Volume 68, Number 11 OBSTETRICAL AND GYNECOLOGICAL SURVEY Copyright * 2013 by Lippincott Williams & Wilkins
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CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA PRA Category 1 Creditsi can be earned in 2013. Instructions for how CME credits can be earned appear on the last page of the Table of Contents.
The Efficacy and Effectiveness of Continuous Glucose Monitoring During Pregnancy: A Systematic Review Daphne N. Voormolen, MD,* J. Hans DeVries, MD,† Inge M. Evers, MD,‡ Ben W. J. Mol,§ and Arie Franx|| *Doctor, Department of Obstetrics and Gynaecology, University Medical Centre Utrecht, Heidelberglaan, Utrecht, the Netherlands; †Doctor, Department of Internal Medicine/Endocrinology, Academic Medical Centre Amsterdam, Amsterdam-Zuidoost, the Netherlands; ‡Doctor, Department of Obstetrics and Gynaecology, Meander Medical Centre Amersfoort, Amersfoort, the Netherlands; §Professor, Department of Obstetrics and Gynaecology, Academic Medical Centre Amsterdam, Amsterdam-Zuidoost, the Netherlands; ||Professor, Obstetrics and Gynaecology, University Medical Centre Utrecht, Heidelberglaan, Utrecht, the Netherlands Objective: Diabetic pregnancies carry a high risk for both mother and child, especially when glycemic control is poor. A novel technique that aims to improve glycemic control is the continuous glucose monitor (CGM). This tool is already in use to improve pregnancy outcome. This review presents the available evidence on the efficacy of CGM use in pregnancy and the effectiveness on pregnancy outcome. Methods: A systematic search was conducted using PubMed, EMBASE, and the Cochrane Libraries for articles on CGM in pregnancy. We evaluated the selected articles with particular attention for clinical and costeffectiveness of CGM to improve pregnancy outcome. Results: We retrieved 5032 articles, 11 of which remained as relevant after selection according to predefined criteria. Most studies were limited to the evaluation of the role of CGM on clinical decision making. Only 2 studies were randomized controlled trials (RCTs) evaluating the effect on pregnancy outcome. One small RCT on retrospective CGM showed a significant reduction in third-trimester HbA1c and a significant reduction in neonatal macrosomia. A second RCT on real-time CGM did not show any effect on either glycemic control or on pregnancy outcome. Conclusions: Current evidence on the efficacy of CGM on improving glycemic control during pregnancy as well as on the effectiveness on pregnancy outcome is limited to 2 RCTs with contradicting results. Evidence on the cost-effectiveness is lacking. Further proper RCTs on the effectiveness and cost-effectiveness of CGM in pregnancy are required before wide implementation in practice. Target Audience: Obstetricians and gynecologists, family physicians and internists Learning Objectives: After completing this CME activity, physicians should be better able to compare the results of the 2 major trials on the efficacy and effectiveness of the continuous glucose monitoring system (CGM) in treating pregnant women with diabetes and evaluate the evidence on the cost-effectiveness of CGMS use in pregnant women with diabetes.
Because maternal diabetes mellitus (DM) is no longer regarded as a contraindication for pregnancy, obstetricians, neonatologists, and physicians have dealt All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Correspondence requests to: Daphne N. Voormolen, MD, UMC Utrecht, the Netherlands. E-mail: [email protected].
with its considerable impact on maternal and perinatal outcomes. Many obstetric morbidities, such as congenital malformations, stillbirths, or macrosomia, are related to poor glycemic control.1Y3 Fortunately, improvements in the management of diabetes, such as strict glycemic control preconceptionally, have improved maternal and fetal perspectives.1,4,5 This led the World Health Organization Europe and the International Diabetes Federation Europe to set common goals in the
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Saint Vincent Declaration in 1989, aiming at pregnancy outcomes in diabetic women equaling those of healthy women.6 Unfortunately and despite much effort, diabetic pregnancies are still at increased risk of complications.1Y3 A nationwide study in the Netherlands showed a high number of complications despite good glycemic control as reflected by HbA1c values of 7% or less. Rates of preeclampsia (13%), preterm delivery (32%), cesarean delivery (44%), congenital malformations (9%), and macrosomia (45%) greatly exceeded rates in the healthy population.1 Further improvement is urgently required, especially considering the worldwide rising incidence of type 2 DM and gestational DM (GDM).7 New techniques quickly gain ground within diabetes care, especially the continuous glucose monitor (CGM). The CGM consists of a subcutaneously placed sensor that measures interstitial fluid glucose levels through electrochemical detection by use of the catalyst glucose oxidase. Every 10 seconds, a glucose value is measured, of which an average value is stored every 5 minutes by the adjacent monitor. In case of the real-time (RT) CGM, the sensor is connected to a transmitter that sends glucose measurements to a monitor on which the values are displayed every 5 minutes and alarms can be set. The CGM provides detailed information on daily glucose fluctuations. Initially, the CGM was retrospective, and data evaluation occurred after the period the CGM was carried. Real-time CGM was introduced quickly thereafter, as a next step to the artificial pancreas, which can be considered the ultimate aim. Sensors must be replaced every 3 to 7 days, depending on the product company, with costs varying between $35 and $100 per sensor. The retrospective monitor has a lifetime of approximately 12 to 18 months, depending on frequency of usage, and costs about $1300. Prices of the RT-CGM equipment (monitor and transmitter) range between $999 and $1339 and must be replaced every 9 to 12 months. In addition to technology, expenses are made for training, education, and intensive guidance by specialized medical staff. Several clinical studies on the
effectiveness of CGM in nonpregnant populations have been done with different results.8 The majority of studies focused on the effect of CGM on biochemical end points such as HbA1c, rather than on clinical end points. But solely monitoring an event does not lead to improved outcome. Benefits that justify CGM use during pregnancy would be reduction of potentially dangerous severe hypoglycemia and reduction of pregnancy complications such as macrosomia. Continuous glucose monitor is an expensive and laborious tool whose clinical implementation should be supported by scientific evidence. In this review, the available scientific evidence on the efficacy (improvement of glycemic control) and on the effectiveness (reducing pregnancy complications) of CGM use during diabetic pregnancy is systematically evaluated and summarized. METHODS Systematic Search A computer-aided search was performed of PubMed, EMBASE, and the Cochrane Libraries using the terms continuous glucose monitoring on February 1, 2013. The syntax is shown in detail in Table 1. A broad search was initially done addressing exclusively the determinant CGM, after which it was narrowed down to the exact domain of pregnancy-related publications on CGM. Subsequently, a hand search of references and related articles was conducted. Article Selection Articles were selected based on a priori formulated inclusion and exclusion criteria. Included were original articles published in peer-reviewed journals and discussing either retrospective or RT-CGM. Furthermore, the study population should comprise pregnant women with either preexisting DM or GDM. Only studies exploring the utility or efficacy of CGM use in pregnancy were included. Of these studies, the
TABLE 1 Search Syntax (Conducted January 2, 2013) Library PubMed
EMBASE (without MEDLINE)
Cochrane (Cochrane reviews and trials)
Syntax
Hits
(Continuous[title/abstract] OR continuously [title/abstract] OR continually [title/abstract] OR continual [title/abstract]) AND (glucose[title/abstract]) AND (monitor* [title/abstract] OR sensor* [title/abstract]) OR (cgm [title/abstract] OR cgms [title/abstract]) (Continuous:ab,ti OR continuously:ab,ti OR continually:ab,ti OR continual:ab,ti) AND (glucose:ab,ti) AND (monitor*:ab,ti OR sensor*:ab,ti) OR (cgm:ab,ti OR cgms:ab,ti) Continuous glucose monitor (title, abstract, keywords)
3420
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FIG. 1. Flow chart.
