we sought to develop a prediction model to identify women with gestational diabetes ( gdm ) who require insulin to achieve glycemic control . glyburide success was defined as any glyburide dose without insulin and > 70% of visits with glycemic control . of 360 women , 63 ( 17.5% ) qualified as glyburide failure and 157 ( 43.6% ) glyburide success . the final prediction model for glyburide failure included prior gdm , gdm diagnosis 26 weeks , 1-hour gct 228 mg / dl , 3-hour gtt 1-hour value 221 mg / dl , 7 post - prandial blood sugars > 120 mg / dl in the week glyburide started , and 1 blood sugar > 200 mg / dl . women with gdm who will require insulin can be identified at initiation of pharmacologic therapy . in 2000 , langer et al published a randomized control trial comparing glyburide and insulin for the treatment of gestational diabetes ( gdm ) . given that glyburide is significantly easier to use and less expensive than insulin , glyburide has become a first - line therapy for many clinicians for the treatment of gdm . the use of glyburide to treat gdm has increased dramatically since 2001 , increasing from 7.4% of prescriptions to treat gdm to 64.5% in 2011 . however , several retrospective studies have found an increased risk of macrosomia or large for gestational age infants in women receiving glyburide compared to those receiving insulin . other retrospective studies have found a higher incidence of preeclampsia in women treated with glyburide compared to insulin . these increased adverse perinatal outcomes in women treated with glyburide may be due to delays in glycemic control in those who ultimately fail glyburide therapy and require treatment with insulin . delay of insulin initiation may result in weeks of hyperglycemia and subsequently increased risks of adverse perinatal outcomes . we therefore we aimed to develop a prediction model for glyburide failure based on factors known at the time of initiation of medical therapy for gdm in order to optimize therapy for women requiring medical therapy . we hypothesized that failure of glyburide therapy can be predicted at the time that pharmacotherapy for gdm is initiated . we conducted a retrospective cohort study of all singletons diagnosed with gdm and treated with glyburide at the university of alabama at birmingham jan 1 , 2007dec 31 , 2013 . subjects were identified from the searchable electronic medical record system using a diagnosis of gestational diabetes and diabetes ; a diagnosis of gestational diabetes was confirmed on review of medical records . the protocol for diagnosing gestational diabetes is to perform a 1-hour glucose tolerance test on all women ; if 135 mg / dl a 3-hour glucose tolerance is performed . subjects were considered to have gestational diabetes if a 3-hour glucose tolerance test was performed and met carpenter - coustan criteria , if a 1-hour glucose challenge test was 200 mg / dl , or if fasting blood sugar was 120 mg / dl . trained personnel ( obstetricians and medical students ) reviewed medical records to abstract detailed patient data using standardized data collection forms . abstracted data included maternal age , ethnicity , socioeconomic status , self - reported prepregnancy height and weight , comorbid medical conditions , obstetric history , blood sugar testing , gestational weight gain , prenatal blood sugar logs , delivery details , and perinatal outcomes . at uab , women with gestational women with risk factors for gestational diabetes , such as obesity or a prior history of gestational diabetes may be screened earlier at the discretion of the provider . all women diagnosed with gestational diabetes receive individualized nutrition counseling and are advised to check their blood sugars fasting and 2-hours after each meal . women are typically seen at 1 week intervals until glycemic targets are reached , and then may have visits every other week until 3436 weeks . glycemic targets are fasting blood sugar < 95mg / dl and 2-hour post - prandial blood sugars < 120 mg / dl . women are started on a pharmacologic agent for gestational diabetes if > 50% of fasting or post - prandial blood sugars are elevated . since 2007 , glyburide has been the first - line agent at uab for gestational diabetes . at uab , glyburide is typically started at 2.55 mg / day ( in single or divided dosing ) and increased by 2.55 mg / day . however , use of glyburide and its dosing was at the discretion of the attending physician ; some patients may have been initiated on other pharmacologic agents such as metformin or insulin as the first line . subjects were included in this analysis if they were diagnosed with gdm and received glyburide for glycemic control . subjects were excluded from this analysis if comorbid conditions other than chronic hypertension were present ( eg systemic lupus erythematosus , hiv , hepatitis ) , any fetal anomaly was diagnosed , or if presentation for prenatal care was late ( > 26 weeks ) . glyburide failure was defined as reaching 20 mg / day of glyburide and then receiving insulin therapy . glyburide success was defined as those treated with any dose of glyburide without receiving insulin and who had demonstrated glycemic control at > 70% of visits . as the median number of visits after starting pharmacotherapy was 6 ( interquartile range 49 ) ; a marker of 70% allowed for 1 visit with poor control and/or medication adjustment . additionally , at least 3 fasting and 3 post - prandial blood sugars had to be recorded to be considered in the glyburide success group . the group that was neither a glyburide failure or success , i.e. those that were continued on glyburide without receiving insulin and had fewer than 70% of prenatal visits without blood sugar control , were classified as poorly controlled on glyburide and excluded from analysis . factors considered included maternal age , prepregnancy body mass index , race , education , insurance , prior pregnancy history including a history of gdm in a prior pregnancy , gestational age at diagnosis , gestational weight gain , one - hour and three - hour glucose challenge test results , and blood sugar log records the week prior to starting glyburide . the liu method was used to identify an optimal cut point for continuous variables . groups were compared using student s t - test or chi - square test as appropriate . clinically relevant covariates for initial inclusion in multivariable models were selected using the results of the stratified analyses , and factors were removed in backwards stepwise fashion , based on significant changes in the exposure adjusted odds ratio or significant differences between hierarchical models using the likelihood ratio test . the cutoff point was selected to minimize false - positive diagnoses ; in other words , specificity for correctly identifying glyburide failure was more important than sensitivity for identifying glyburide failure . receiver operator characteristics curves were created to estimate the predictive value of the final model . all analyses were performed using stata se , version 13.0 ( college station , tx ) . of 1,212 women identified with gdm , 145 were excluded for being unable to confirm a diagnosis of gdm with laboratory testing , 82 for major medical comorbidities , 29 for fetal anomalies , 61 for late prenatal care and 493 for being managed by diet therapy alone , leaving 402 subjects for analysis . of these 402subjects , only 39 were initiated directly on insulin ( for suspicion of pregestation diabetes ) and 3 on metformin , leaving 360 subjects with a2 gdm initiated on glyburide after diet failure ( figure 1 ) . of the 360 subjects , 63 ( 17.5% ) were classified as glyburide failure and 157 ( 43.6% ) as glyburide success . the remaining 140 ( 38.9% ) were managed on glyburide alone without meeting the success criteria of > 70% of prenatal visits with blood sugar control . those successfully managed on glyburide and those failing glyburide were similar with regards to maternal age , race , nulliparity , chronic hypertension , prepregnancy body mass index , prior cesarean , and prior macrosomic infant ( table 1 ) . women who failed glyburide therapy were less likely to have public health insurance and more likely to smoke or to have had gdm in a prior pregnancy . with regards to pregnancy and gdm diagnosis , women who failed glyburide therapy were diagnosed at an earlier gestational age , had higher 1-hour glucose challenge test values , higher fasting and one - hour values on the three - hour glucose tolerance test ( table 2 ) . on blood sugar logs on the week prior to initiating glyburide , women who failed glyburide had more fasting blood sugars > 100 mg / dl , more post - prandial values > 120 mg / dl , and more blood sugars > 200 mg / dl . factors significant in the final model are demonstrated in table 3 and box 1 and include gdm in a prior pregnancy , gestational age at diagnosis 26 weeks , a 1 hour glucose challenge test value 228 mg / dl , a 1-hour value on the three hour glucose tolerance test 221 , 7 or more 2-hour postprandial blood sugars > 120 mg / dl on blood sugar log for the week prior , 1 or more blood sugar > 200 mg / dl on blood sugar log for the week prior . this model classified women as glyburide failure if the calculated risk of failure based on the equation in box 1 was 75% . as each factor was added to the model , the percentage of women correctly classified increased , as did the sensitivity and specificity . the final model correctly classified 80.9% of women , with a sensitivity of 39.7% and a specificity of 97.5% . over 5,000 iterations , the sensitivity of the model ranged from 32.340.3% and the specificity ranged