during the study period of 15 february 2009 to 15 february 2011 , all danish - speaking pregnant women with pregestational diabetes referred to the center for pregnant women with diabetes , rigshospitalet , before 14 completed gestational weeks with one living intrauterine fetus ( n = 222 ) , were offered participation in the study ( fig .
patients were referred from the capital region of denmark and region zealand , covering 2.4 million inhabitants .
exclusion criteria were present use of real - time cgm ( n = 7 ) , severe mental or psychiatric barriers ( n = 4 ) , diabetic nephropathy ( n = 3 ) , or severe concurrent comorbidity ( one with severe psoriasis and two with previous gastric bypass surgery ) . if a woman had more than one pregnancy in the study period ( n = 4 ) , the woman was only offered inclusion at first referral . among eligible patients , a total of 123 ( 79% ) women with type 1 diabetes and 31 ( 67% ) women with type 2 diabetes were accepted to take part in the study , of whom 79 ( 51% ) women were randomized to intermittent use of real - time cgm in pregnancy in addition to routine pregnancy care ( see below ) .
the major reason for rejecting participation was the possibility of real - time cgm allocation .
( a high - quality color representation of this figure is available in the online issue . )
the research protocol was approved by the danish national committee on biomedical research ethics and the danish data protection agency .
they were offered time to think it through , often with their partner , before accepting participation .
most women gave written informed consent , were randomized , and had allocated intervention initiated later the same day and at the latest before 14 completed weeks .
many women had been informed about the running of the trial beforehand by their local diabetologists , who had all received written information .
all women in both study arms followed the routine pregnancy care program for pregestational diabetes with antenatal visits at our clinic at 8 , 12 , 21 , 27 , and 33 gestational weeks .
self - monitored plasma glucose measurements were recommended seven times daily ( before and 1.5 h after each main meal and at bedtime ) , and diet and insulin doses were adjusted by the women themselves every third day and in collaboration with an experienced diabetologist every second week .
treatment goals for self - monitored plasma glucose values were 4.06.0 mmol / l preprandially , 4.08.0 mmol / l 1.5 h postprandially , and 6.08.0 mmol / l prebedtime .
at single - standing preprandial self - monitored plasma glucose values > 8.0 and > 10.0
mmol / l , supplementary rapid - acting insulin was recommended ( 12 and 24 insulin units in the first half of pregnancy and thereafter 24 and 46 insulin units , respectively ) . at self - monitored plasma glucose values
< 4.0 mmol / l and/or mild hypoglycemia ( see below ) , supplementary carbohydrate intake of 20 g was recommended . for hba1c ,
the aim was < 5.6% ( 38 mmol / mol ) after 20 weeks ( 28 ) .
hba1c was measured on a dca 2000 analyzer by a latex immunoagglutination inhibition method ( dca 2000 ; bayer , mishawaka , in ) .
blood pressure was measured as formerly described ( 25 ) , and if > 135/85 mmhg , treatment was initiated ( 29 ) .
elevated urine albumin excretion was defined as albumin - to - creatinine ratio 30 mg / mmol in a random urine sample ( 25 ) .
obstetrical ultrasound scanning was performed at all five routine visits and when indicated ( 7 ) . at first pregnancy visit ,
all women had a dietitian appointment for individual dietary planning following national guidelines for diabetes diet .
carbohydrate counting was mainly used in women on insulin pumps , and specific recording of dietary data was not performed . women with bmi < 30 kg / m were advised to gain 1015 kg in pregnancy , whereas women with bmi > 30 kg / m were advised to stay weight - neutral in the first half of pregnancy and thereafter to limit weight gain to 5 kg . all women visited our clinic and/or their local diabetes clinic at 2-week intervals throughout pregnancy , at which time hba1c , blood pressure , weight , and urine examination were registered .
twenty - seven ( 22% ) women with type 1 diabetes were on insulin pump therapy ( mainly initiated before pregnancy ) with rapid - acting insulin analogs .
most of these women used insulin pumps that could be connected to the prescribed real - time cgm system .
the majority were using the bolus calculator , but they did not have the possibility of low glucose suspend .
women with type 1 diabetes on multiple daily injections were treated with rapid- and long - acting insulin analogs ( n = 66 ) , rapid - acting insulin analogs with intermediate nph insulin ( n = 19 ) , human short - acting and intermediate nph insulin ( n = 9 ) , or human short - acting insulin and long - acting insulin analog ( n = 2 ) .
all but one of 31 women with type 2 diabetes received insulin therapy in pregnancy with insulin aspart mix ( n = 14 ) , intermediate nph insulin combined with rapid - acting insulin analog or human short - acting insulin ( n = 12 ) , or solely intermediate nph insulin ( n = 3 ) or rapid - acting insulin analog ( n = 1 ) .