ones addressing the effect of CGM on glycemic control and on pregnancy outcome were considered of most significance. RESULTS Systematic Search Results of the search are shown in a flowchart (Fig. 1). The search of the 3 search engines combined generated 7657 articles. After filtering doubles, a total of 5032 articles remained to be screened for selection. Article Selection After screening titles and abstracts, 43 articles were potentially relevant, and therefore the full texts were assessed. Seventeen articles were excluded because they describe glycemic profiles as collected from CGM under varying conditions, without addressing CGM efficacy or effectiveness.9Y24 Four articles studied CGM within the context of closed loop during pregnancy, reporting safety and algorithms.25Y28 Another
3 articles were excluded that correlated CGM measurements with fetal growth.29Y31 In 1 article, CGM was used to estimate maternal and fetal risk, whereas others presented descriptive CGM data in cases of congenital malformation, polyhydramnios, or macrosomia.32Y35 Furthermore, a study on the use of CGM to diagnose GDM was eliminated.36 Also, 1 article was excluded because of the fact it comprised a study population that had already been reported on in a previous publication.37 Finally, 2 articles on the validation and accuracy of CGM in pregnancy were excluded.38,39 Two articles were selected from screening references. Both were excluded because one appeared to be a case report,40 and the other was a review article.41 Finally, 11 articles were included in this review. Articles Characteristics of the 11 studies are shown in Table 2. All 11 studies were relatively small. They included a total of 539 women, and the largest study included 154 patients.42 Seven studies used retrospective CGM,
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TABLE 2 Characteristics of Included Studies Year
Author
Design
2008
43
Murphy et al
Prospective RCT
2012
Secher et al44
Prospective RCT
2011 2003
Petrovski et al45 Chen et al46
2003
Yogev et al47
2003
Yogev et al48
2007
McLachlan et al49
2004
Kerssen et al50
2009
Ghio et al51
Prospective RCT Prospective observational study Prospective observational study Prospective Observational study Prospective observational study
Prospective observational study Prospective observational study
2008
Iafusco et al52
Prospective observational study
2007
Kestila et al53
RCT
Diabetes (n)
CGM
DM 1 (46)
Retrospective
CGM Use
GA
5Y7 d every 4Y6 wk (mean no. periods 4.2)
8Y32
6 d every 4Y9 wk
8Y33
DM 2 (25) DM 1 (123) DM 2 (31) DM 1 (25) GDM (57)
Real time Retrospective
24 h/d or every other week Single period of 72 h
DM (6)
Retrospective
72 h and another 72 h after 2Y4 wk
24Y32
GDM (2) DM 1 (34)
Retrospective
72 consecutive h
16Y32
DM 1 (8)
Retrospective
Single period of 72 h
10Y34
DM 2 (10) GDM (37) DM 1 (31)
Retrospective
48 h
Real time
DM 1 (8)
Real time
DM 2 (2) GDM (3) DM 1 (18)
4 Retrospective
14 Real time GDM (73)
Retrospective
? to birth 24Y36
9Y38
24 h before delivery
36 T 1
72 h during betamethasone treatment and during delivery
30Y32
Single period of 47.4 T 2.5 h
22Y34
GA indicates gestational age at which CGM was used.
whereas the more recent studies used RT-CGM. Results of all studies are summarized in Table 3. Two randomized controlled trials (RCTs) were conducted to evaluate the efficacy and effectiveness of CGM during pregnancy. Murphy et al43 randomly allocated pregnant women with DM type 1 or 2 to either standard antenatal care with self-monitoring of blood glucose (SMBG) (n = 33) or to standard antenatal care with additional CGM use (n = 38). Most of the patients administered insulin by multiple daily injections and a minority by means of insulin pump therapy (numbers not provided). Retrospective CGM was planned every 4 to 6 weeks for a period of 5 to 7 consecutive days and was executed on average 4.2 times per pregnancy. Lower HbA1c values were seen throughout the first and second trimester in the CGM group, but this difference did not reach statistical significance until at 32 to 36 weeks of gestation when the mean HbA1c level in the CGM group was 5.8% (SD, 0.6%) and 6.4% (SD, 0.7%) in the control group (P = 0.007). The incidence of macrosomia (defined as birth weight Q90th centile) was significantly lower in the CGM group: 35% opposed to 60% in the control group. The odds ratio for reduced macrosomia was 0.36 (95%
confidence interval, 0.13-0.98; P = 0.05). Comparison of other outcomes such as mode of delivery and neonatal morbidity was not significantly different. It must be noted that the intervention group included 3 twin pregnancies. After exclusion of these twins, however, the difference in birth weight centiles remained significant (P = 0.04). The intervention arm also included 4 children with birth weights under the 10th centile, whereas there were none in the control group (P = 0.1). Logically, this affected the mean birth weight of the intervention group for the better, although a birth weight below the 10th centile must be considered an unwanted result. A high-quality RCT by Secher et al44 randomized women with either type 1 or 2 DM and a singleton pregnancy for the additional use of RT-CGM (n = 79) or standard antenatal care (n = 75). The CGM was intermittently planned at 8, 12, 21, 27, and 33 weeks of gestation and was executed at least 3 times by 75% of the women. At baseline, HbA1c values were similar and remained so at 33 gestational weeks with HbA1c in the CGM group of 43 mmol/mol (32-62 mmol/mol) versus 43 mmol/mol (29-66 mmol/mol) in the control group (P = 0.40). Percentages of women experiencing
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TABLE 3 Results of Included Studies Article
Efficacy
Murphy et al43
- No statistical difference between HbA1c levels during first and second trimester - At 32Y36 wk of gestation HbA1c level in CGM group was 5.8% vs 6.4% in the control arm (P = 0.007)
Secher et al44
- No difference in HbA1c at 33 gestational wk: 43 mmol/mol with CGM vs 43 in control arm (P = 0.40) - No difference in severe hypoglycemia 16% with CGM vs 16% in controls (P = 0.91) - Lower HbA1c value in constant CGMS in first trimester 6.82% vs 6.52% with intermittent CGM (P G 0.05) - Comparable HbA1c levels in further pregnancy - 39 Unknown nocturnal hypoglycemic eventsVmean total time of undetected hyperglycemia 132 T 31 min/d (insulin group) and 94 T 23 min/d (diet group) - Mean total time of undetected hyperglycemia 152 (T33) vs 89 (T17) during second registration (P G 0.03) - No significant difference in HbA1c level, fructosamine level, and the occurrence of hypoglycemia after treatment adjustment - All patients had undetected hyperglycemia (mean, 192 T 28 min/d)
Petrovski et al45
Chen et al46
Yogev et al47
Yogev et al48
Effectiveness
Other Outcome
- Mean birth weight centile 69 in CGM group vs 93 (P = 0.02) - Macrosomia 35% vs 60% in controls (P = 0.05)
- Odds risk for reduced macrosomia 0.36 (95% confidence interval, 0.13-0.98; P = 0.05) - No statistical difference in macrosomia: 43% with CGM vs 30% in controls (P = 0.09) - Comparable maternal and fetal outcome (preeclampsia, cesarean delivery, neonatal hypoglycemia) No significant difference in macrosomia: 8.6% in the constant CGM group vs 9.8% in the intermittent group (NS)
Treatment adjusted in 46 of 57 patients based on additional CGM data
Insulin regimen changed in 8 of 8 patients based on additional CGM data
In 24 of 34 patients (70%), the insulin regimen based on SMBG was altered based on additional CGM data
- 58 Nocturnal hypoglycemic events were detected (1Y4 h before symptoms or detection by SMBG) McLachlan et al49
42/68 (62%) of the CGM measurements provided additional information. The reports were most helpful in cases with DM type 1 37/48 Patients felt the benefits outweighed the inconvenience
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TABLE 3 (Continued) Article Kerssen et al
Efficacy
Effectiveness
50
Ghio et al51
Iafusco et al52
Kestila et al53
Other Outcome Difference in treatment adjustments based on 2 CGM days ranged from 29%Y48%. It was significantly higher in the high day-to-day variability group, 48 vs 33% (P = 0.01)
Neonatal hypoglycemia occurred in 2 cases. Neonatal plasma glucose values at 60 min after birth were inversely related to maternal blood sugar levels at 24, 8, and 1 h before delivery and at birth time. After multivariate analyses, maternal blood sugar level at time of birth solely remained independently related to neonatal hypoglycemia - No newborns developed respiratory distress syndrome - No hypoglycemic episodes were recorded during the first 72 h after birth No significant difference in perinatal outcome
severe hypoglycemia were similar in both groups (13 vs 16%, P = 0.55). As for pregnancy outcomes, no significant differences were found either. The predefined primary outcome was prevalence of macrosomia (defined as birth weight Q90th centile), for which the study was powered. The rate of macrosomia was 43% in the CGM group as opposed to 30% in the control group (P = 0.09). Other maternal and fetal outcome measures were similar too for both groups (eg, preeclampsia, cesarean delivery, preterm delivery, and neonatal hypoglycemia). The prevalence of macrosomia for DM type 1 patients on insulin pump therapy (n = 26) was 55% in the controls and 20% in the RT-CGM group (P = 0.10). Comprehensive details on study design and methods are provided in the article; this contributes to the high quality of the trial. In summary, both RCTs provide conflicting results on the efficacy and effectiveness of CGM use during pregnancy. Difference in efficacy and effectiveness of CGM used intermittently or continuously was investigated in a prospective RCT by Petrovski et al.45 Twenty-five pregnant women with type 1 DM on insulin pump
