Comment on: Hernandez et al. Patterns of Glycemia in Normal Pregnancy: Should the Current Therapeutic Targets Be Challenged? Diabetes Care 2011;34:1660–1668
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Abstract
The article by Hernandez et al. (1) makes a useful contribution to documenting normoglycemia
in pregnancy. Although the current target glucose levels in managing gestational diabetes
(GDM) are for the most part based on case-control studies, the author's statement
that macrosomia still occurs if these targets are met is belied by the Maternal-Fetal
Medicine Units Network report of a 7.1% large-for-gestational-age (LGA) rate when
these targets are attained (2). Two more important concerns exist: the veracity of
the data and using 1 SD above a weighted mean as a proposed target for glycemic control
in GDM.
Based on their review of data from 255 pregnant women, the weighted mean fasting blood
glucose was 70.9 ± 7.8 mg/dL, yet the Hyperglycemia and Adverse Pregnancy Outcomes
study with 23,316 women reported a mean ± SD fasting plasma glucose of 80.9 ± 6.9
mg/dL. This 10 mg/dL difference is not explained in the article and raises concerns
about the reliability of the data from the 12 studies with small numbers used versus
data from over 23,000 women—at least for the fasting glucose level. It is of note
that when it comes to picking a fasting target glucose, the authors use the International
Association of Diabetes in Pregnancy Study Groups diagnostic threshold of 92 mg/dL
as a therapeutic target, 13 milligrams above their logical level of 79 mg/dL (weighted
mean +1 SD) if they wish to be consistent.
The authors dismiss the use of +2 SD as target values associated with normalcy with
suggestions for an upper limit target of weighted mean +1 SD in the possible hope
that this will result in lower rates of macrosomia. Such a move will likely increase
the small-for-gestational-age (SGA) rate (3) with no guarantees that the LGA rate
will decline; the long-term consequences of SGA may well be worse than LGA (4). The
authors rightly point out that factors other than glucose may drive LGA, and it is
noteworthy that over time controlling glucose has had positive results in terms of
perinatal mortality, but the lack of impact on LGA is striking (5). Perhaps such a
focus on glucose in GDM will have negative outcomes.
I would certainly concur with the authors’ call for prospective studies to specifically
test therapeutic targets in GDM, but changing target levels of glycemia to those suggested
by the authors, 122 and 110 mg/dL at 1 and 2 h postprandially, based on data that
provided a fasting glucose that is inconsistent with that found in the general pregnant
population and using a 1-SD cutoff is problematic. If the treatment studies reported
to date can normalize LGA rates (2) using targets of 95, 140, and 120 mg/dL for fasting,
1 h, and 2 h postprandially, respectively, it should take a prospective intervention
study to provoke a change. Rather than normoglycemia, maybe we should focus on euglycemia
in its true etymological meaning: good glucose.
The relationship between optimal levels of glycemic control and perinatal outcome was assessed in a prospective study of 334 gestational diabetic women and 334 subjects matched for control of obesity, race, and parity. All women with gestational diabetes mellitus were instructed in the use of a memory-based reflectance meter. They were treated with the same metabolic goal according to a predetermined protocol. Three groups were identified on the basis of mean blood glucose level throughout pregnancy (low, less than or equal to 86 mg/dl; mid, 87 to 104 mg/dl; and high, greater than or equal to 105 mg/dl). The low group had a significantly higher incidence of small-for-gestational-age infants (20%). In contrast, the incidence of large-for-gestational-age infants was 21-fold higher in the mean blood glucose category than in the low mean blood glucose category (24% vs. 1.4%, p less than 0.0001). An overall incidence of 11% small-for-gestational-age and 12% large-for-gestational-age infants was calculated for the control group. A significantly higher incidence of small-for-gestational-age infants (20% vs. 11%, p less than 0.001) was found between the control and the low category. In the high mean blood glucose category an approximate twofold increase was found in the incidence of large-for-gestational-age infants when compared with the control group (p less than 0.03). No significant difference was found between the control and mean blood glucose categories (87 to 104 mg/dl). Our data suggest that a relationship exists between level of glycemic control and neonatal weight. This information is helpful in targeting the level of glycemic control while optimizing pregnancy outcome in gestational diabetes comparable to the general population.