patients were recommended to administer rapid - acting insulin shortly before meals throughout pregnancy . during labor and delivery ,
self - monitored plasma glucose measurements were performed hourly , aiming for plasma glucose levels of 4.07.0 mmol / l .
for study purpose , participants were asked to perform eight daily self - monitored plasma glucose measurements for 6 days , including measurements at 3 a.m. , at study visits at 8 , 12 , 21 , 27 , and 33 weeks .
registration of self - monitored plasma glucose values for study purpose was handled as previously described ( 7,25 ) .
all women were offered free use of a blood glucose meter with corresponding test strips ( contour ; bayer , wakimachi , japan ) .
results on hba1c and insulin doses were obtained at all five study visits and shortly before delivery at median 36 ( range 2939 ) weeks .
mild hypoglycemia was defined as events familiar to the patient as hypoglycemia and managed by the patient , whereas severe hypoglycemia was defined as self - reported events with symptoms of hypoglycemia requiring help from another person to actively administer oral carbohydrate or injection of glucose or glucagon in order to restore normal blood glucose level ( 7 ) .
information on mild and severe hypoglycemic events was obtained in detailed questionnaires and structured interviews at all study visits and shortly after delivery , as previously described ( 7 ) . during the study period ,
thyroid dysfunction was treated in 32 women with levothyroxine ( n = 29 ) , thiamazole ( n = 2 ) , or propylthiouracil ( n = 1 ) , resulting in normal thyroid function in all women .
a computer - generated randomization program was used and treatment allocation was properly concealed using automated telephone allocation service ( paravox ) provided by an independent organization .
trained research personnel ( a.l.s . or project nurse ) provided the women with their arm allocation .
participants in the intervention arm were offered intermittent real - time cgm ( guardian real - time continuous glucose monitoring system with the sof - sensor ; medtronic minimed , northridge , ca ) for 6 days at the first pregnancy visit at 8 weeks and at 12 , 21 , 27 and 33 weeks , on top of routine pregnancy care .
the women were encouraged to use real - time cgm continuously , especially in cases of hypoglycemia unawareness ( 7,24 ) .
a small number of women were only willing to use real - time cgm for 3 days per monitoring period , which was accepted . blinded real - time cgm was not performed in the control arm . at the first pregnancy visit
, women were allocated to intervention in which they were educated in sensor insertion and the maintenance of the system on a one - to - one basis for 1 to 2 h by a trained diabetes caregiver ( a.l.s . or one of two project nurses ) ( 25 ) .
they were instructed to continue performing self - monitored plasma glucose measurements as recommended and to verify the accuracy of real - time cgm glucose values with self - monitored plasma glucose measurement before making management decisions . at real - time cgm alarms with subsequent plasma glucose < 4.0
real - time cgm alarms for hyperglycemia were tackled on an individual basis , including physical exercise like walking or supplementary rapid - acting insulin .
patients were encouraged to contact the clinic at any time and were offered visits on weekdays other than those planned if convenient .
the majority of the women preferred to have the sensor inserted in the abdominal skin , but in late pregnancy , during labor or caesarean section , some patients chose to insert the sensor in the upper arm . at enrollment , all women were advised to set the hypoglycemic alarm ( mainly at 3.5
mmol / l ) ( 25 ) . in order to limit excessive alarms , it was in general recommended that patients deactivate the alarm for hyperglycemia , but the alarm was sometimes set at the patient s request ( mainly at 10.0
alarm limits were flexible , and patients were supported in individual alarm settings . shortly after each monitoring period , downloaded real - time cgm data were printed out , with hard copies given to both the participants and health professionals .
each real - time cgm reading was discussed with a diabetes caregiver ( mainly a.l.s .
using locally developed guidelines on how to interpret real - time cgm readings in pregnancy ( supplementary fig .
the primary focus was glycemic trends during nighttime with emphasis on the prevention of hypoglycemia .
thereafter , hypoglycemia and pre- and postprandial glucose values during the daytime were evaluated , aiming for glucose values between 4.0 and 8.0
therapeutic adjustments in diet , exercise , and insulin doses were primarily based on self - monitored plasma glucose values , in combination with real - time cgm data .
the prescribed device was the only real - time cgm system available at the danish market during study preparation .
the prevalence of large - for - gestational - age infants [ i.e. , infant birth weight 90th centile adjusted for sex and gestational age ( 31 ) ] was predefined as the primary outcome of this study . to reflect neonatal morbidity , the prevalence of preterm delivery ( < 37 weeks of gestation ) and/or severe neonatal hypoglycemia ( 2-h plasma glucose < 2.5
mmol / l treated with intravenous glucose infusion ) was selected as the secondary combined end point prior to study onset .