11 of 36 patients with CGM received antidiabetic treatment vs 3 of 37 controls (P = 0.0149)
therapy were randomized to either continuous CGM use (24 h/d) or intermittent use (24 h every other day). A significant difference was found in HbA1c in the first trimester in the advantage of the continuous group, 6.52 T 1.3 opposed by 6.82 T 0.7 (P G 0.05). This was not observed in the other trimesters. Furthermore, the occurrence of severe hypoglycemic events and diabetic ketoacidosis differed significantly, despite very low numbers: 1 severe hypoglycemic event in the continuous CGM group and 2 events in the intermittent group (P G 0.05), of which one occurred when CGM was not used. No significant difference was found in perinatal outcome. It must be noted that the authors found no incidents of neonatal hypoglycemia and 8.6% macrosomia in the continuous group and 9.8% in the intermittent group. These numbers are much lower than generally observed in a diabetic population. This may have been due to the definition of macrosomia as birth weight greater than 4000 kg instead of a centile adjusted for gestational age. Five studies investigated the effect of CGM use during pregnancy on clinical decision making. They collected data from both the CGM and SMBG of their
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subjects. Difference in treatment strategy based on either one of these techniques was investigated. Chen et al46 studied the additional information CGM offers compared with SMBG in 57 GDM patients and the effect on decision making. Data of both strategies were collected and evaluated for every patient, and consequent treatment decisions were based on both methods separately. In 46 (81%) of the 57 cases, the initial therapeutic regimen based on the SBGM measurements was changed after evaluating additional CGM data. Mainly, nocturnal hypoglycemias and several hyperglycemic episodes were shown by the CGM data that were undetected by SMBG. Yogev et al47 applied a similar study protocol to 6 pregnant type 1 DM patients and 2 GDM patients. All treatments based on SMBG were altered after reevaluation with use of CGM data. Motives for change were undiagnosed nocturnal hypoglycemia or prolonged postprandial hyperglycemia, which were not detected by SMBG. After 2 to 4 weeks, the CGM was executed another 72 hours to evaluate differences after treatment adjustment. The mean total time of undetected hyperglycemia was 152 (T33) versus 89 (T17) during the second recording (P G 0.03). No significant difference was observed in HbA1c level, fructosamine level, and the occurrence of hypoglycemia. In another small study performed by Yogev et al,48 34 consecutive pregnant women with DM type 1 were prospectively included. All patients performed SMBG and received in addition a retrospective CGM during 3 days. Insulin regimen was adapted for every patient twice, by the same physician, based on data derived from SMBG and CGM separately. All patients experienced hyperglycemia undetected by SMBG with a mean of 192 T 28 min/d. Continuous glucose monitor also revealed 58 events of nocturnal hypoglycemia 1 to 4 hours before symptoms or detection by SMBG. The insulin regimen based on SMBG was changed in 24 patients (70%) upon evaluation of CGM results. McLachlan et al49 found similar results. The study population comprised DM type 1, DM type 2, and GDM patients all receiving CGM for 72 hours in addition to SMBG. Of the 68 CGM recordings, 42 affected decision making (62%), mostly due to revealed postprandial hyperglycemia. Furthermore, patient feedback on CGM use was evaluated, showing that 37 (77%) of 48 women reported that the benefits of the CGM outweighed the inconvenience. Kerssen et al50 investigated the day-to-day variability of glucose profiles for the consistency of treatment adjustments. They used 48 consecutive hours of CGM data of 31 women with diabetes type 1 throughout pregnancy. Recordings of every patient were separated
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into 2 days and shown to experts. Based on 24-hour data, treatment was adjusted when deemed necessary. Patients were classified as having high or low day-to-day variability, based on visual inspection and mean absolute difference. The difference between treatment adjustments based on both days of CGM data from each patient ranged from 29% to 48%. For the high day-to-day variability, this was significantly higher, 48 versus 33% (P = 0.01). Three studies used the RT-CGM at a specific moment in diabetic pregnancies, namely, during delivery. One may argue that strict regulation of intrapartum blood glucose values reduces the newborn’s risk of hypoglycemia. Ghio et al51 investigated the effect of RT-CGM use during labor on the rate of neonatal hypoglycemia in an uncontrolled prospective study. Thirteen women with either pregestational or gestational diabetes and undergoing an elective cesarean delivery at 36 weeks of gestation were given a CGM 24 hours before surgery. Insulin and dextrose infusions were adjusted by predefined algorithms based on the CGM measurements. In 2 cases, the neonates had hypoglycemia. Although neonatal glucose values at 60 minutes after birth were inversely related to maternal blood sugar levels at 24, 8, and 1 hour before delivery and at birth time, only the value at time of birth was independently related to neonatal hypoglycemia after multivariate analyses. Iafusco et al52 combined RT-CGM registration with intravenous infusion of insulin during 2 moments of betamethasone administration between the 30th and 32nd week of gestation and during delivery. Eighteen women with DM type 1 used CGM for 72 hours during those 2 events. It was an uncontrolled prospective study. Initially, the retrospective CGM was used; however, after 4 inclusions, the study protocol was switched to RT-CGM. They aimed for the prevention of respiratory distress and neonatal hypoglycemia. Continuous intravenous insulin infusion was managed based on CGM data, and constant glucose levels could be maintained between 100 and 150 mg/dL during betamethasone treatment and during vaginal delivery and between 80 and 100 mg/dL in case of cesarean delivery. None of the children had either respiratory distress or hypoglycemia. Although definite conclusions cannot be drawn from the 2 aforementioned studies, they indicate a potential indication for specific usage of the CGM in pregnancy. Finally, the study of Kestila et al53 was included in this review. They randomly allocated GDM patients to SMBG or CGM to evaluate the role of CGM in detecting requirement of antidiabetic treatment. There
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was a significant difference between the groups in the number of patients receiving antihyperglycemic drug therapy (P = 0.015), 11 of 36 in the CGM group opposed to 3 of 37 in the SBGM group. Retrospective evaluation showed that only 5 of the 36 patients on CGM would have met the criteria to start antidiabetic treatment based on their SBGM data, thereby missing half of the indications. No significant difference in pregnancy outcome was reported; however, the study was not powered for such evaluations. Because of the heterogeneity of the studies this review holds, meta-analysis is not useful. Only 2 RCTs are published that have fundamentally different study protocols, the most important discrepancy being that one studied retrospective CGM, whereas the other studied RT-CGM. Studies on the cost-effectiveness of using CGM in diabetic pregnancies lack entirely. DISCUSSION The modern technique of continuous glucose monitoring has gained ground quickly within obstetric diabetes care, with the aim to improve pregnancy outcome through optimizing glycemic control. However, from this review, it must be concluded that the wide introduction of CGM into the multidisciplinary care for pregnant women with diabetes lacks convincing scientific evidence. Key questions that remain to be answered are: what is the added value of CGM during pregnancy for improving glycemic control, and even more importantly, does CGM improve pregnancy outcome? In other words, what is the efficacy and the effectiveness of CGM in pregnancy? Subsequently, cost-effectiveness should be evaluated. A Cochrane review by Langendam et al8 on CGM for type 1 DM concludes that available evidence shows improvement in glycemic control, defined as a decline in HbA1c level, for adult nonpregnant patients with poorly controlled diabetes when using RT-CGM in tandem with an insulin pump. Their meta-analyses indicate that after 6 months HbA1c values of adult patients who initiated RT-CGM sensor augmented insulin pump therapy declined more than those in patients with multiple daily insulin injections and SMBG (mean difference in change, j0.7%, (95% confidence interval, j0.8% to j0.50%). The risk for hypoglycemia seems increased for CGM users. Nonpregnant women are not reported as selected subgroup. Factors related to CGM effect are the percentage of time the CGM is used and combination of CGM with insulin pump therapy, Langendam et al8 underline the potential usefulness of CGM use during pregnancy, but they conclude there is no scientific evidence to support this.
