Continuous glucose monitoring in pregnant women with type 1 diabetes: an observational cohort study of 186 pregnancies

Despite improved glycaemic control, the prevalence of macrosomia and large for gestational age (LGA) remains high in babies born to women with type 1 diabetes, affecting approximately one-half of these newborn infants [1‐3]. In addition to an increased risk of obstetric and neonatal adverse outcomes [4], LGA infants have an increased risk of developing obesity, diabetes and cardiovascular disease in later life [5‐8].

Fetal exposure to maternal hyperglycaemia is thought to be the major determinant of fetal overgrowth in pregnancies in women with type 1 diabetes [9]. Thus, the overarching goal of prenatal care in these women is to achieve near normal glycaemic control, usually estimated by self-monitoring of plasma glucose and HbA_1c. However, HbA_1c may not adequately reflect fetal glycaemic exposure as it represents an average measure of glycaemic control in the preceding 2–3 months and does not capture acute glucose fluctuations or intra- and inter-day glycaemic variability [10‐12]. Moreover, tight glycaemic control may be difficult to accomplish, given the complexity of insulin dose adjustment required to account for gestational changes in insulin sensitivity and variability in insulin absorption during pregnancy [13, 14]. Recent data have shown that fewer than 50% of pregnant women with diabetes in the UK reach target HbA_1c levels [15].

Continuous glucose monitoring (CGM) technology provides unique insights into daily glycaemic control and permits a better understanding of how glycaemic patterns and glucose variability may influence pregnancy outcomes. The effectiveness of intermittent use of CGM in pregestational diabetes (type 1 diabetes and type 2 diabetes) in improving glycaemic control and reducing the risk of macrosomia has been evaluated in two randomised controlled trials, in the UK and Denmark, with conflicting results [16, 17]. Merged data from the two studies showed that LGA was associated with trimester-specific differences in daily glucose patterns, i.e. with lower mean glucose and less glycaemic variability in the first trimester and with higher mean glucose and more variable glucose levels in the second and third trimesters [18]. Other groups have similarly shown that higher glycaemic variability, especially during late pregnancy, may increase the risk of LGA [19, 20]. A more recent trial, CONCEPTT, found that continuous use of real-time CGM in pregnancies in women with type 1 diabetes resulted in greater reduction in HbA_1c, more time spent in the target range, less time spent above the target range and reduced glucose variability. Furthermore, neonatal outcomes were improved, including a lower incidence of LGA infants and a decrease in neonatal hypoglycaemia [21]. The extent to which the CGM-derived measures of glucose control are associated with LGA in a clinical setting is, however, unclear.

In our regions in southwestern Sweden, women with type 1 diabetes are offered a CGM device as part of routine pregnancy care. Here, we report CGM summary data from a cohort of Swedish women who received pregnancy care during the years 2014 to 2017, using the recently published international consensus recommendation for optimal analysis of CGM data [22]. The aim of the study was to determine patterns of maternal glucose control during different phases of pregnancy and to examine whether these patterns are associated with LGA and a predefined adverse neonatal composite outcome (NCO).

In this study, using CGM-derived measures to describe glucose control, we found that mean glucose levels, SD of mean glucose levels, and time spent in and outside the target range (3.5–7.8 mmol/l) during the second and third trimesters were the most important predictors of LGA and neonatal outcomes. The maternal and neonatal outcomes did not differ between rtCGM users and iCGM users. The glucose patterns were comparable between the two groups throughout pregnancy, except for lower LBGI and less time spent below target in rtCGM users.

To our knowledge, this is the first study to analyse a large clinical dataset of CGM readings during pregnancy in a contemporary real-world setting. It is also the first study to report summary CGM data on the use of Freestyle Libre in pregnancies in women with type 1 diabetes. Not surprisingly, there was a clear trend of improved glucose control with increasing gestational age. The percentage of time spent in target range increased from 50% in the first trimester to 60% in the third trimester. These figures are somewhat higher than reported by Murphy et al from the first randomised controlled trial of intermittent use of CGM in pregnancy [30]. In their cohort of type 1 diabetes women, the corresponding proportions were 43% and 56%, respectively. The time spent above target in late pregnancy was similar to ours (33% vs 34%), whereas the time spent below target was higher (13% vs 7%). A more narrow definition of target range (3.9–7.8 mmol/l) may account for some of these differences. Although CGM users in the CONCEPTT study spent substantially higher time in target (68%) and less time below target (3%) compared with previous studies, the proportion of time spent above target remained high (27%) [21]. These results indicate that additional strategies might be required to optimise glucose control in pregnancies in women with type 1 diabetes―in particular to minimise postprandial glucose excursions. Closed-loop therapy in pregnancy has shown promise in reducing time in hypoglycaemia, but for now, no effect has been demonstrated on time in hyperglycaemia [31, 32].