other pregnancy outcomes were defined as follows : miscarriage ( before 22 weeks ) , preeclampsia [ blood pressure 140/90 and proteinuria ( 29 ) ] , birth weight sd score ( z - score ) , neonatal hypoglycemia ( 2-h plasma glucose < 2.5
mmol / l ) , and major congenital malformation ( i.e. , abnormality requiring surgery and/or resulting in permanent injury ) . based on the assumption that the prevalence of large - for - gestational - age infants was 50% in our study population ( 7 ) and that the use of real - time cgm could reduce it to 20% , and a type 1 error of 5% and a type 2 error of 20% , the number of patients needed in each arm was 45 .
we intended to analyze predefined primary and secondary outcome parameters of women receiving intervention versus control subjects in the entire study population , as well as in the subpopulation of women with type 1 diabetes .
the study population of 154 women ( of whom 123 had type 1 diabetes ) was therefore judged to have sufficient power to detect a possible effect of real - time cgm on the prevalence of large - for - gestational - age infants in the entire study population , as well as in women with type 1 diabetes alone .
we compared the characteristics of the women using the fisher exact test or  test when appropriate for categorical variables and t test or mann  whitney test when appropriate for continuous variables .
continuous variables were given as median ( range ) , and categorical variables were given as numbers ( percentage ) .
analyses were done on an intention - to - treat basis , counting 154 subjects at baseline , and thereafter with the exclusion of women with miscarriages ( n = 5 ) .
we primarily analyzed data as planned by comparing women allocated to real - time cgm with control subjects in the entire study population and in women with type 1 diabetes alone .
we also analyzed the prevalence of severe hypoglycemia and main outcome parameters in women using real - time cgm per protocol , and despite limited numbers , we analyzed glycemic control and pregnancy outcomes in women with type 2 diabetes and the prevalence of large - for - gestational - age infants in women with type 1 diabetes on insulin pump therapy .
six infants were excluded from calculations on neonatal hypoglycemia because of intravenous glucose infusion prior to routine 2-h plasma glucose measurements ( n = 5 ) or perinatal death ( n = 1 ) ( fig . 1 , table 3 , and supplementary table 3 ) .
glucose data in table 2 and supplementary table 1 were based on 25,546 self - monitored plasma glucose values , and glucose fractions ( % ) have been calculated for each individual participant after sorting glucose values into intervals ( 3.9 , 4.07.9 , and 8.0 mmol / l ) .
statistical analyses were performed using stata 11.1 se software ( stata corp . , college station , tx ) .
during the study period of 15 february 2009 to 15 february 2011 , all danish - speaking pregnant women with pregestational diabetes referred to the center for pregnant women with diabetes , rigshospitalet , before 14 completed gestational weeks with one living intrauterine fetus ( n = 222 ) , were offered participation in the study ( fig .
patients were referred from the capital region of denmark and region zealand , covering 2.4 million inhabitants .
exclusion criteria were present use of real - time cgm ( n = 7 ) , severe mental or psychiatric barriers ( n = 4 ) , diabetic nephropathy ( n = 3 ) , or severe concurrent comorbidity ( one with severe psoriasis and two with previous gastric bypass surgery ) . if a woman had more than one pregnancy in the study period ( n = 4 ) , the woman was only offered inclusion at first referral . among eligible patients , a total of 123 ( 79% ) women with type 1 diabetes and 31 ( 67% ) women with type 2 diabetes were accepted to take part in the study , of whom 79 ( 51% ) women were randomized to intermittent use of real - time cgm in pregnancy in addition to routine pregnancy care ( see below ) .
the major reason for rejecting participation was the possibility of real - time cgm allocation .
( a high - quality color representation of this figure is available in the online issue . )
the research protocol was approved by the danish national committee on biomedical research ethics and the danish data protection agency .
they were offered time to think it through , often with their partner , before accepting participation .
most women gave written informed consent , were randomized , and had allocated intervention initiated later the same day and at the latest before 14 completed weeks .
many women had been informed about the running of the trial beforehand by their local diabetologists , who had all received written information .
all women in both study arms followed the routine pregnancy care program for pregestational diabetes with antenatal visits at our clinic at 8 , 12 , 21 , 27 , and 33 gestational weeks .
self - monitored plasma glucose measurements were recommended seven times daily ( before and 1.5 h after each main meal and at bedtime ) , and diet and insulin doses were adjusted by the women themselves every third day and in collaboration with an experienced diabetologist every second week .
treatment goals for self - monitored plasma glucose values were 4.06.0 mmol / l preprandially , 4.08.0 mmol / l 1.5 h postprandially , and 6.08.0 mmol / l prebedtime . at single - standing preprandial self - monitored plasma glucose values
> 8.0 and > 10.0 mmol / l , supplementary rapid - acting insulin was recommended ( 12 and 24 insulin units in the first half of pregnancy and thereafter 24 and 46 insulin units , respectively ) . at self - monitored plasma glucose values < 4.0 mmol / l and/or mild hypoglycemia ( see below ) , supplementary carbohydrate intake of 20 g was recommended . for hba1c ,
the aim was < 5.6% ( 38 mmol / mol ) after 20 weeks ( 28 ) .
