Patterns of Glycemia in Normal Pregnancy

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 PregnancyOutcomes (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.