Whereas the review of Langendam et al8 focuses solely on type 1 diabetes, we evaluated literature on CGM use for all types of diabetes, including pregestational and gestational diabetes. Continuous glucose monitor accuracy assessment in pregnancy was done by Kerssen et al.39 They showed CGM to be accurate in pregnancy, although it seemed less accurate in the hypoglycemic range, as was also seen in nonpregnant diabetes patients.8 When applying the CGM strategy to an obstetric population, some aspects need to be considered. First, knowledge on physiological glycemic profiles during pregnancy is a prerequisite for recognition and adjustment of pathological profiles. During the course of pregnancy, glucose metabolism changes because of interacting placental hormones and alterations of tissue insulin sensitivity. When setting therapeutic targets, those physiological changes must be taken into account. Hewapathirana et al54 reviewed 7 articles (including 7Y57 patients) presenting continuous glucose profiles of nondiabetic pregnancies. In summary, throughout pregnancy, fasting blood glucose levels remain unchanged; postprandial glucose rises, although the glucose range remains narrow. The glycemic target range for diabetic pregnant patients should mirror profiles of healthy pregnant women rather than healthy nonpregnant women. Although the need of meticulous fine tuning to target values can be debated, it is clear that good glycemic control during pregnancy reduces perinatal complications. Nonetheless, it is likely that complications in diabetic pregnancy can only be partially attributed to hyperglycemia per se and other metabolic determinants contribute.55 For instance, Schaefer et al56 showed that maternal levels of triglycerides and free fatty acids are significantly related to high birth weight. Also, the principle of fetal genetic imprinting (fetal gene regulation caused by excess lipid exposure through epigenetic mechanisms) suggests fundamental effects of the diabetic environment during embryo development, which is momentarily out of therapeutic reach.57 It could very well be that the maximum effect of tightening glycemic control has already been reached, and the potential role of different therapeutic targets should be explored. Possibly, the CGM intervention cannot provide additional improvement in pregnancy outcome. Furthermore, the emotional burden of CGM should be taken into account. A key element for the success of CGM is patient motivation. Pregnant women have a drive to optimize conditions for a healthy child. On the other hand, women may be overwhelmed by continuous glycemic profiles, medical information, and obstetric examination. Several trials show a noteworthy
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number of women discontinuing the study because of discontent. Discomfort of the device, requirement for confirmatory SMBG measurements, and false alarms are disadvantages of the (RT-)CGM in addition to overdose of medical information.58 Secher et al59 investigated the self-reported satisfaction and considerations to refuse CGM of 68 diabetic patients during early pregnancy. Improved understanding of their diabetes was reported by 52%. Overall, the CGM was fairly tolerated, although 36% of the patients had the CGM removed early and 10 women (15%) did not wish to use the CGM again. Underlying reasons were amongst others technical challenges, too many alarms, induced stress, or CGM inaccuracy. Continuous glucose monitor compliance was not affected by baseline characteristics such as severe hypoglycemias, preceding pregnancy, HbA1c, professional education level, or continuous subcutaneous insulin infusion treatment. Continuous glucose monitor is a treatment strategy requiring costly equipment and intensive guidance by medical and nursing staff. In the light of rising health care costs, evaluation of cost-effectiveness should be included in randomized trials. Some cost-effectiveness analyses were performed for CGM use in nonpregnant patients.58,60 Calculations were based on the effect of CGM use on future diabetic complications via reduction of HbA1c, an accepted procedure in diabetology. However, this remains a translation from an intermediate outcome; evidence for a positive effect on clinical outcome, for example, microvascular and macrovascular complications, has not yet been provided. Pregnancy is a condition of limited duration, and therefore a device should show benefit more quickly. However, the efficacy of CGM for this purpose remains to be clarified. The majority of articles published on CGM and pregnancy can be summarized as reports of first local clinical experiences. Only 2 high-quality RCTs were performed both using a different type of CGM, and these yielded conflicting results. Whether diabetic women truly benefit from CGM during pregnancy must be clarified by larger trials with subgroup analysis for different types of diabetes. Furthermore, it must be identified which patients benefit from retrospective CGM and which patients must be considered for RT-CGM use. At present, a national multicenter RCT including a cost-effectiveness analysis is being conducted in the Netherlands, evaluating the effect of additional retrospective CGM use on pregnancy outcome in 300 women with DM type 1, DM type 2G or GDM.61 In view of the lack of evidence that we demonstrated in this review, data provided by this and other comparative effectiveness studies are needed to justify the use
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and costs of CGM in the care for pregnant women with diabetes. CONCLUSIONS The existing scientific evidence on CGM efficacy and effectiveness during pregnancy as presented in this review is limited. Up to now, only 2 RCTs have been published, and these yielded contradicting results. There is an urgent need for scientific evidence to provide good patient information and to substantiate current clinical practice. REFERENCES 1. Evers IM, de Valk HW, Visser GH. Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands. BMJ. 2004;328:915. 2. Temple R, Aldridge V, Greenwood R, et al. Association between outcome of pregnancy and glycaemic control in early pregnancy in type 1 diabetes: population based study. BMJ. 2002;325:1275Y1276. 3. Lowe LP, Metzger BE, Dyer AR, et al. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: associations of maternal A1c and glucose with pregnancy outcomes. Diabetes Care. 2012;35:574Y580. 4. Loeken MR. Advances in understanding the molecular causes of diabetes-induced birth defects. J Soc Gynecol Investig. 2006; 13:2Y10. 5. Bell R, Glinianaia SV, Tennant PW, et al. Peri-conception hyperglycaemia and nephropathy are associated with risk of congenital anomaly in women with pre-existing diabetes: a population-based cohort study. Diabetologia. 2012. 6. Diabetes care and research in Europe: the Saint Vincent declaration. Diabet Med. 1990;7:360. 7. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047Y1053. 8. Langendam M, Luijf YM, Hooft L, et al. Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2012;1:CD008101. 9. Su JB, Wang XQ, Chen JF, et al. Glycemic variability in gestational diabetes mellitus and its association with beta cell function. Endocrine. 2013;43:370Y375. 10. Mazze R, Yogev Y, Langer O. Measuring glucose exposure and variability using continuous glucose monitoring in normal and abnormal glucose metabolism in pregnancy. J Matern Fetal Neonatal Med. 2012;25:1171Y1175. 11. Murphy HR, Rayman G, Duffield K, et al. Changes in the glycemic profiles of women with type 1 and type 2 diabetes during pregnancy. Diabetes Care. 2007;30:2785Y2791. 12. Cypryk K, Pertynska-Marczewska M, Szymczak W, et al. Evaluation of metabolic control in women with gestational diabetes mellitus by the continuous glucose monitoring system: a pilot study. Endocr Pract. 2006;12:245Y250. 13. Buhling KJ, Winkel T, Wolf C, et al. Optimal timing for postprandial glucose measurement in pregnant women with diabetes and a non-diabetic pregnant population evaluated by the continuous glucose monitoring system (CGMS). J Perinat Med. 2005;33: 125Y131. 14. Ben-Haroush A, Yogev Y, Chen R, et al. The postprandial glucose profile in the diabetic pregnancy. Am J Obstet Gynecol. 2004;191:576Y581. 15. Kerssen A, Evers IM, de Valk HW, et al. Poor glucose control in women with type 1 diabetes mellitus and ’safe’ hemoglobin A1c
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36. Hijazi SA, Bowker H, Issa BG. Continuous glucose monitoring as a diagnostic tool in gestational diabetes. Diabet Med. 2010;27:169Y170. 37. Petrovski G, Dimitrovski C, Adamova K, et al. Insulin pump therapy using continuous glucose monitoring improve pregnancy outcome in type 1 diabetics. Diabetes Technol Ther. 2011;13:262. 38. Kerssen A, de Valk HW, Visser GH. Validation of the continuous glucose monitoring system (CGMS) by the use of two CGMS simultaneously in pregnant women with type 1 diabetes mellitus. Diabetes Technol Ther. 2005;7:699Y706. 39. Kerssen A, de Valk HW, Visser GH. The continuous glucose monitoring system during pregnancy of women with type 1 diabetes mellitus: accuracy assessment. Diabetes Technol Ther. 2004;6:645Y651. 40. Worm D, Nielsen LR, Mathiesen ER, et al. Continuous glucose monitoring system with an alarm: a tool to reduce hypoglycemic episodes in pregnancy with diabetes. Diabetes Care. 2006;29: 2759Y2760. 41. Combs CA. Continuous glucose monitoring and insulin pump therapy for diabetes in pregnancy. J Matern Fetal Neonatal Med. 2012;25:2025Y2027. 42. Secher AL, Ringholm L, Andersen HU, et al. The effect of realtime continuous glucose monitoring in diabetic pregnancyVa randomised controlled trial. Diabetologia. 2012;55:S40. 43. Murphy HR, Rayman G, Lewis K, et al. Effectiveness of continuous glucose monitoring in pregnant women with diabetes: randomised clinical trial. BMJ. 2008;337:a1680. 44. Secher AL, Ringholm L, Andersen HU, et al. The effect of realtime continuous glucose monitoring in pregnant women with diabetes: a randomized controlled trial. Diabetes Care. 2013;36:1877Y1883. 45. Petrovski G, Dimitrovski C, Bogoev M, et al. Is there a difference in pregnancy and glycemic outcome in patients with type 1 diabetes on insulin pump with constant or intermittent glucose monitoring? A pilot study. Diabetes Technol Ther. 2011;13: 1109Y1113. 46. Chen R, Yogev Y, Ben-Haroush A, et al. Continuous glucose monitoring for the evaluation and improved control of gestational diabetes mellitus. J Matern Fetal Neonatal Med. 2003;14:256Y260. 47. Yogev Y, Ben-Haroush A, Chen R, et al. Continuous glucose monitoring for treatment adjustment in diabetic pregnanciesV a pilot study. Diabet Med. 2003;20:558Y562. 48. Yogev Y, Chen R, Ben-Haroush A, et al. Continuous glucose monitoring for the evaluation of gravid women with type 1 diabetes mellitus. Obstet Gynecol. 2003;101:633Y638. 49. McLachlan K, Jenkins A, O’Neal D. The role of continuous glucose monitoring in clinical decision-making in diabetes in pregnancy. Aust N Z J Obstet Gynaecol. 2007;47:186Y190. 50. Kerssen A, de Valk HW, Visser GH. Day-to-day glucose variability during pregnancy in women with type 1 diabetes mellitus: glucose profiles measured with the continuous glucose monitoring system. BJOG. 2004;111:919Y924. 51. Ghio A, Lencioni C, Romero F, et al. A real-time continuous glucose monitoring for diabetic women during the delivery. Diabetologia. 2009;52:S462. 52. Iafusco D, Stoppoloni F, Salvia G, et al. Use of real time continuous glucose monitoring and intravenous insulin in type 1 diabetic mothers to prevent respiratory distress and hypoglycaemia in infants. BMC Pregnancy Childbirth. 2008;8:23. 53. Kestila KK, Ekblad UU, Ronnemaa T. Continuous glucose monitoring versus self-monitoring of blood glucose in the treatment of gestational diabetes mellitus. Diabetes Res Clin Pract. 2007;77:174Y179. 54. Hewapathirana NM, O’Sullivan E, Murphy HR. Role of continuous glucose monitoring in the management of diabetic pregnancy. Curr Diab Rep. 2012;13:34Y42. 55. Herrera E, Ortega-Senovilla H. Disturbances in lipid metabolism in diabetic pregnancyVare these the cause of the problem? Best Pract Res Clin Endocrinol Metab. 2010;24:515Y525.