hba1c was measured on a dca 2000 analyzer by a latex immunoagglutination inhibition method ( dca 2000 ; bayer , mishawaka , in ) .
blood pressure was measured as formerly described ( 25 ) , and if > 135/85 mmhg , treatment was initiated ( 29 ) .
elevated urine albumin excretion was defined as albumin - to - creatinine ratio 30 mg / mmol in a random urine sample ( 25 ) .
obstetrical ultrasound scanning was performed at all five routine visits and when indicated ( 7 ) . at first pregnancy visit ,
all women had a dietitian appointment for individual dietary planning following national guidelines for diabetes diet .
carbohydrate counting was mainly used in women on insulin pumps , and specific recording of dietary data was not performed .
women with bmi < 30 kg / m were advised to gain 1015 kg in pregnancy , whereas women with bmi > 30 kg / m were advised to stay weight - neutral in the first half of pregnancy and thereafter to limit weight gain to 5 kg .
all women visited our clinic and/or their local diabetes clinic at 2-week intervals throughout pregnancy , at which time hba1c , blood pressure , weight , and urine examination were registered .
twenty - seven ( 22% ) women with type 1 diabetes were on insulin pump therapy ( mainly initiated before pregnancy ) with rapid - acting insulin analogs .
most of these women used insulin pumps that could be connected to the prescribed real - time cgm system .
the majority were using the bolus calculator , but they did not have the possibility of low glucose suspend .
women with type 1 diabetes on multiple daily injections were treated with rapid- and long - acting insulin analogs ( n = 66 ) , rapid - acting insulin analogs with intermediate nph insulin ( n = 19 ) , human short - acting and intermediate nph insulin ( n = 9 ) , or human short - acting insulin and long - acting insulin analog ( n = 2 ) . all but one of 31 women with type 2 diabetes received insulin therapy in pregnancy with insulin aspart mix ( n = 14 ) , intermediate nph insulin combined with rapid - acting insulin analog or human short - acting insulin ( n = 12 ) , or solely intermediate nph insulin ( n = 3 ) or rapid - acting insulin analog ( n = 1 ) .
patients were recommended to administer rapid - acting insulin shortly before meals throughout pregnancy . during labor and delivery ,
self - monitored plasma glucose measurements were performed hourly , aiming for plasma glucose levels of 4.07.0 mmol / l . for study purpose , participants were asked to perform eight daily self - monitored plasma glucose measurements for 6 days , including measurements at 3 a.m. , at study visits at 8 , 12 , 21 , 27 , and 33 weeks .
registration of self - monitored plasma glucose values for study purpose was handled as previously described ( 7,25 ) .
all women were offered free use of a blood glucose meter with corresponding test strips ( contour ; bayer , wakimachi , japan ) .
results on hba1c and insulin doses were obtained at all five study visits and shortly before delivery at median 36 ( range 2939 ) weeks .
mild hypoglycemia was defined as events familiar to the patient as hypoglycemia and managed by the patient , whereas severe hypoglycemia was defined as self - reported events with symptoms of hypoglycemia requiring help from another person to actively administer oral carbohydrate or injection of glucose or glucagon in order to restore normal blood glucose level ( 7 ) .
information on mild and severe hypoglycemic events was obtained in detailed questionnaires and structured interviews at all study visits and shortly after delivery , as previously described ( 7 ) .
during the study period , 30 women received antihypertensive treatment , mainly methyldopa ( n = 27 ) .
eight women were treated with antidepressive medicine  six of them with selective serotonin reuptake inhibitors .
thyroid dysfunction was treated in 32 women with levothyroxine ( n = 29 ) , thiamazole ( n = 2 ) , or propylthiouracil ( n = 1 ) , resulting in normal thyroid function in all women .
a computer - generated randomization program was used and treatment allocation was properly concealed using automated telephone allocation service ( paravox ) provided by an independent organization .
participants were stratified according to type of diabetes . trained research personnel ( a.l.s . or project nurse ) provided the women with their arm allocation .
participants in the intervention arm were offered intermittent real - time cgm ( guardian real - time continuous glucose monitoring system with the sof - sensor ; medtronic minimed , northridge , ca ) for 6 days at the first pregnancy visit at 8 weeks and at 12 , 21 , 27 and 33 weeks , on top of routine pregnancy care .
the women were encouraged to use real - time cgm continuously , especially in cases of hypoglycemia unawareness ( 7,24 ) .
a small number of women were only willing to use real - time cgm for 3 days per monitoring period , which was accepted . blinded real - time cgm was not performed in the control arm . at the first pregnancy visit
, women were allocated to intervention in which they were educated in sensor insertion and the maintenance of the system on a one - to - one basis for 1 to 2 h by a trained diabetes caregiver ( a.l.s . or one of two project nurses ) ( 25 ) .