from 97.499.4% . the area under the curve for the model over 5,000 iterations ranged from 0.860.87 , demonstrating that this model is robust . because early gestational age at diagnosis and a 1 hour glucose challenge test value > 200 mg / dl are frequently considered markers of pregestational diabetes , we re - evaluated the prediction model excluding subjects with either of these markers . of the 98 subjects remaining , 13 failed glyburide therapy and 85 achieved good glucose control on glyburide . the model predicts glyburide failure with 30.8% sensitivity and 98.8% specificity and an area under the curve of 0.87 . when this model was applied to all 360 women started on glyburide ( including the 140 women in the poorly controlled on glyburide category ) , 40 ( 11% ) women were predicted to have a glyburide failure . of these 40 , 25 ( 62.5% ) failed glyburide and 4 ( 10% ) were poorly controlled on glyburide . if this model were applied prospectively , only 11 ( 3.1% ) women would have been falsely predicted as glyburide failure . the majority of women who will reach a maximum dose of glyburide without achieving glycemic control can be identified at the time glyburide is initiated . we developed a prediction model with a specificity of 97.5% for those who will fail glyburide therapy and require insulin therapy . this prediction model classified only 11% of our subjects as glyburide failure with a low false positive rate . the trade - off of the model having a high specificity is a relatively low sensitivity of only 40% . however , we feel that a sensitivity of 40% of women who will fail glyburide being identified by the model is a vast improvement over initiating a patient on glyburide and waiting several weeks to determine success or failure of treatment . additionally , we purposely elected to build a model with an emphasis on specificity for several reasons . secondly , glyburide is significantly less expensive than insulin and does not require additional visits for diabetic education . therefore , we felt a model that is more specific ( fewer predictions of glyburide failure when glyburide may succeed ) was preferable to a model that was more sensitive . several factors included in the model may actually be associated factors associated with pregestational diabetes , such as extremely elevated fasting values , a one hour glucose challenge test > 200 mg / dl , a prior pregnancy complicated by gestational diabetes , or an early gestational age at diagnosis . however , because these women were diagnosed during pregnancy and had no known history of diabetes outside of pregnancy , we included them in the cohort . as many women first diagnosed during pregnancy may be considered for a trial of oral medications , particularly as they are unlikely to be familiar with insulin , this is representative of clinical practice . indeed , these patients are those who will most likely benefit from aggressive treatment of blood sugars by direct initiation on insulin without a trial of glyburide . additionally , when we applied the model to a cohort of women excluding markers of pregestational diabetes , the model continued to perform robustly , with a specificity of 98.8% . several prior studies have examined risk factors for requiring insulin therapy for glycemic control in gdm . in a prospective study , chmait et al determined that the the most important markers of glyburide failure were gestational age ( < 30 weeks ) and mean blood glucose values ( fasting blood sugar > 110 mg / dl , 1-hour post - prandial values > 140 mg / dl ) at initiation of glyburide . however , the chosen criteria in this study were only 65% specific for identifying glyburide success or failure . this would lead to a falsely identifying glyburide failure in almost 1/3 of patients in the population , potentially using the more expensive and more cumbersome insulin in women who could achieve glycemic control with glyburide . another study to identify predictors glyburide failure versus glyburide success confirm the importance of gestational age at glyburide initiation , but found that gestational at diagnosis prior to 25 weeks ( as opposed to 30 weeks ) was associated with an 8-fold increase in the risk of glyburide failure . rochon et al also sought to identify factors predictive of glyburide failure . in this study , glyburide failure was defined as anybody who was started on glyburide and switched to insulin , not just women who failed to achieve glycemic control on a maximum dose of glyburide and switched to insulin . unlike other studies , gestational age at diagnosis was not significantly associated with glyburide failure . factors associated with glyburide failure included a glucose challenge test value greater than 200 mg / dl and a fasting blood sugar value greater than 95 mg / dl . first , we had a large