ReviewObstetricsIs it time to revisit the Pedersen hypothesis in the face of the obesity epidemic?
Section snippets
The Pedersen hypothesis
Although first formulated in the 1920s, Jorgen Pedersen is generally given credit for the hyperglycemia-hyperinsulinemia hypothesis or, as it is more commonly referred to today, the Pedersen hypothesis.8 The hypothesis as stated by Pedersen is as follows: “Maternal hyperglycemia results in fetal hyperglycemia and, hence, in hypertrophy of fetal islet tissue with insulin hypersecretion. This again means a greater fetal utilization of glucose. This phenomenon will explain several abnormal
The metabolic environment of pregnant women is evolving
In the 1950s when Pedersen cared for pregnant women with preexisting diabetes, the overwhelming majority of these women had type 1 diabetes. One of the primary goals of management was to maintain optimal glucose control and decrease the risk of ketoacidosis. Hence, these women were treated using insulin along with a diet of between 1800-2000 calories (90 g of protein, 80 g of fat, and 180-200 g of carbohydrate) distributed over 6 meals.15 Many of these women were quite thin because this was the
Fetal macrosomia despite excellent glucose control: a role for maternal lipids?
Clinically, despite what is apparently excellent glucose control, some pregnant women with diabetes of any classification, GDM, type 1 or type 2, have a large or macrosomic fetus.20 We often attribute this to unrecognized hyperglycemia despite intermittent home blood glucose monitoring values within the normal range. Continuous glucose monitoring in pregnant women with diabetes has provided data supporting the concept that improved glucose control, as estimated by hemoglobin A1c in later
Is macrosomia or increased birthweight a sufficient measure of fetal overgrowth?
In the past 5 years, there has emerged solid clinical data based, on randomized clinical trials, that treatment of women with GDM can improve outcomes, in particular limiting fetal overgrowth. Both the Australian Carbohydrate Intolerance Study in Pregnant Women and the Maternal-Fetal Medicine Network (MFMU) trials have shown that treatment of GDM with lifestyle measures such as diet decreases the rate of macrosomia and in the case of the MFMU decreased fetal adiposity.24, 25
At birth, the human
Metabolic adaptations to pregnancy: role of lipids
There is a decreased ability of insulin to suppress lipolysis in late pregnancy.34, 35 In addition to the increase in glucose after an oral glucose challenge or after a meal, there are significant increases in circulating lipids during human pregnancy (Table). In the third trimester, obese women have higher triglyceride, very low density lipoproteins (VLDL)-cholesterol, and lower high-density lipoprotein (HDL) concentrations as compared with lean women.36, 37, 38, 39 Similarly, women with GDM
Perinatal metabolic programming
Why is it important to investigate issues related to maternal obesity and fetal overgrowth? Certainly from a clinical perspective, fetal macrosomia affects our clinical management of the obese pregnant women. There is the increased risk of spontaneous abortion, congenital anomalies, stillbirth, shoulder dystocia, and cesarean delivery in obese pregnant women.31 Furthermore, because of the increased prevalence of obesity, as many as 15-20% of pregnant women may soon be classified as having GDM.
Molecular mechanisms accounting for metabolic programming of the offspring
Based on the clinical evidence reviewed in the aforementioned text, changes in maternal lipid metabolism in pregnancy may account for an increased availability of lipid substrates for fetal growth and nutrition. The question then is what are the mechanisms that make the fetus fatter when maternal homeostasis becomes unbalanced, as with diabetes and obesity? Can increased fetal fat accretion be solely a result of excess maternal derived energy substrates? Are other factors increased in obesity
Impact of maternal metabolic homeostasis on fetal lipid metabolism
The factors regulating lipid accumulation in adipose tissue need to be considered to understand the contribution of increased energy substrates to fetal adiposity. Triglycerides represent the primary component of lipid stores in fetal as well as adult adipose tissue. There are 2 primary sources for triglyceride synthesis in mature adipocytes: (1) circulating FFAs and (2) nonlipid precursors such as carbohydrates. Fatty acids are directly esterified into triglycerides, whereas carbohydrates
Impact of maternal inflammation on fetal lipid metabolism
The energy-rich condition of obesity is associated with the activation of inflammatory pathways present in adipose tissue. The combined metabolic and immune dysregulation results in an increased in circulating chemokines, cytokines, and inflammatory mediators. In pregnancy complicated by obesity, the maternal adipose tissue and the placenta both contribute to increase systemic inflammation.60 The chronic inflammatory milieu in pregnancy, associated with obesity and GDM, has provided the basis
Conclusion
The Pedersen hypothesis has generated an incredible stimulus for investigating and understanding diabetes-related pregnancy disorders in the second half of the 20th century. The obesity epidemic in the 21st century is unfortunately opening new opportunities through which to envision in utero perinatal metabolic programming. We are hopeful that the combination of additional knowledge accumulating from ongoing research may result in a better understanding of the mechanisms resulting in fetal
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Cited by (269)
The environmental risk factors associated with fetal macrosomia: An umbrella review
2024, Pediatrics and NeonatologyAntenatal depression moderated the association between gestational diabetes mellitus and fetal hyperinsulinism
2023, American Journal of Obstetrics and Gynecology MFMMaternal insulin resistance in pregnancy is associated with fetal fat deposition: findings from a longitudinal study
2023, American Journal of Obstetrics and GynecologyRelationship of maternal body weight and gestational diabetes mellitus with large-for-gestational-age babies at birth in Taiwan: The TMICS cohort
2022, Taiwanese Journal of Obstetrics and GynecologyCitation Excerpt :FFA concentrations in women with GDM have been linked to newborn belly circumference and neonatal fat mass at birth accessed by ultrasound estimates in one previous investigation [35]. Increasing evidence suggests that the metabolic and endocrine environment may influence lipogenesis in the fetus, though the mechanisms of fatty acid esterification in fetal adipose tissue are still unknown [36]. Maternal overweightness or obesity is a strong risk factor for obstetric problems during gestation and for fetal problems including neural tube defects, increased fetal mortality and fetal overgrowth [37].
This study was supported in part by National Institutes of Health—National Institute of Child Health and Human Development Grant HD22965 and Clinical and Translational Science Awards Grant UL-1 RR 024989.
Reprints not available from the authors.