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Continuous Glucose Monitoring During Pregnancy 56. Schaefer-Graf UM, Graf K, Kulbacka I, et al. Maternal lipids as strong determinants of fetal environment and growth in pregnancies with gestational diabetes mellitus. Diabetes Care. 2008; 31:1858Y1863. 57. Heerwagen MJ, Miller MR, Barbour LA, et al. Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. Am J Physiol Regul Integr Comp Physiol. 2010;299: R711YR722. 58. Huang ES, O’Grady M, Basu A, et al. The cost-effectiveness of continuous glucose monitoring in type 1 diabetes. Diabetes Care. 2010;33:1269Y1274.
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59. Secher AL, Madsen AB, Ringholm L, et al. Patient satisfaction and barriers to initiating real-time continuous glucose monitoring in early pregnancy in women with diabetes. Diabet Med. 2012;29:272Y277. 60. McQueen RB, Ellis SL, Campbell JD, et al. Cost-effectiveness of continuous glucose monitoring and intensive insulin therapy for type 1 diabetes. Cost Eff Resour Alloc. 2011;9:13. 61. Voormolen DN, Devries JH, Franx A, et al. Effectiveness of continuous glucose monitoring during diabetic pregnancy (GlucoMOMS trial); a randomised controlled trial. BMC Pregnancy Childbirth. 2012;12:164.
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CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA PRA Category 1 Creditsi can be earned in 2013. Instructions for how CME credits can be earned appear on the last page of the Table of Contents.
The Efficacy and Effectiveness of Continuous Glucose Monitoring During Pregnancy: A Systematic Review Daphne N. Voormolen, MD,* J. Hans DeVries, MD,† Inge M. Evers, MD,‡ Ben W. J. Mol,§ and Arie Franx|| *Doctor, Department of Obstetrics and Gynaecology, University Medical Centre Utrecht, Heidelberglaan, Utrecht, the Netherlands; †Doctor, Department of Internal Medicine/Endocrinology, Academic Medical Centre Amsterdam, Amsterdam-Zuidoost, the Netherlands; ‡Doctor, Department of Obstetrics and Gynaecology, Meander Medical Centre Amersfoort, Amersfoort, the Netherlands; §Professor, Department of Obstetrics and Gynaecology, Academic Medical Centre Amsterdam, Amsterdam-Zuidoost, the Netherlands; ||Professor, Obstetrics and Gynaecology, University Medical Centre Utrecht, Heidelberglaan, Utrecht, the Netherlands Objective: Diabetic pregnancies carry a high risk for both mother and child, especially when glycemic control is poor. A novel technique that aims to improve glycemic control is the continuous glucose monitor (CGM). This tool is already in use to improve pregnancy outcome. This review presents the available evidence on the efficacy of CGM use in pregnancy and the effectiveness on pregnancy outcome. Methods: A systematic search was conducted using PubMed, EMBASE, and the Cochrane Libraries for articles on CGM in pregnancy. We evaluated the selected articles with particular attention for clinical and costeffectiveness of CGM to improve pregnancy outcome. Results: We retrieved 5032 articles, 11 of which remained as relevant after selection according to predefined criteria. Most studies were limited to the evaluation of the role of CGM on clinical decision making. Only 2 studies were randomized controlled trials (RCTs) evaluating the effect on pregnancy outcome. One small RCT on retrospective CGM showed a significant reduction in third-trimester HbA1c and a significant reduction in neonatal macrosomia. A second RCT on real-time CGM did not show any effect on either glycemic control or on pregnancy outcome. Conclusions: Current evidence on the efficacy of CGM on improving glycemic control during pregnancy as well as on the effectiveness on pregnancy outcome is limited to 2 RCTs with contradicting results. Evidence on the cost-effectiveness is lacking. Further proper RCTs on the effectiveness and cost-effectiveness of CGM in pregnancy are required before wide implementation in practice. Target Audience: Obstetricians and gynecologists, family physicians and internists Learning Objectives: After completing this CME activity, physicians should be better able to compare the results of the 2 major trials on the efficacy and effectiveness of the continuous glucose monitoring system (CGM) in treating pregnant women with diabetes and evaluate the evidence on the cost-effectiveness of CGMS use in pregnant women with diabetes.
Because maternal diabetes mellitus (DM) is no longer regarded as a contraindication for pregnancy, obstetricians, neonatologists, and physicians have dealt All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Correspondence requests to: Daphne N. Voormolen, MD, UMC Utrecht, the Netherlands. E-mail: [email protected].
with its considerable impact on maternal and perinatal outcomes. Many obstetric morbidities, such as congenital malformations, stillbirths, or macrosomia, are related to poor glycemic control.1Y3 Fortunately, improvements in the management of diabetes, such as strict glycemic control preconceptionally, have improved maternal and fetal perspectives.1,4,5 This led the World Health Organization Europe and the International Diabetes Federation Europe to set common goals in the
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Saint Vincent Declaration in 1989, aiming at pregnancy outcomes in diabetic women equaling those of healthy women.6 Unfortunately and despite much effort, diabetic pregnancies are still at increased risk of complications.1Y3 A nationwide study in the Netherlands showed a high number of complications despite good glycemic control as reflected by HbA1c values of 7% or less. Rates of preeclampsia (13%), preterm delivery (32%), cesarean delivery (44%), congenital malformations (9%), and macrosomia (45%) greatly exceeded rates in the healthy population.1 Further improvement is urgently required, especially considering the worldwide rising incidence of type 2 DM and gestational DM (GDM).7 New techniques quickly gain ground within diabetes care, especially the continuous glucose monitor (CGM). The CGM consists of a subcutaneously placed sensor that measures interstitial fluid glucose levels through electrochemical detection by use of the catalyst glucose oxidase. Every 10 seconds, a glucose value is measured, of which an average value is stored every 5 minutes by the adjacent monitor. In case of the real-time (RT) CGM, the sensor is connected to a transmitter that sends glucose measurements to a monitor on which the values are displayed every 5 minutes and alarms can be set. The CGM provides detailed information on daily glucose fluctuations. Initially, the CGM was retrospective, and data evaluation occurred after the period the CGM was carried. Real-time CGM was introduced quickly thereafter, as a next step to the artificial pancreas, which can be considered the ultimate aim. Sensors must be replaced every 3 to 7 days, depending on the product company, with costs varying between $35 and $100 per sensor. The retrospective monitor has a lifetime of approximately 12 to 18 months, depending on frequency of usage, and costs about $1300. Prices of the RT-CGM equipment (monitor and transmitter) range between $999 and $1339 and must be replaced every 9 to 12 months. In addition to technology, expenses are made for training, education, and intensive guidance by specialized medical staff. Several clinical studies on the
effectiveness of CGM in nonpregnant populations have been done with different results.8 The majority of studies focused on the effect of CGM on biochemical end points such as HbA1c, rather than on clinical end points. But solely monitoring an event does not lead to improved outcome. Benefits that justify CGM use during pregnancy would be reduction of potentially dangerous severe hypoglycemia and reduction of pregnancy complications such as macrosomia. Continuous glucose monitor is an expensive and laborious tool whose clinical implementation should be supported by scientific evidence. In this review, the available scientific evidence on the efficacy (improvement of glycemic control) and on the effectiveness (reducing pregnancy complications) of CGM use during diabetic pregnancy is systematically evaluated and summarized. METHODS Systematic Search A computer-aided search was performed of PubMed, EMBASE, and the Cochrane Libraries using the terms continuous glucose monitoring on February 1, 2013. The syntax is shown in detail in Table 1. A broad search was initially done addressing exclusively the determinant CGM, after which it was narrowed down to the exact domain of pregnancy-related publications on CGM. Subsequently, a hand search of references and related articles was conducted. Article Selection Articles were selected based on a priori formulated inclusion and exclusion criteria. Included were original articles published in peer-reviewed journals and discussing either retrospective or RT-CGM. Furthermore, the study population should comprise pregnant women with either preexisting DM or GDM. Only studies exploring the utility or efficacy of CGM use in pregnancy were included. Of these studies, the
TABLE 1 Search Syntax (Conducted January 2, 2013) Library PubMed
EMBASE (without MEDLINE)
Cochrane (Cochrane reviews and trials)
Syntax
Hits
(Continuous[title/abstract] OR continuously [title/abstract] OR continually [title/abstract] OR continual [title/abstract]) AND (glucose[title/abstract]) AND (monitor* [title/abstract] OR sensor* [title/abstract]) OR (cgm [title/abstract] OR cgms [title/abstract]) (Continuous:ab,ti OR continuously:ab,ti OR continually:ab,ti OR continual:ab,ti) AND (glucose:ab,ti) AND (monitor*:ab,ti OR sensor*:ab,ti) OR (cgm:ab,ti OR cgms:ab,ti) Continuous glucose monitor (title, abstract, keywords)
3420
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FIG. 1. Flow chart.