number ( n=63 ) of women who failed glyburide therapy . this is approximately 35 times larger than other studies we identified in the literature of women who failed glyburide therapy . additionally , we had detailed patient level data that included gdm testing results and blood sugar logs for the entire pregnancy . this detailed data enabled us to consider a multitude of factors that may be important in determining glyburide failure , including blood sugar values the week prior to glyburide initiation . furthermore , we considered only factors known at the time glyburide was initiated in the prediction model . although information obtained later in pregnancy may also be associated with glyburide failure , this information is not available to clinicians at the time of the decision to initiate glyburide or insulin ; consequently , it does not belong in a clinically useful prediction model . we used an empiric method ( the liu method ) to define optimal thresholds of continuous variables to use in our prediction model , rather than outcomes considered clinically important traditionally ( i.e. a glucose challenge test of 200 mg / dl or gestational age prior to 20 weeks ) . consequently , we optimized the sensitivity and specificity of our model . finally , a stringent definition of glyburide failure ( i.e. reaching a dose of 20 mg / day of glyburide and initiation on insulin ) and glyburide success ( i.e. > 70% of visits with glycemic control ) was used , limiting misclassification bias due to provider judgment or patient preferences for glyburide versus insulin . one potential weakness of this study is that we excluded subjects who were poorly controlled on glyburide when developing our prediction model , thus excluding 39% of the cohort . thus , the ideal comparison group to failing glyburide therapy is a group of women who actually achieved glycemic control with glyburide . also , in a retrospective study although we collected significant amounts of detailed patient - level information ( including weekly blood sugar logs and medication doses ) , we did not collect data on information such as patient refusal of insulin or patient s access to medication . therefore , some may have had improved blood sugar control with simply higher doses of glyburide , others may have actually been recommended to start insulin but refused or delivered before it could be initiated . when this group of women was included and the model applied , the model continued to perform well with a low positive rate . finally , although our clinical practice typically gives every patient a trial of glyburide , some patients ( less than 10% ) were initiated on insulin without first receiving glyburide therapy . their exclusion may have impacted the model by excluding women most likely to fail glyburide therapy , although this may be preferred as it mimics what happens in clinical practice . women who were initiated directly on insulin without a trial of glyburide were more likely to have had a prior pregnancy complicated by gdm than those given a trial of glyburide , but were otherwise similar with respect to age , prepregnancy bmi , and race ( data available upon request ) . therefore , we do not feel that their exclusion significantly altered our results . in sum , we have developed a prediction model based on factors known at the time of glyburide initiation to predict those who will ultimately fail glyburide therapy and require insulin . this model has excellent specificity in order to avoid initiating insulin in a patient who could achieve glycemic control with glyburide therapy . application of this model prospectively should be investigated to determine if starting women at high risk of glyburide failure directly on insulin can improve perinatal outcomes .
objectivewe sought to develop a prediction model to identify women with gestational diabetes ( gdm ) who require insulin to achieve glycemic control.study designretrospective cohort of all singletons with gdm treated with glyburide 20072013 . 
 glyburide failure was defined as reaching glyburide 20 mg / day and receiving insulin . 
 glyburide success was defined as any glyburide dose without insulin and > 70% of visits with glycemic control . 
 multivariable logistic regression analysis was performed to create a prediction model.resultsof 360 women , 63 ( 17.5% ) qualified as glyburide failure and 157 ( 43.6% ) glyburide success . 
 the final prediction model for glyburide failure included prior gdm , gdm diagnosis 26 weeks , 1-hour gct 228 mg / dl , 3-hour gtt 1-hour value 221 mg / dl , 7 post - prandial blood sugars > 120 mg / dl in the week glyburide started , and 1 blood sugar > 200 mg / dl . 
 the model accurately classified 81% of subjects.conclusionswomen with gdm who will require insulin can be identified at initiation of pharmacologic therapy .