they were instructed to continue performing self - monitored plasma glucose measurements as recommended and to verify the accuracy of real - time cgm glucose values with self - monitored plasma glucose measurement before making management decisions . at real - time cgm alarms with subsequent plasma glucose < 4.0
real - time cgm alarms for hyperglycemia were tackled on an individual basis , including physical exercise like walking or supplementary rapid - acting insulin .
patients were encouraged to contact the clinic at any time and were offered visits on weekdays other than those planned if convenient .
the majority of the women preferred to have the sensor inserted in the abdominal skin , but in late pregnancy , during labor or caesarean section , some patients chose to insert the sensor in the upper arm . at enrollment , all women were advised to set the hypoglycemic alarm ( mainly at 3.5
mmol / l ) ( 25 ) . in order to limit excessive alarms , it was in general recommended that patients deactivate the alarm for hyperglycemia , but the alarm was sometimes set at the patient s request ( mainly at 10.0
shortly after each monitoring period , downloaded real - time cgm data were printed out , with hard copies given to both the participants and health professionals .
each real - time cgm reading was discussed with a diabetes caregiver ( mainly a.l.s .
using locally developed guidelines on how to interpret real - time cgm readings in pregnancy ( supplementary fig .
the primary focus was glycemic trends during nighttime with emphasis on the prevention of hypoglycemia .
thereafter , hypoglycemia and pre- and postprandial glucose values during the daytime were evaluated , aiming for glucose values between 4.0 and 8.0
therapeutic adjustments in diet , exercise , and insulin doses were primarily based on self - monitored plasma glucose values , in combination with real - time cgm data .
the prescribed device was the only real - time cgm system available at the danish market during study preparation .
the prevalence of large - for - gestational - age infants [ i.e. , infant birth weight 90th centile adjusted for sex and gestational age ( 31 ) ] was predefined as the primary outcome of this study . to reflect neonatal morbidity ,
the prevalence of preterm delivery ( < 37 weeks of gestation ) and/or severe neonatal hypoglycemia ( 2-h plasma glucose < 2.5 mmol / l treated with intravenous glucose infusion ) was selected as the secondary combined end point prior to study onset .
other pregnancy outcomes were defined as follows : miscarriage ( before 22 weeks ) , preeclampsia [ blood pressure 140/90 and proteinuria ( 29 ) ] , birth weight sd score ( z - score ) , neonatal hypoglycemia ( 2-h plasma glucose < 2.5
mmol / l ) , and major congenital malformation ( i.e. , abnormality requiring surgery and/or resulting in permanent injury ) .
based on the assumption that the prevalence of large - for - gestational - age infants was 50% in our study population ( 7 ) and that the use of real - time cgm could reduce it to 20% , and a type 1 error of 5% and a type 2 error of 20% , the number of patients needed in each arm was 45 .
we intended to analyze predefined primary and secondary outcome parameters of women receiving intervention versus control subjects in the entire study population , as well as in the subpopulation of women with type 1 diabetes .
the study population of 154 women ( of whom 123 had type 1 diabetes ) was therefore judged to have sufficient power to detect a possible effect of real - time cgm on the prevalence of large - for - gestational - age infants in the entire study population , as well as in women with type 1 diabetes alone .
we compared the characteristics of the women using the fisher exact test or  test when appropriate for categorical variables and t test or mann  whitney test when appropriate for continuous variables .
continuous variables were given as median ( range ) , and categorical variables were given as numbers ( percentage ) .
analyses were done on an intention - to - treat basis , counting 154 subjects at baseline , and thereafter with the exclusion of women with miscarriages ( n = 5 ) .
we primarily analyzed data as planned by comparing women allocated to real - time cgm with control subjects in the entire study population and in women with type 1 diabetes alone .
we also analyzed the prevalence of severe hypoglycemia and main outcome parameters in women using real - time cgm per protocol , and despite limited numbers , we analyzed glycemic control and pregnancy outcomes in women with type 2 diabetes and the prevalence of large - for - gestational - age infants in women with type 1 diabetes on insulin pump therapy .
six infants were excluded from calculations on neonatal hypoglycemia because of intravenous glucose infusion prior to routine 2-h plasma glucose measurements ( n = 5 ) or perinatal death ( n = 1 ) ( fig . 1 , table 3 , and supplementary table 3 ) .
glucose data in table 2 and supplementary table 1 were based on 25,546 self - monitored plasma glucose values , and glucose fractions ( % ) have been calculated for each individual participant after sorting glucose values into intervals ( 3.9 , 4.07.9 , and 8.0 mmol / l ) .
statistical analyses were performed using stata 11.1 se software ( stata corp . , college station , tx ) .
during the period of 15 february 2009 to 15 february 2011 , 123 women with type 1 diabetes and 31 with type 2 diabetes , with a median age of 32 ( range 1943 ) years , baseline hba1c of 6.7% ( 5.310.7 ) ( 50 [ 3493 ] mmol / mol ) , pregestational bmi of 25.0 ( 18.452.7 ) kg / m , and diabetes duration of 11 ( 138 ) years , were included in the trial .
