Our results suggest that the use of supplementary continuous glucose monitoring as an educational tool during pregnancy is associated with improved maternal glycaemic control. The results were clinically and statistically significant, as the infants of mothers in the intervention arm (continuous glucose monitoring) had a lower birth weight and a reduced risk of macrosomia than those of mothers in the control arm (standard antenatal care).
The observed differences in maternal HbA1c
levels, reflecting mean blood glucose levels over the preceding 4-6 weeks, began to emerge at 28 weeks but did not reach statistical significance until after 32 weeks’ gestation. Earlier studies of postprandial finger prick testing also found better glycaemic control in late gestation, with improvements in blood glucose levels during the second and third trimesters and in HbA1c
levels before delivery.19 31
levels do not improve until the third trimester may reflect the physiological delay between improved glycaemic control and clearance of glycated haemoglobin from the circulation. A learning curve also exists for women and health professionals when using continuous glucose monitoring to optimise lifestyle and therapeutic management, which in our experience takes several consultations. Indeed, we consistently observed that improvements in glycaemic profiles were achieved gradually over pregnancy, rather than after one consultation (data not shown). This emphasises the importance of using the data from continuous glucose monitoring as a tool to facilitate patient education and shared problem solving, and the necessity to reinforce the benefits over several visits. We have previously shown the influence of prepregnancy care on early glycaemic control and hypothesise that initiating continuous glucose monitoring earlier in pregnancy—ideally before conception—may help to achieve an earlier impact on glycaemic control.
Several possible explanations may contribute to the observed improvements in maternal and neonatal outcomes. Generally, in standard antenatal care women measure their blood glucose levels before and after meals, variably at intervals of one or two hours, with only the most motivated achieving the minimum of 10 daily tests required to document fluctuations in glucose levels.20
The continuous glucose monitoring profiles obtained in this study yielded maximal information about the frequency, magnitude, and duration of glucose excursions. We believe that the increased scrutiny of glucose excursions facilitated by continuous glucose monitoring may have contributed to increased motivation and compliance with self management, in particular glucose testing after meals among women in the intervention group. The visual impact of continuous glucose monitoring rapidly focused clinical input towards reducing hyperglycaemic spikes, which are less apparent from a patient diary or glucose meter download but essential if seeking to limit the transfer of glucose to a fetus. The continuous glucose monitoring data also provided feedback on the adequacy of prandial and basal insulin levels, day to day variability in diet, physical activity, and management of hypoglycaemia, with positive feedback to re-enforce optimal self management. Although women in the intervention arm had had diabetes for longer than women in the control arm this would not be expected to contribute to improvement in glycaemic control.
The relative contribution of hyperglycaemia compared with obesity in the development of macrosomia is controversial32
but as we adjusted the birthweight centiles for maternal height and weight, and baseline maternal body mass indices were similar in both groups, the observed differences in birth weight are most likely attributable to the improvements obtained in glycaemic control. Admittedly, HbA1c
levels are markers of average glycaemic control and do not provide detailed insight into hyperglycaemic spikes, implicated in the pathogenesis of macrosomia. The absence of comparative blinded continuous glucose data in women who received standard antenatal care means that we can only speculate on more complex differences in glycaemia between the groups.
Although we cannot fully exclude the possibility that tight glycaemic control contributed to fetal growth restriction, only one infant of a mother in the intervention arm had a birthweight standard deviation score below −2. Four infants of mothers in the intervention arm and no infants of mothers in the control arm were born small for gestational age. Ten per cent of infants would of course be expected to have a birthweight centile of 10% or less, and four of 37 (11%) is not significantly different from this prediction (P=0.1). Indeed, the most strikingly apparent difference in the number of infants who were small for gestational age between the two arms is the absolute absence of such infants of mothers in the control arm, reflecting the overall trend towards larger babies. Significant neonatal morbidity was, however, relatively uncommon in both groups, with only 17% preterm deliveries and 22% of infants admitted to neonatal care compared with 37% and 56% of infants nationally.4
Strengths and limitations of the study
This trial combined recent technological advances in glucose monitoring with a pragmatic educational approach, suitable for widespread implementation in real life clinical settings. It fills a gap identified by the National Institute for Health and Clinical Excellence for more research into continuous glucose monitoring and the need for data not only on interim glucose and HbA1c levels but also on diabetes related morbidity, including pregnancy and neonatal outcomes. Furthermore, the randomised design was robust, with high recruitment and retention rates. None of our exclusion criteria were applied, such that 76% of women participated, and despite the moderate inconvenience of wearing a glucose sensor, 80% of women used continuous glucose monitoring at least once per trimester. Only minimal equipment was required, with three continuous glucose monitors, costing about £1500 (€1889; $2693) each per centre—one monitor for every six pregnancies and four glucose sensors (about £40 each) per pregnancy. Carrying out the trial in a routine clinical setting with judicious use of resources and equipment is key to the generalisability and replicability of the intervention.