Despite the well-known influence of maternal glucose on infant birth weight (BW), the prevalence of large for gestational age (LGA) infants (≥90th percentile for age) has been increasing steadily over decades, particularly in pregnancies complicated by pregestational or gestational diabetes mellitus (1). Although the overall prevalence of macrosomia (BW ≥4,000 g) is 17–29% in women with untreated gestational diabetes, the majority of macrosomic infants are born to women with obesity but no gestational diabetes (2,3). Moreover, epidemiologic data show that a higher BW is associated with higher BMI and glucose intolerance later in life (4,5), suggesting life-long metabolic implications for offspring. Recent data from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study suggested that concentrations of maternal glucose below the previously accepted diagnostic thresholds for gestational diabetes are predictive of LGA and fetal hyperinsulinemia (6). On the basis of this landmark study, the International Association of Diabetes in Pregnancy Study Group and the American Diabetes Association (ADA) recommended new lower diagnostic criteria for gestational diabetes (7,8). However, a significant number of women with gestational diabetes whose glucose values are within the current targeted therapeutic ranges deliver macrosomic infants (9). Although glucose plays a major role in fetal growth, this paradox underscores the likely role of other nutrients in fetal growth, but also the need to critically reexamine our definition of “normal” maternal patterns of glycemia and the effects on fetal growth. The new diagnostic criteria recommended by the International Association of Diabetes in Pregnancy Study Group and ADA are expected to increase the prevalence of gestational diabetes to 18%. Thus, treatment targets may need to be reevaluated. Historically, the treatment goal in pregnancies complicated by diabetes has been to mimic patterns of glycemia in normal pregnancy (1). Although the HAPO study better defined abnormal glycemic thresholds for the diagnosis of gestational diabetes based on fetal outcomes, the current clinical guidelines for defining treatment targets (10–13) are less rigorous given that optimal therapeutic targets remain untested in randomized trials (14). Further, there has been a reluctance to compare descriptive data in “normal” pregnant women because of the difficulty of comparing major differences in study design, patient characteristics, and methodology. Nevertheless, ∼5 decades of research have helped define “normal” maternal glucose metabolism. The intent of this review is to offer the clinician 1) a clear graphic representation of available glucose data collected in “normal” pregnancy (i.e., a pooled analysis of weighted averages across 12 studies involving nonobese patients); 2) a full discussion of study methodologies and limitations; and 3) a proposal of more aggressive therapeutic targets that may be prospectively tested for the prevention of fetal macrosomia. RESEARCH DESIGN AND METHODS Literature search strategy and inclusion of evidence PubMed was searched broadly using keywords such as pregnancy, glycemia, glucose, diurnal patterns, and gestational diabetes. Reference lists in review papers, original manuscripts, and expert reports were compared with findings in PubMed. Data were included if they provided information on glycemic patterns in normal pregnancy, excluding type 1 or 2 diabetes or gestational diabetes. Patterns needed to have been established using diurnal profiling techniques such as hospital admission with frequent blood sampling, serial measures of self-monitored blood glucose (SMBG), or a continuous glucose monitoring system (CGMS). The patterns of glycemia required characterization during controlled or ad libitum dietary intake to include the effect of incretin hormones and the enteroinsular axis (15). Thus, investigations using a glucose challenge or glucose infusion were not considered. Graphic portrayal of data and weighted averages Exact data were plotted as reported in text or tables by the original authors. When data were only shown in figures, the mean and variance were taken from the graphs. In some cases, complete patterns of glycemia were not reported between meals. For graphic purposes, if a premeal value was not reported, the 24-h mean was used as the between-meal glucose concentration. In the graphs, postprandial (PP) spikes are 1 h (60–70 min) and 2 h after a meal as reported. Because test statistics were not uniformly reported and methodologies for measuring glucose concentrations were variable, a formal meta-analysis was not possible. Thus, this is a pooled analysis of 12 studies that met our inclusion criteria. Weighted means and SDs were calculated as the product of the mean reported value and sample size for each study. The sum of the products across studies was then calculated and divided by the total number of study participants. In addition, mean 1- and 2-h PP glucose concentrations were calculated across three meals (breakfast, lunch, and dinner). Data are presented as weighted mean ± SD. RESULTS Twelve studies met the criteria for inclusion with a total of 255 pregnant women with normal weight and glucose tolerance (Table 1). Table 2 reports data from the included studies, and Fig. 1A graphically depicts the patterns of glycemia. The mean gestational week of study was 33.8 ± 2.3 weeks (range 24–40.8 ± 0.09–8.1 weeks). Most of the women had a BMI 27 kg/m2) women were shown to have higher preprandial and PP glucose, compared with normal-weight control subjects, and the PP peak was delayed 15 min (22). Unexpectedly, these obese women also had lower nocturnal glycemia compared with control subjects (22). In contrast, Porter