ones addressing the effect of CGM on glycemic control and on pregnancy outcome were considered of most significance. RESULTS Systematic Search Results of the search are shown in a flowchart (Fig. 1). The search of the 3 search engines combined generated 7657 articles. After filtering doubles, a total of 5032 articles remained to be screened for selection. Article Selection After screening titles and abstracts, 43 articles were potentially relevant, and therefore the full texts were assessed. Seventeen articles were excluded because they describe glycemic profiles as collected from CGM under varying conditions, without addressing CGM efficacy or effectiveness.9Y24 Four articles studied CGM within the context of closed loop during pregnancy, reporting safety and algorithms.25Y28 Another
3 articles were excluded that correlated CGM measurements with fetal growth.29Y31 In 1 article, CGM was used to estimate maternal and fetal risk, whereas others presented descriptive CGM data in cases of congenital malformation, polyhydramnios, or macrosomia.32Y35 Furthermore, a study on the use of CGM to diagnose GDM was eliminated.36 Also, 1 article was excluded because of the fact it comprised a study population that had already been reported on in a previous publication.37 Finally, 2 articles on the validation and accuracy of CGM in pregnancy were excluded.38,39 Two articles were selected from screening references. Both were excluded because one appeared to be a case report,40 and the other was a review article.41 Finally, 11 articles were included in this review. Articles Characteristics of the 11 studies are shown in Table 2. All 11 studies were relatively small. They included a total of 539 women, and the largest study included 154 patients.42 Seven studies used retrospective CGM,
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TABLE 2 Characteristics of Included Studies Year
Author
Design
2008
43
Murphy et al
Prospective RCT
2012
Secher et al44
Prospective RCT
2011 2003
Petrovski et al45 Chen et al46
2003
Yogev et al47
2003
Yogev et al48
2007
McLachlan et al49
2004
Kerssen et al50
2009
Ghio et al51
Prospective RCT Prospective observational study Prospective observational study Prospective Observational study Prospective observational study
Prospective observational study Prospective observational study
2008
Iafusco et al52
Prospective observational study
2007
Kestila et al53
RCT
Diabetes (n)
CGM
DM 1 (46)
Retrospective
CGM Use
GA
5Y7 d every 4Y6 wk (mean no. periods 4.2)
8Y32
6 d every 4Y9 wk
8Y33
DM 2 (25) DM 1 (123) DM 2 (31) DM 1 (25) GDM (57)
Real time Retrospective
24 h/d or every other week Single period of 72 h
DM (6)
Retrospective
72 h and another 72 h after 2Y4 wk
24Y32
GDM (2) DM 1 (34)
Retrospective
72 consecutive h
16Y32
DM 1 (8)
Retrospective
Single period of 72 h
10Y34
DM 2 (10) GDM (37) DM 1 (31)
Retrospective
48 h
Real time
DM 1 (8)
Real time
DM 2 (2) GDM (3) DM 1 (18)
4 Retrospective
14 Real time GDM (73)
Retrospective
? to birth 24Y36
9Y38
24 h before delivery
36 T 1
72 h during betamethasone treatment and during delivery
30Y32
Single period of 47.4 T 2.5 h
22Y34
GA indicates gestational age at which CGM was used.
whereas the more recent studies used RT-CGM. Results of all studies are summarized in Table 3. Two randomized controlled trials (RCTs) were conducted to evaluate the efficacy and effectiveness of CGM during pregnancy. Murphy et al43 randomly allocated pregnant women with DM type 1 or 2 to either standard antenatal care with self-monitoring of blood glucose (SMBG) (n = 33) or to standard antenatal care with additional CGM use (n = 38). Most of the patients administered insulin by multiple daily injections and a minority by means of insulin pump therapy (numbers not provided). Retrospective CGM was planned every 4 to 6 weeks for a period of 5 to 7 consecutive days and was executed on average 4.2 times per pregnancy. Lower HbA1c values were seen throughout the first and second trimester in the CGM group, but this difference did not reach statistical significance until at 32 to 36 weeks of gestation when the mean HbA1c level in the CGM group was 5.8% (SD, 0.6%) and 6.4% (SD, 0.7%) in the control group (P = 0.007). The incidence of macrosomia (defined as birth weight Q90th centile) was significantly lower in the CGM group: 35% opposed to 60% in the control group. The odds ratio for reduced macrosomia was 0.36 (95%
confidence interval, 0.13-0.98; P = 0.05). Comparison of other outcomes such as mode of delivery and neonatal morbidity was not significantly different. It must be noted that the intervention group included 3 twin pregnancies. After exclusion of these twins, however, the difference in birth weight centiles remained significant (P = 0.04). The intervention arm also included 4 children with birth weights under the 10th centile, whereas there were none in the control group (P = 0.1). Logically, this affected the mean birth weight of the intervention group for the better, although a birth weight below the 10th centile must be considered an unwanted result. A high-quality RCT by Secher et al44 randomized women with either type 1 or 2 DM and a singleton pregnancy for the additional use of RT-CGM (n = 79) or standard antenatal care (n = 75). The CGM was intermittently planned at 8, 12, 21, 27, and 33 weeks of gestation and was executed at least 3 times by 75% of the women. At baseline, HbA1c values were similar and remained so at 33 gestational weeks with HbA1c in the CGM group of 43 mmol/mol (32-62 mmol/mol) versus 43 mmol/mol (29-66 mmol/mol) in the control group (P = 0.40). Percentages of women experiencing
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TABLE 3 Results of Included Studies Article
Efficacy
Murphy et al43
- No statistical difference between HbA1c levels during first and second trimester - At 32Y36 wk of gestation HbA1c level in CGM group was 5.8% vs 6.4% in the control arm (P = 0.007)
Secher et al44
- No difference in HbA1c at 33 gestational wk: 43 mmol/mol with CGM vs 43 in control arm (P = 0.40) - No difference in severe hypoglycemia 16% with CGM vs 16% in controls (P = 0.91) - Lower HbA1c value in constant CGMS in first trimester 6.82% vs 6.52% with intermittent CGM (P G 0.05) - Comparable HbA1c levels in further pregnancy - 39 Unknown nocturnal hypoglycemic eventsVmean total time of undetected hyperglycemia 132 T 31 min/d (insulin group) and 94 T 23 min/d (diet group) - Mean total time of undetected hyperglycemia 152 (T33) vs 89 (T17) during second registration (P G 0.03) - No significant difference in HbA1c level, fructosamine level, and the occurrence of hypoglycemia after treatment adjustment - All patients had undetected hyperglycemia (mean, 192 T 28 min/d)
Petrovski et al45
Chen et al46
Yogev et al47
Yogev et al48
Effectiveness
Other Outcome
- Mean birth weight centile 69 in CGM group vs 93 (P = 0.02) - Macrosomia 35% vs 60% in controls (P = 0.05)
- Odds risk for reduced macrosomia 0.36 (95% confidence interval, 0.13-0.98; P = 0.05) - No statistical difference in macrosomia: 43% with CGM vs 30% in controls (P = 0.09) - Comparable maternal and fetal outcome (preeclampsia, cesarean delivery, neonatal hypoglycemia) No significant difference in macrosomia: 8.6% in the constant CGM group vs 9.8% in the intermittent group (NS)
Treatment adjusted in 46 of 57 patients based on additional CGM data
Insulin regimen changed in 8 of 8 patients based on additional CGM data
In 24 of 34 patients (70%), the insulin regimen based on SMBG was altered based on additional CGM data
- 58 Nocturnal hypoglycemic events were detected (1Y4 h before symptoms or detection by SMBG) McLachlan et al49
42/68 (62%) of the CGM measurements provided additional information. The reports were most helpful in cases with DM type 1 37/48 Patients felt the benefits outweighed the inconvenience
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TABLE 3 (Continued) Article Kerssen et al
Efficacy
Effectiveness
50
Ghio et al51
Iafusco et al52
Kestila et al53
Other Outcome Difference in treatment adjustments based on 2 CGM days ranged from 29%Y48%. It was significantly higher in the high day-to-day variability group, 48 vs 33% (P = 0.01)
Neonatal hypoglycemia occurred in 2 cases. Neonatal plasma glucose values at 60 min after birth were inversely related to maternal blood sugar levels at 24, 8, and 1 h before delivery and at birth time. After multivariate analyses, maternal blood sugar level at time of birth solely remained independently related to neonatal hypoglycemia - No newborns developed respiratory distress syndrome - No hypoglycemic episodes were recorded during the first 72 h after birth No significant difference in perinatal outcome
severe hypoglycemia were similar in both groups (13 vs 16%, P = 0.55). As for pregnancy outcomes, no significant differences were found either. The predefined primary outcome was prevalence of macrosomia (defined as birth weight Q90th centile), for which the study was powered. The rate of macrosomia was 43% in the CGM group as opposed to 30% in the control group (P = 0.09). Other maternal and fetal outcome measures were similar too for both groups (eg, preeclampsia, cesarean delivery, preterm delivery, and neonatal hypoglycemia). The prevalence of macrosomia for DM type 1 patients on insulin pump therapy (n = 26) was 55% in the controls and 20% in the RT-CGM group (P = 0.10). Comprehensive details on study design and methods are provided in the article; this contributes to the high quality of the trial. In summary, both RCTs provide conflicting results on the efficacy and effectiveness of CGM use during pregnancy. Difference in efficacy and effectiveness of CGM used intermittently or continuously was investigated in a prospective RCT by Petrovski et al.45 Twenty-five pregnant women with type 1 DM on insulin pump