Interestingly, we found no differences in maternal and neonatal outcomes between women using iCGM and rtCGM, which may support the non-inferior use of iCGM in pregnancy. However, the observational design of the study means that firm conclusions cannot be drawn. Of note, women using rtCGM more often used insulin pumps and had a longer duration of diabetes. Compared with iCGM users, they also spent less time in hypoglycaemia throughout pregnancy. Real-world data from Sweden suggest that insulin pump users have higher HbA_1c levels when starting pump therapy compared with non-pump users and are more likely to be women and aged 20–30 years [33]. Although glycaemic control measured by HbA_1c was similar between rtCGM users and iCGM users at baseline, this does not preclude previous differences at the time of pump therapy initiation. These circumstances mean it is likely that glycaemic disturbance in rtCGM users was more severe and these women were in greater need of a CGM system with an alarm function.

Poor glycaemic control assessed by HbA_1c has long been associated with accelerated fetal growth, particularly during the second and third trimesters [2, 12, 34‐36]. Accordingly, in this study, HbA_1c was an important glucose variable, predicting LGA and neonatal outcomes―in particular, third trimester HbA_1c. In our cohort, 36% of the women reached the target HbA_1c level of <48 mmol/mol (6.5%) in early pregnancy and 70% in the second and the third trimesters. These results are more favourable than those recently reported from a nationwide study in the UK, in which 16% reached the corresponding HbA_1c target in early pregnancy and 40% reached it after 24 weeks of gestation [15]. Nevertheless, the 53% prevalence of LGA infants is high and confirms previous findings that a substantial proportion of pregnancies among women with type 1 diabetes result in delivery of LGA infants [1‐3, 21]. Our results are not directly comparable with most other studies because of differences in the definition of LGA. Using the same definition of LGA as we did (birthweight >2 SD of the ultrasound-based intrauterine reference curve), Law et al reported an LGA prevalence of 45.6% in their subgroup of 68 Danish women with pregestational diabetes randomised to intermittent use of CGM during pregnancy [18]. Taking into account that 21% of the women had type 2 diabetes, their reported LGA prevalence can be considered similar to ours. We have previously reported an LGA prevalence of 23% in pregnancies among women with type 2 diabetes, as opposed to 50% among those with type 1 diabetes [36]. Tightened glucose control early in pregnancy might possibly have changed our results. It has been argued that glycaemic control needs to be optimised very early in pregnancy to prevent fetal overgrowth as a consequence of early establishment of fetal hyperinsulinaemia, a driver of the fetal glucose steal phenomenon [37].

Given that HbA_1c provides a retrospective measure of average glucose levels, it is less likely to detect short-term variation in glucose levels that might be relevant in the development of LGA. However, no significant associations were found between any of the CGM measurements and LGA in the first trimester. Our data support findings from previous studies suggesting that relatively high glucose levels during the second and third trimester are predictive of LGA and adverse neonatal outcomes [12, 16, 18]. Furthermore, the SD of mean glucose in the second and third trimesters were significantly associated with LGA and NCO, respectively. Several studies have demonstrated an association between various CGM-derived measures of glucose variability and birthweight [18‐20, 38]. In line with this, women in the CGM group of the CONCEPTT study had reduced SD and lower MAGE, indicating less glycaemic variability [21]. In contrast, Mulla et al did not observe any trimester-specific associations between glycaemic variability (CV%) and birthweight in a retrospective cohort study of 41 women with type 1 diabetes using real-time CGM for up to 30 consecutive days in each trimester [39]. Some of these discrepancies between studies may have arisen from differences in study design and from the use of different surrogate measures of glycaemic variability. It is important to note that the previous studies―except CONCEPTT―were based on intermittent use of CGM.

Our study should be interpreted in the context of its limitations and strengths. First, this was a clinically based observational study, which precludes us from making causal inferences. Second, the women used two different types of CGM, either rtCGM or iCGM, which may have affected the quality of glycaemic variability measurements. Third, the women were predominantly of European descent which may possibly limit the generalisability to other populations. Fourth, we followed the recently published data on use of CGM outside of pregnancy and required that there was a minimum of 14 consecutive days of data with at least 80% coverage for inclusion [22]. Considering the rapidly changing phases of insulin demands during pregnancy, 7-day profiles may better reflect the dynamic changes during pregnancy. Strengths of the study include the access to a large number of CGM readings based on optimal reports from CGM devices worn on a near-daily basis. From a clinical point of view, the observational design of the study―considering real-world data from all women using a CGM device during pregnancy―is a strength. Furthermore, information on important confounders, such as age, BMI and smoking, was available and controlled for in the logistic regression models [40].

In the present study, we sought to gain local experience of wearing CGM during pregnancy. Despite the use of CGM throughout pregnancy, the day-to-day glucose control was not optimal and the incidence of LGA remained high. There is a need for greater support from the diabetes team during pregnancy for technical assistance and intensified focus on postprandial hyperglycaemia, including dietary advice/carbohydrate counting and a supported active approach to prandial insulin adjustments. Because of ease of use and low cost, the iCGM system has become increasingly popular in Sweden among both individuals with diabetes and caregivers. The system has been considered safe and accurate for use in pregnant women with diabetes [41, 42]. It is our clinical experience that many women prefer to use iCGM rather than rtCGM in pregnancy. Further randomised trials to assess the impact of iCGM vs rtCGM on glucose control and neonatal outcomes in pregnancy are warranted.