baseline data were comparable between women randomized to real - time cgm ( n = 79 ) and control subjects ( n = 75 ) , both in the entire population ( table 1 ) , and when stratified according to type of diabetes ( data not shown ) .
eligible women unwilling to participate ( n = 47 ) were similar to included women with respect to type of diabetes , age , pregestational bmi , baseline hba1c , and parity , but had slightly shorter duration of diabetes ( data not shown ) .
the included women were seen in our clinic at all five study visits at 8 ( 513 ) , 12 ( 1114 ) , 21 ( 1925 ) , 27 ( 2129 ) , and 33 ( 3235 ) weeks .
self - monitored plasma glucose measurements were documented seven times daily in relation to all study visits in both arms ( table 1 for baseline data ) .
real - time cgm was initiated at first pregnancy visit in all 79 women allocated to intervention and was generally well tolerated without severe side effects .
forty - nine ( 64% ) women with either type 1 or type 2 diabetes used real - time cgm per protocol ( i.e. , at 8 , 12 , 21 , 27 , and 33 weeks or more ) . near - continuous real - time cgm use ( at least 60% of the time ) was only chosen by five ( 7% ) women .
baseline clinical data in 154 included pregnant women with pregestational diabetes hba1c , self - monitored plasma glucose values , and plasma glucose profiles of biochemical hypo- or hyperglycemia were similar throughout pregnancy in women using real - time cgm versus control subjects for the entire study population ( table 2 ) , and for the subpopulation of women with type 1 diabetes alone ( supplementary table 1 ) .
the women experienced 4 ( 014 ) mild hypoglycemic events per week , with no difference between the arms .
the percentage of women experiencing severe hypoglycemia at least once after inclusion was also similar ( 16 vs. 16% ; p = 0.91 ) .
of 38 ( 63% ) women with type 1 diabetes using real - time cgm per protocol , 4 ( 11% ) experienced severe hypoglycemia during the intervention period compared with 11 ( 19% ) among 59 control subjects ( p = 0.28 ) .
nineteen ( 16% ) women with type 1 diabetes experienced 59 severe hypoglycemic events , and 5 ( 17% ) women with type 2 diabetes experienced 15 severe hypoglycemic events during study participation , with no difference between the arms ( data not shown ) .
five women in the intervention arm experienced in total seven episodes of severe hypoglycemia despite ongoing and technically successful real - time cgm .
insulin dosages were similar between women in the intervention versus control arm , both as absolute values and as percentages of pregestational dose at all study visits ( table 1 for baseline data and supplementary table 2 for the entire pregnancy according to type diabetes ) .
glycemic control during pregnancy in 149 women with live births the 154 pregnancies resulted in five miscarriages and 149 live births .
the predefined primary outcome , large - for - gestational - age infants , occurred to a similar extent in both arms ( 45 vs. 34% ; p = 0.19 ) , and no difference was found between the predefined secondary outcome : the prevalence of preterm delivery and/or severe neonatal hypoglycemia ( 29 vs. 22% ; p = 0.36 ) ( table 3 ) .
other maternal and perinatal parameters were also comparable between the arms . even in the subpopulation of women with type 1 diabetes ,
similar results were found regardless of real - time cgm allocation ( supplementary table 3 ) .
maternal and perinatal outcomes in 154 included women with pregestational diabetes for 49 ( 64% ) women with either type 1 or type 2 diabetes using real - time cgm per protocol , the figures for large - for - gestational - age infants and preterm delivery and/or severe neonatal hypoglycemia compared with control subjects ( n = 73 ) were 49 versus 34% ( p = 0.10 ) and 24 versus 22% ( p = 0.75 ) , respectively . for women with type 1 diabetes on insulin pumps ( n = 26 ) , the prevalence of large - for - gestational - age infants was 55 versus 20% ( p = 0.10 ) between the real - time cgm and control arms .
major congenital malformations occurred in two infants of women with type 1 diabetes ( one ventricular septal defect combined with coarctation of the aorta and one congenitally corrected transposition of the great arteries ) .
one case of perinatal death occurred shortly after delivery in an infant of a woman with type 2 diabetes due to severe shoulder dystocia .
hba1c , self - monitored plasma glucose values , and plasma glucose profiles of biochemical hypo- or hyperglycemia were similar throughout pregnancy in women using real - time cgm versus control subjects for the entire study population ( table 2 ) , and for the subpopulation of women with type 1 diabetes alone ( supplementary table 1 ) .
the women experienced 4 ( 014 ) mild hypoglycemic events per week , with no difference between the arms .
the percentage of women experiencing severe hypoglycemia at least once after inclusion was also similar ( 16 vs. 16% ; p = 0.91 ) .
