriers to performing clinical trials in pregnant women. Clinical trials with regard to labor management may be particularly difficult in the current obstetrical environment, which is highly litigious and influenced by patient and provider preferences for care. Well-designed observational studies are a reasonable alternative and can provide the necessary data to guide the development of clinical practice guidelines for labor management. Observational studies should primarily focus on insulin-requiring gestational diabetics (i.e., class A2), since this population is at higher risk of macrosomia or cesarean delivery. Alternatively, observational studies of diet and insulin-controlled gestational diabetics might include stratified analyses, which would provide outcome data at different levels of severity. Finally, future studies should adjust for other potential confounders, including sociodemographics and clinical factors related to intrapartum management.

Our review of 16 cohort studies identified several risk factors that are amenable to targeted interventions. One limitation of the current body of literature, however, is the inconsistency in the specific risk factors that have been assessed. Future studies should first focus on specific categories of risk factors, such as anthropometric measures (e.g., weight, BMI) or reproductive-related factors (e.g., parity). Second, future studies should collect data on pertinent covariates and adjust for relevant confounders in multivariate analysis. Third, women should be recruited for longitudinal study at the time of diagnosis of gestational diabetes. Fourth, several studies included in this review were based on convenience sampling, which may have biased the results; random or purposeful sampling of participants would yield a more representative group of participants.

Early identification of women with type 2 diabetes is paramount to achieving high quality of care and the ability to avoid diabetic complications due to delays in diagnosis. Future studies should focus on comparisons of the FBG and the standard 75-gm OGTT in postpartum women. Such comparisons would provide relevant data on the ability to screen women with a simple, time-efficient test, as compared to the burdensome OGTT. Studies should be conducted in diverse populations so that there is confidence that the findings are generalizable to other populations. The conduct of these studies in certain sub-groups (e.g., women with a family history of type 2 diabetes or prior gestational diabetes) is also warranted. Finally, studies of the reproducibility of test results will be critical to the development of broadly acceptable clinical guidelines for testing.

Implications

The results of this systematic review have important implications for clinical practice and public health policy. Clinicians and policymakers should be aware that the available data, while limited, do not suggest that there are adverse maternal or neonatal outcomes associated with the use of oral diabetic agents (i.e., glyburide), insulin lispro, or various insulin regimens. The efficacy of insulin analogs or glyburide in achieving maternal glucose targets or preventing episodes of maternal or neonatal hypoglycemia remains unclear. Several measures of maternal and neonatal morbidity, such as perineal tears, operative vaginal delivery, have not been evaluated, and several measures have only been evaluated in one or two studies. Also, it is unclear what glucose thresholds should be used to initiate insulin, insulin analogues, or glyburide in patients on diet alone.

Clinicians should also be aware that there is currently insufficient evidence to develop clear guidelines for labor induction or elective cesarean delivery in women with gestational diabetes. The conduct of well-designed clinical trials or observational studies may provide insight into evidenced-based management.

For public health policymakers, our conclusion is that measures of obesity and antepartum glucose values are the most consistent and substantiated risk factors for type 2 diabetes in women with gestational diabetes. With findings from the Diabetes Prevention Trial106 highlighting the effect of lifestyle modifications on the primary prevention of type 2 diabetes in high-risk populations, our review suggests that the effectiveness of these interventions should be tested in women with a prior history of gestational diabetes.

Finally, we conclude that there are insufficient data to recommend alternative tests to the 75-gm OGTT for the detection of type 2 diabetes in women with gestational diabetes. Public health policymakers should work with health care researchers and national organizations (e.g., the ACOG and ADA) to further evaluate the effectiveness and timeliness of postpartum screening for type 2 diabetes in women with gestational diabetes. Further investigation can provide the data needed to develop broadly acceptable postpartum screening guidelines.

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