Some limitations should also be considered. Firstly, the women were predominantly of white European ethnicity, which may limit applicability to women from other cultures and ethnic backgrounds. Secondly, health professionals were not blinded and therefore we cannot fully exclude the possibility of bias in clinical management. Every effort was, however, made to standardise antenatal contacts between groups, with no difference in the frequency or duration of clinical appointments, dietary advice, obstetric input, or fetal surveillance, and no clinical input during attachment of the continuous glucose sensor. Thirdly, differences in maternal characteristics, with longer duration of diabetes in the intervention group, perhaps contributed to some of the effect on infant outcomes, although would not explain the improvements in glycaemic control. Fourthly, the number of women studied is small and larger multicentre trials are required to assess fully the many factors implicated in fetal growth and to document the true costs and benefits of the intervention.
Putting the study in context
Several pilot studies have reported on the potential of continuous glucose monitoring to assist in adjustment of the insulin dose during pregnancy, but our randomised intervention study showed efficacy in maternal glycaemic control. Outside pregnancy, randomised studies have shown improvements in interim blood glucose excursions and HbA1c
levels associated with continuous glucose monitoring,33
but no studies have shown improvements in diabetes related complications or morbidity. Our study has filled a gap in the evidence base, as recognised by the National Institute for Health and Clinical Excellence,25
suggesting that new technologies can be used to reduce the risk of diabetes related complications in pregnancy.
The observed reductions in birth weight are particularly important in view of the widespread prevalence of macrosomia, affecting over half of all infants born to mothers with diabetes in the United Kingdom. Other advances, including insulin delivery by continuous subcutaneous infusion, have failed to reduce the risk of macrosomia. A recent Cochrane review found a significant increase in birth weight associated with pump therapy (weighted mean difference 220.56 g).34
In our experience insulin pumps remain limited by user input, particularly in the frequency of blood glucose testing after meals, following physical activity and correction of hypoglycaemia. As most of the women in our study were using multiple daily injections we suggest that further study of continuous glucose monitoring in women treated by pump is indicated, to determine the effectiveness in this group.
These results show that continuous glucose monitoring during routine antenatal care can provide added benefits to the pregnancy outcomes for women with diabetes and their infants. Additional benefits on intention to treat analysis were a reduction in HbA1c levels in the third trimester and reduced birth weight and risk of macrosomia. The consequences of birth weight are not limited to immediately apparent delivery injuries, which can be prevented by caesarean section, as infants born large for gestational age have an increased longer term risk of insulin resistance, obesity, and type 2 diabetes. The widespread prevalence and lasting effects of maternal hyperglycaemia suggest that this should be considered a potentially important target for public health strategies, aiming to reduce the burden of obesity in childhood.
Although rates of macrosomia were reduced in women using continuous glucose monitoring, they remain 3.5 times higher than the general maternity population. This suggests that despite continuous glucose monitoring helping women to improve average glycaemic control in late pregnancy, it is still inadequate for achieving optimal day to day glucose control and birth weights comparable with the background population. Perhaps newer generation devices for real time continuous glucose monitoring will offer the potential for a more rapid impact on glycaemic control earlier in pregnancy. Advances in computational approaches for calculating postprandial glucose fluxes35
and the development of closed loop systems36
may offer additional tools to aim for further reduction in risk of macrosomia in future decades.
We have shown that supplementary continuous glucose monitoring provided in a routine clinical setting leads to better glycaemic control and reduced risk of macrosomia. If confirmed by other studies these data have important implications for the antenatal management of women with diabetes as well as the immediate and longer term health of their infants.
What is already known on this topic
- Continuous glucose monitoring is a potentially beneficial educational tool, with benefits on glycaemic control
- NICE have called for research during pregnancy, to focus on pregnancy complications and infant outcomes
What this study adds
- Continuous glucose monitoring is associated with improved maternal glycaemic control and reduced infant birth weight and risk of macrosomia
- The beneficial effects on pregnancy complications potentially offer longer term health benefits for the infants of mothers with diabetes