of 38 ( 63% ) women with type 1 diabetes using real - time cgm per protocol , 4 ( 11% ) experienced severe hypoglycemia during the intervention period compared with 11 ( 19% ) among 59 control subjects ( p = 0.28 ) .
nineteen ( 16% ) women with type 1 diabetes experienced 59 severe hypoglycemic events , and 5 ( 17% ) women with type 2 diabetes experienced 15 severe hypoglycemic events during study participation , with no difference between the arms ( data not shown ) .
five women in the intervention arm experienced in total seven episodes of severe hypoglycemia despite ongoing and technically successful real - time cgm .
insulin dosages were similar between women in the intervention versus control arm , both as absolute values and as percentages of pregestational dose at all study visits ( table 1 for baseline data and supplementary table 2 for the entire pregnancy according to type diabetes ) .
the predefined primary outcome , large - for - gestational - age infants , occurred to a similar extent in both arms ( 45 vs. 34% ; p = 0.19 ) , and no difference was found between the predefined secondary outcome : the prevalence of preterm delivery and/or severe neonatal hypoglycemia ( 29 vs. 22% ; p = 0.36 ) ( table 3 ) .
other maternal and perinatal parameters were also comparable between the arms . even in the subpopulation of women with type 1 diabetes ,
similar results were found regardless of real - time cgm allocation ( supplementary table 3 ) .
maternal and perinatal outcomes in 154 included women with pregestational diabetes for 49 ( 64% ) women with either type 1 or type 2 diabetes using real - time cgm per protocol , the figures for large - for - gestational - age infants and preterm delivery and/or severe neonatal hypoglycemia compared with control subjects ( n = 73 ) were 49 versus 34% ( p = 0.10 ) and 24 versus 22% ( p = 0.75 ) , respectively . for women with type 1 diabetes on insulin pumps ( n = 26 ) , the prevalence of large - for - gestational - age infants was 55 versus 20% ( p = 0.10 ) between the real - time cgm and control arms .
major congenital malformations occurred in two infants of women with type 1 diabetes ( one ventricular septal defect combined with coarctation of the aorta and one congenitally corrected transposition of the great arteries ) .
one case of perinatal death occurred shortly after delivery in an infant of a woman with type 2 diabetes due to severe shoulder dystocia .
in this randomized trial , intermittent use of real - time cgm in pregnancy , in addition to self - monitored plasma glucose measurements seven times daily , did not improve glycemic control or pregnancy outcome in women with pregestational diabetes .
these findings are disappointing in the light of real - time cgm efficiency in nonpregnant patients ( 16 ) .
however , participants in trials demonstrating an effect on hba1c in both nonpregnant ( 8,11,12,1719 ) and pregnant ( 27 ) populations had higher baseline hba1c compared our cohort of women .
the negative findings of this trial are in line with a study on well - controlled nonpregnant patients , in whom hba1c was not further improved by real - time cgm ( 9 ) .
recent data indicate the importance of frequent real - time cgm use ( 16 ) .
our study was designed with intermittent real - time cgm use in relation to five routine antenatal visits at our clinic , but the women were encouraged to use real - time cgm continuously and offered much support and flexibility in scheduling to attain frequent real - time cgm use . still , only very few women were willing to use real - time cgm continuously .
our aim was to improve our routine pregnancy care and therefore to intervene on an unselected cohort of women .
( 27 ) , whereas studies on nonpregnant patients with improved hba1c due to real - time cgm mainly cover selected and highly motivated patients , willing to use real - time cgm continuously ( 10,12,1719 ) . in this trial
, sufficient numbers of women were included , and proper allocation with equal distribution of women with type 1 diabetes was secured with computer - generated randomization provided by an independent organization .
study arms were comparable at baseline , both in the entire cohort and when analyzed according to type diabetes .
we believe that our study design was robust , despite it not being blinded , and broadly comparable to that of murphy et al .
real - time cgm had been used for several years in our clinic , and we have previously published case reports suggesting beneficial effects of real - time cgm in pregnancy ( 24,26 ) .
therefore , we had expected high compliance to real - time cgm in this trial .
however , the relatively low number of per - protocol users has also been observed in the nonpregnant population ( 17,18 ) , and the average use of cgm was comparable to the former study on pregnant women ( 27 ) .
we have previously published the results of a questionnaire on patient satisfaction with real - time cgm in early pregnancy based on the present population of women ( 25 ) .
this survey demonstrated that real - time cgm inaccuracy compared with self - monitored plasma glucose values , technical challenges , and skin irritation limit compliance ( 25 ) , which is in line with previous studies of nonpregnant ( 12,3235 ) and pregnant ( 27 ) patients . during the first period of real - time cgm , our women experienced up to 12 alarms per 24 h ,
future development of the real - time cgm systems , leading to improved accuracy in the hypoglycemic range and fewer alarms , may improve compliance .