et al. (23) did not observe differences in nocturnal glycemia between women with and without a history of macrosomia (Table 1). The former study is the most highly cited study (22) in support of current clinical practice for PP glucose monitoring (13). However, the week of pregnancy during which CGMS was worn varied between 21 and 37 weeks of gestation, diet was not controlled (or reported), and the CGMS analysis of the data was generally not well described (22). Thus, interpretation of the data is limited. Other groups using CGMS have attempted to control sources of variance (24), but even women with normal pregnancies seem to have a wide range of glucose concentrations (Table 1) (26). In the most controlled CGMS study to date (27), PP blood glucose concentrations increased up to 36 weeks of gestation despite a self-reported constant caloric intake; macronutrient composition of the diet was not reported. Because the study was well controlled for the week of pregnancy, this report provides perhaps the best interpretable data from CGMS yet published. In summary, the inpatient studies were less “real-world,” but the physical activity and dietary intake were highly controlled, so they likely best captured the normal physiology of pregnancy. On the other hand, the CGMS studies, although less controlled, better depict free-living conditions. Both types of studies require careful interpretation but provide important information. Taken together, the data reveal a range of glycemia in glucose-tolerant women, yet a remarkably similar pattern among studies (Fig. 1A ). Basis for the currently recommended therapeutic targets The current clinical recommendations for treatment targets in pregnancies complicated by diabetes are not uniform internationally or primarily based on the studies listed in Table 1. Although the therapeutic targets were chosen to attenuate the risk for fetal macrosomia, they have never been prospectively tested compared with lower targets (12,13). Even when current glucose targets are achieved in the pregnancy affected by diabetes, macrosomia still occurs and in utero programming may have a lasting metabolic impact on the offspring (40,41). The current therapeutic targets of ≤95 mg/dL for FBG, 130 mg/dL was associated with a high risk of fetal macrosomia. In 1992, Combs et al. (43) reported that in pregnant women with class B through RF diabetes, a 1-h PP target equal to 130 mg/dL during gestational weeks 29–32 suggested a reduction in macrosomia incidence without increasing the incidence of SGA. Previously, it had been thought that monitoring preprandial versus PP glucose concentrations were equally effective in preventing macrosomia (44). However, data from women with pregestational diabetes (45,46) and later with gestational diabetes (44) established the relation between PP glucose and infant body weight/fetal macrosomia, as well as other infant outcomes (47). The randomized study of de Veciana et al. in 1995 (44) demonstrated that targeting a 1-h PP glucose (compared with preprandial) in women with gestational diabetes was superior in the reduction of macrosomia incidence. In this study, an FBG threshold of 25,000 women with an average BMI of 28 kg/m2 and determined that LGA and a cord C-peptide ≥90th percentile were 1.75 times higher at an FBG ≥92 mg/dL (6). Thus, there are strong data to support that this fasting diagnostic threshold might be adopted as an FBG therapeutic target. However, there are no equivalent data for PP targets. On the basis of our pooled analysis, we suggest prospective controlled studies are needed to test more aggressive therapeutic targets for PP glycemia in pregnancies affected by diabetes, uncomplicated by underlying vascular disease, hypertension, or smoking, and controlled for BMI and gestational age. On the basis of the weighted means, the ±1 SD above the weighted mean for a 1-h PP glucose ranges from 96 to 122 mg/dL and the ±2 SD ranges from 83 to 135 mg/dL. For the 2-h PP target, ±1 SD above the weighted mean ranges from 89 to 110 mg/dL, and ±2 SDs above the weighted mean ranges from 79 to 119 mg/dL. Although the glucose targets 2 SDs above the weighted means (135 mg/dL for 1 h and 119 mg/dL for 2 h) are similar to the current therapeutic targets, it is important to keep in mind that these values are the high end of the SD range. Thus, if a woman with gestational diabetes consistently demonstrates a glucose concentration at or ∼135 mg/dL 1 h after a meal, her average value will significantly exceed the population mean of 110 mg/dL. Although observing that +2 SD values are helpful for understanding normality in a population, it is possible that targeting the mean or the +1 SD range of values will result in a lower risk of macrosomia and, more important, excess neonatal adiposity (59). Therefore, we suggest testing PP targets at +1 SD above the calculated weighted means, 122 and 110 mg/dL (120 and 110 mg/dL, rounded for clinical use) for 1 and 2 h, respectively (Fig. 1B ), in women without significant risks for placental insufficiency. We also strongly recommend that recent data supporting a role for maternal lipids as a significant contributor to excess fetal growth be concurrently evaluated in such future studies (60). CONCLUSIONS The results of 45 years of data characterizing glycemia in normal pregnancy strongly support the need for future prospective studies that specifically test lower therapeutic PP glycemic targets for gestational diabetes, and possibly obese patients, to potentially limit a looming epidemic of fetal macrosomia.
From the Division of Endocrinology and Metabolism, Department of Medicine, Alberta
Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
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