11 of 36 patients with CGM received antidiabetic treatment vs 3 of 37 controls (P = 0.0149)
therapy were randomized to either continuous CGM use (24 h/d) or intermittent use (24 h every other day). A significant difference was found in HbA1c in the first trimester in the advantage of the continuous group, 6.52 T 1.3 opposed by 6.82 T 0.7 (P G 0.05). This was not observed in the other trimesters. Furthermore, the occurrence of severe hypoglycemic events and diabetic ketoacidosis differed significantly, despite very low numbers: 1 severe hypoglycemic event in the continuous CGM group and 2 events in the intermittent group (P G 0.05), of which one occurred when CGM was not used. No significant difference was found in perinatal outcome. It must be noted that the authors found no incidents of neonatal hypoglycemia and 8.6% macrosomia in the continuous group and 9.8% in the intermittent group. These numbers are much lower than generally observed in a diabetic population. This may have been due to the definition of macrosomia as birth weight greater than 4000 kg instead of a centile adjusted for gestational age. Five studies investigated the effect of CGM use during pregnancy on clinical decision making. They collected data from both the CGM and SMBG of their
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Continuous Glucose Monitoring During Pregnancy
subjects. Difference in treatment strategy based on either one of these techniques was investigated. Chen et al46 studied the additional information CGM offers compared with SMBG in 57 GDM patients and the effect on decision making. Data of both strategies were collected and evaluated for every patient, and consequent treatment decisions were based on both methods separately. In 46 (81%) of the 57 cases, the initial therapeutic regimen based on the SBGM measurements was changed after evaluating additional CGM data. Mainly, nocturnal hypoglycemias and several hyperglycemic episodes were shown by the CGM data that were undetected by SMBG. Yogev et al47 applied a similar study protocol to 6 pregnant type 1 DM patients and 2 GDM patients. All treatments based on SMBG were altered after reevaluation with use of CGM data. Motives for change were undiagnosed nocturnal hypoglycemia or prolonged postprandial hyperglycemia, which were not detected by SMBG. After 2 to 4 weeks, the CGM was executed another 72 hours to evaluate differences after treatment adjustment. The mean total time of undetected hyperglycemia was 152 (T33) versus 89 (T17) during the second recording (P G 0.03). No significant difference was observed in HbA1c level, fructosamine level, and the occurrence of hypoglycemia. In another small study performed by Yogev et al,48 34 consecutive pregnant women with DM type 1 were prospectively included. All patients performed SMBG and received in addition a retrospective CGM during 3 days. Insulin regimen was adapted for every patient twice, by the same physician, based on data derived from SMBG and CGM separately. All patients experienced hyperglycemia undetected by SMBG with a mean of 192 T 28 min/d. Continuous glucose monitor also revealed 58 events of nocturnal hypoglycemia 1 to 4 hours before symptoms or detection by SMBG. The insulin regimen based on SMBG was changed in 24 patients (70%) upon evaluation of CGM results. McLachlan et al49 found similar results. The study population comprised DM type 1, DM type 2, and GDM patients all receiving CGM for 72 hours in addition to SMBG. Of the 68 CGM recordings, 42 affected decision making (62%), mostly due to revealed postprandial hyperglycemia. Furthermore, patient feedback on CGM use was evaluated, showing that 37 (77%) of 48 women reported that the benefits of the CGM outweighed the inconvenience. Kerssen et al50 investigated the day-to-day variability of glucose profiles for the consistency of treatment adjustments. They used 48 consecutive hours of CGM data of 31 women with diabetes type 1 throughout pregnancy. Recordings of every patient were separated
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into 2 days and shown to experts. Based on 24-hour data, treatment was adjusted when deemed necessary. Patients were classified as having high or low day-to-day variability, based on visual inspection and mean absolute difference. The difference between treatment adjustments based on both days of CGM data from each patient ranged from 29% to 48%. For the high day-to-day variability, this was significantly higher, 48 versus 33% (P = 0.01). Three studies used the RT-CGM at a specific moment in diabetic pregnancies, namely, during delivery. One may argue that strict regulation of intrapartum blood glucose values reduces the newborn’s risk of hypoglycemia. Ghio et al51 investigated the effect of RT-CGM use during labor on the rate of neonatal hypoglycemia in an uncontrolled prospective study. Thirteen women with either pregestational or gestational diabetes and undergoing an elective cesarean delivery at 36 weeks of gestation were given a CGM 24 hours before surgery. Insulin and dextrose infusions were adjusted by predefined algorithms based on the CGM measurements. In 2 cases, the neonates had hypoglycemia. Although neonatal glucose values at 60 minutes after birth were inversely related to maternal blood sugar levels at 24, 8, and 1 hour before delivery and at birth time, only the value at time of birth was independently related to neonatal hypoglycemia after multivariate analyses. Iafusco et al52 combined RT-CGM registration with intravenous infusion of insulin during 2 moments of betamethasone administration between the 30th and 32nd week of gestation and during delivery. Eighteen women with DM type 1 used CGM for 72 hours during those 2 events. It was an uncontrolled prospective study. Initially, the retrospective CGM was used; however, after 4 inclusions, the study protocol was switched to RT-CGM. They aimed for the prevention of respiratory distress and neonatal hypoglycemia. Continuous intravenous insulin infusion was managed based on CGM data, and constant glucose levels could be maintained between 100 and 150 mg/dL during betamethasone treatment and during vaginal delivery and between 80 and 100 mg/dL in case of cesarean delivery. None of the children had either respiratory distress or hypoglycemia. Although definite conclusions cannot be drawn from the 2 aforementioned studies, they indicate a potential indication for specific usage of the CGM in pregnancy. Finally, the study of Kestila et al53 was included in this review. They randomly allocated GDM patients to SMBG or CGM to evaluate the role of CGM in detecting requirement of antidiabetic treatment. There
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was a significant difference between the groups in the number of patients receiving antihyperglycemic drug therapy (P = 0.015), 11 of 36 in the CGM group opposed to 3 of 37 in the SBGM group. Retrospective evaluation showed that only 5 of the 36 patients on CGM would have met the criteria to start antidiabetic treatment based on their SBGM data, thereby missing half of the indications. No significant difference in pregnancy outcome was reported; however, the study was not powered for such evaluations. Because of the heterogeneity of the studies this review holds, meta-analysis is not useful. Only 2 RCTs are published that have fundamentally different study protocols, the most important discrepancy being that one studied retrospective CGM, whereas the other studied RT-CGM. Studies on the cost-effectiveness of using CGM in diabetic pregnancies lack entirely. DISCUSSION The modern technique of continuous glucose monitoring has gained ground quickly within obstetric diabetes care, with the aim to improve pregnancy outcome through optimizing glycemic control. However, from this review, it must be concluded that the wide introduction of CGM into the multidisciplinary care for pregnant women with diabetes lacks convincing scientific evidence. Key questions that remain to be answered are: what is the added value of CGM during pregnancy for improving glycemic control, and even more importantly, does CGM improve pregnancy outcome? In other words, what is the efficacy and the effectiveness of CGM in pregnancy? Subsequently, cost-effectiveness should be evaluated. A Cochrane review by Langendam et al8 on CGM for type 1 DM concludes that available evidence shows improvement in glycemic control, defined as a decline in HbA1c level, for adult nonpregnant patients with poorly controlled diabetes when using RT-CGM in tandem with an insulin pump. Their meta-analyses indicate that after 6 months HbA1c values of adult patients who initiated RT-CGM sensor augmented insulin pump therapy declined more than those in patients with multiple daily insulin injections and SMBG (mean difference in change, j0.7%, (95% confidence interval, j0.8% to j0.50%). The risk for hypoglycemia seems increased for CGM users. Nonpregnant women are not reported as selected subgroup. Factors related to CGM effect are the percentage of time the CGM is used and combination of CGM with insulin pump therapy, Langendam et al8 underline the potential usefulness of CGM use during pregnancy, but they conclude there is no scientific evidence to support this.