the main barrier in obtaining strict maternal glycemic control is the high risk of severe hypoglycemia , occurring in up to 45% of pregnant women with type 1 diabetes ( 7 ) .
a reduction of severe hypoglycemic events due to real - time cgm has been suggested in a study of nonpregnant patients ( 11 ) and in our case study of pregnant women with hypoglycemia unawareness ( 26 ) .
therefore , elimination of nocturnal hypoglycemic episodes was emphasized in our guidelines on the interpretation of real - time cgm readings in pregnancy .
this may have lead to slightly higher nocturnal glucose levels and could at least partly explain the tendency toward higher birth weight z - score in the intervention arm .
the self - monitored plasma glucose levels , which were mainly performed during daytime , and the number of women experiencing at least one severe hypoglycemic event after inclusion were similar in spite of real - time cgm allocation .
however , among women with type 1 diabetes using real - time cgm per protocol , there was a tendency toward fewer women with severe hypoglycemia compared with women in the control arm , but numbers were low .
surprisingly , we could document severe hypoglycemic events during ongoing real - time cgm without hypoglycemic alarms to warn the patient .
this again calls for improved real - time cgm accuracy in the hypoglycemic range and future studies on continuous real - time cgm in pregnant women at high risk of severe hypoglycemia . whether a sum of imbalances including tendencies toward higher pregestational bmi , fewer smokers , and higher weight gain in pregnancy in women in the intervention arm could have
the majority of the women with type 1 diabetes in this trial were on basal bolus therapy with multiple daily injections , but patients on insulin pumps may benefit more from real - time cgm ( 18 ) .
however , not even in the subset of women treated with insulin pumps in this study was a tendency toward a beneficial effect on large - for - gestational - age infants seen . in conclusion , our data do not support intermittent real - time cgm on a routine basis in an unselected pregnant population of women with pregestational diabetes , already performing self - monitored plasma glucose measurements seven times per day .
careful introduction to real - time cgm and interpretation of the real - time cgm readings were offered , but otherwise , the two arms were treated similarly regarding diet , exercise , and insulin therapy .
the negative finding of this trial may lead to intensified focus on dietary advice , including carbohydrate counting , stable day - to - day carbohydrate intake , especially in late gestation ( 36 ) , and weight gain within the institute of medicine recommendations ( 37 ) .
this trial does not rule out that real - time cgm may be efficient in highly selected pregnant women , and whether introducing continuous real - time cgm prior to pregnancy can reduce the risk of severe hypoglycemia and enhance pregnancy outcome is yet to be examined .
 objectiveto assess whether intermittent real - time continuous glucose monitoring ( cgm ) improves glycemic control and pregnancy outcome in unselected women with pregestational diabetes.research design and methodsa total of 123 women with type 1 diabetes and 31 women with type 2 diabetes were randomized to use real - time cgm for 6 days at 8 , 12 , 21 , 27 , and 33 weeks in addition to routine care , including self - monitored plasma glucose seven times daily , or routine care only . 
 to optimize glycemic control , real - time cgm readings were evaluated by a diabetes caregiver . 
 hba1c , self - monitored plasma glucose , severe hypoglycemia , and pregnancy outcomes were recorded , with large - for - gestational - age infants as the primary outcome.resultswomen assigned to real - time cgm ( n = 79 ) had baseline hba1c similar to that of women in the control arm ( n = 75 ) ( median 6.6 [ range 5.310.0 ] vs. 6.8% [ 5.310.7 ] ; p = 0.67 ) ( 49 [ 3486 ] vs. 51 mmol / mol [ 3493 ] ) . 
 forty - nine ( 64% ) women used real - time cgm per protocol . at 33 weeks , hba1c ( 6.1 [ 5.17.8 ] vs. 6.1% [ 4.88.2 ] ; p = 0.39 ) ( 43 [ 3262 ] vs. 43 mmol / mol [ 2966 ] ) and self - monitored plasma glucose ( 6.2 [ 4.77.9 ] vs. 6.2 
 mmol / l [ 4.97.9 ] ; p = 0.64 ) were comparable regardless of real - time cgm use , and a similar fraction of women had experienced severe hypoglycemia ( 16 vs. 16% ; p = 0.91 ) . 
 the prevalence of large - for - gestational - age infants ( 45 vs. 34% ; p = 0.19 ) and other perinatal outcomes were comparable between the arms.conclusionsin this randomized trial , intermittent use of real - time cgm in pregnancy , in addition to self - monitored plasma glucose seven times daily , did not improve glycemic control or pregnancy outcome in women with pregestational diabetes . 
RESEARCH DESIGN AND METHODS
Patients
Management of diabetes in pregnancy
Other medications
Randomization
Intervention
Pregnancy outcome parameters
Sample size
Statistical analysis
RESULTS
Glycemic control
Pregnancy complications and outcome
CONCLUSIONS