Whereas the review of Langendam et al8 focuses solely on type 1 diabetes, we evaluated literature on CGM use for all types of diabetes, including pregestational and gestational diabetes. Continuous glucose monitor accuracy assessment in pregnancy was done by Kerssen et al.39 They showed CGM to be accurate in pregnancy, although it seemed less accurate in the hypoglycemic range, as was also seen in nonpregnant diabetes patients.8 When applying the CGM strategy to an obstetric population, some aspects need to be considered. First, knowledge on physiological glycemic profiles during pregnancy is a prerequisite for recognition and adjustment of pathological profiles. During the course of pregnancy, glucose metabolism changes because of interacting placental hormones and alterations of tissue insulin sensitivity. When setting therapeutic targets, those physiological changes must be taken into account. Hewapathirana et al54 reviewed 7 articles (including 7Y57 patients) presenting continuous glucose profiles of nondiabetic pregnancies. In summary, throughout pregnancy, fasting blood glucose levels remain unchanged; postprandial glucose rises, although the glucose range remains narrow. The glycemic target range for diabetic pregnant patients should mirror profiles of healthy pregnant women rather than healthy nonpregnant women. Although the need of meticulous fine tuning to target values can be debated, it is clear that good glycemic control during pregnancy reduces perinatal complications. Nonetheless, it is likely that complications in diabetic pregnancy can only be partially attributed to hyperglycemia per se and other metabolic determinants contribute.55 For instance, Schaefer et al56 showed that maternal levels of triglycerides and free fatty acids are significantly related to high birth weight. Also, the principle of fetal genetic imprinting (fetal gene regulation caused by excess lipid exposure through epigenetic mechanisms) suggests fundamental effects of the diabetic environment during embryo development, which is momentarily out of therapeutic reach.57 It could very well be that the maximum effect of tightening glycemic control has already been reached, and the potential role of different therapeutic targets should be explored. Possibly, the CGM intervention cannot provide additional improvement in pregnancy outcome. Furthermore, the emotional burden of CGM should be taken into account. A key element for the success of CGM is patient motivation. Pregnant women have a drive to optimize conditions for a healthy child. On the other hand, women may be overwhelmed by continuous glycemic profiles, medical information, and obstetric examination. Several trials show a noteworthy
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Continuous Glucose Monitoring During Pregnancy
number of women discontinuing the study because of discontent. Discomfort of the device, requirement for confirmatory SMBG measurements, and false alarms are disadvantages of the (RT-)CGM in addition to overdose of medical information.58 Secher et al59 investigated the self-reported satisfaction and considerations to refuse CGM of 68 diabetic patients during early pregnancy. Improved understanding of their diabetes was reported by 52%. Overall, the CGM was fairly tolerated, although 36% of the patients had the CGM removed early and 10 women (15%) did not wish to use the CGM again. Underlying reasons were amongst others technical challenges, too many alarms, induced stress, or CGM inaccuracy. Continuous glucose monitor compliance was not affected by baseline characteristics such as severe hypoglycemias, preceding pregnancy, HbA1c, professional education level, or continuous subcutaneous insulin infusion treatment. Continuous glucose monitor is a treatment strategy requiring costly equipment and intensive guidance by medical and nursing staff. In the light of rising health care costs, evaluation of cost-effectiveness should be included in randomized trials. Some cost-effectiveness analyses were performed for CGM use in nonpregnant patients.58,60 Calculations were based on the effect of CGM use on future diabetic complications via reduction of HbA1c, an accepted procedure in diabetology. However, this remains a translation from an intermediate outcome; evidence for a positive effect on clinical outcome, for example, microvascular and macrovascular complications, has not yet been provided. Pregnancy is a condition of limited duration, and therefore a device should show benefit more quickly. However, the efficacy of CGM for this purpose remains to be clarified. The majority of articles published on CGM and pregnancy can be summarized as reports of first local clinical experiences. Only 2 high-quality RCTs were performed both using a different type of CGM, and these yielded conflicting results. Whether diabetic women truly benefit from CGM during pregnancy must be clarified by larger trials with subgroup analysis for different types of diabetes. Furthermore, it must be identified which patients benefit from retrospective CGM and which patients must be considered for RT-CGM use. At present, a national multicenter RCT including a cost-effectiveness analysis is being conducted in the Netherlands, evaluating the effect of additional retrospective CGM use on pregnancy outcome in 300 women with DM type 1, DM type 2G or GDM.61 In view of the lack of evidence that we demonstrated in this review, data provided by this and other comparative effectiveness studies are needed to justify the use
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and costs of CGM in the care for pregnant women with diabetes. CONCLUSIONS The existing scientific evidence on CGM efficacy and effectiveness during pregnancy as presented in this review is limited. Up to now, only 2 RCTs have been published, and these yielded contradicting results. There is an urgent need for scientific evidence to provide good patient information and to substantiate current clinical practice. REFERENCES 1. Evers IM, de Valk HW, Visser GH. Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands. BMJ. 2004;328:915. 2. Temple R, Aldridge V, Greenwood R, et al. Association between outcome of pregnancy and glycaemic control in early pregnancy in type 1 diabetes: population based study. BMJ. 2002;325:1275Y1276. 3. Lowe LP, Metzger BE, Dyer AR, et al. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: associations of maternal A1c and glucose with pregnancy outcomes. Diabetes Care. 2012;35:574Y580. 4. Loeken MR. Advances in understanding the molecular causes of diabetes-induced birth defects. J Soc Gynecol Investig. 2006; 13:2Y10. 5. Bell R, Glinianaia SV, Tennant PW, et al. Peri-conception hyperglycaemia and nephropathy are associated with risk of congenital anomaly in women with pre-existing diabetes: a population-based cohort study. Diabetologia. 2012. 6. Diabetes care and research in Europe: the Saint Vincent declaration. Diabet Med. 1990;7:360. 7. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047Y1053. 8. Langendam M, Luijf YM, Hooft L, et al. Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2012;1:CD008101. 9. Su JB, Wang XQ, Chen JF, et al. Glycemic variability in gestational diabetes mellitus and its association with beta cell function. Endocrine. 2013;43:370Y375. 10. Mazze R, Yogev Y, Langer O. Measuring glucose exposure and variability using continuous glucose monitoring in normal and abnormal glucose metabolism in pregnancy. J Matern Fetal Neonatal Med. 2012;25:1171Y1175. 11. Murphy HR, Rayman G, Duffield K, et al. Changes in the glycemic profiles of women with type 1 and type 2 diabetes during pregnancy. Diabetes Care. 2007;30:2785Y2791. 12. Cypryk K, Pertynska-Marczewska M, Szymczak W, et al. Evaluation of metabolic control in women with gestational diabetes mellitus by the continuous glucose monitoring system: a pilot study. Endocr Pract. 2006;12:245Y250. 13. Buhling KJ, Winkel T, Wolf C, et al. Optimal timing for postprandial glucose measurement in pregnant women with diabetes and a non-diabetic pregnant population evaluated by the continuous glucose monitoring system (CGMS). J Perinat Med. 2005;33: 125Y131. 14. Ben-Haroush A, Yogev Y, Chen R, et al. The postprandial glucose profile in the diabetic pregnancy. Am J Obstet Gynecol. 2004;191:576Y581. 15. Kerssen A, Evers IM, de Valk HW, et al. Poor glucose control in women with type 1 diabetes mellitus and ’safe’ hemoglobin A1c
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