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FUEL METABOLISM IN DEVIANT FETAL GROWTH IN OFFSPRING OF DIABETIC WOMEN
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FUEL METABOLISM IN DEVIANT FETAL GROWTH IN OFFSPRING OF DIABETIC WOMEN Moshe Hod, MD, and Oded Langer, MD
Pregnancy is a unique metabolic state in which the woman must provide substrates and fuels not only for her own energy needs but also for the growth and metabolic requirements of the conceptus. Human fetal growth results from an interplay of maternal, placental, and fetal factors. The nutritional supply to the fetus provided by the uteroplacental circulation and the transfer of substrates across the placenta are probably the major contributors to the complicated process that regulates fetal 90 Significant correlation exists between the levels of maternal plasma glucose, amino acids, free fatty acids, and triglycerides and the newborn birth weight in different maternal disease states.%, n, The relative influence of each abnormality combined with other factors such as maternal and fetal substrate concentration, uterine blood flow, and placental size and function remains controversial, thus, requiring more investigation in humans. Human intrauterine growth has received considerable attention in recent years, mainly because, from an obstetric viewpoint, it remains the most important sign of fetal well-being with short- and long-term implications for the rest of life. The human conceptus begins life as a single large cell (0.1 mm in diameter), and, during the 266 days of gestation following fertilization,
From the Perinatal Division, Department of Obstetrics and Gynecology, Beilinson Medical Center, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv University, Israel (MH); and the Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (OL)
OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA VOLUME 23 NUMBER 1 * MARCH 1996
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it increases in size, weight, and surface area in a rapid and markedly nonlinear fashion.8 The fertilized egg divides and differentiates into more than 200 different cell types. From fertilization to delivery, the length of the conceptus increases by a factor of 5000, surface area by a factor of 61 X lo6, and weight by a factor of nearly 6 x 1012.s The organization, orchestration, and specialization in cellular function of this delicate and complex process require control mechanisms. Collection of information to define these mechanisms is ongoing. In this article, we review the processes that are involved in abnormal fetal growth that are caused by abnormalities in maternal metabolic environment. To present the data regarding studies of the various fields involved in normal and abnormal metabolism in human pregnancy, the review is divided according to the three compartments (maternal, placental, and fetal) that, as a whole, represent the pregnant state.
IMPLICATIONS FOR THE FETUS-FUEL-MEDIATED TERATOGENESIS
In 1954 Pedersen and coworkers70,71 hypothesized that maternal hyperglycemia leads to fetal hyperinsulinemia. This concept was later expanded, and evidence was presented83 that fetal hyperinsulinemia suppresses the production of surfactant, promotes various growth factors, and induces relative fetal hypoxemia, thus, leading to various neonatal morbidities (Figs. 1 and 2). In 1979 Freinkel and coworkers1"18, 30 suggested that pregnancy constitutes a "tissue culture experience'' in which normal nutrients during intrauterine development may also act as pharmacologic agents above and beyond their simple nutritive function. They pointed out that most major fuels in the pregnant woman have an easy access to the fetus in a concentration-dependent fashion, thus, delimiting the incubation medium in which fetal cells arise and undergo organization, differentiation, function, and maturation. Freinkel designated these potentially pharmacologic actions of maternal metabolites as "fuel-mediated teratogenesis."lP1s, 30 This phenomenon can occur at any time during pregnancy. If it appears very early in pregnancy, at the time of ongoing organogenesis (between 2 and 6 weeks' postimplantation), it can exert a teratogenic effect that will result in early fetal loss and growth delay, with or without malformations. Later during the second and third trimesters, it will result in behavioral, anthropometric, and metabolic abnormalities, such as macrosomia, nervous system development delay, birth trauma, and various neonatal complications (organic, metabolic, and hematologic) (see Fig. 2)?7
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Figure 1. Maternal metabolic environment and its effect on placental and fetal compartments. HPL = human placental lactogen; FFA = free fatty acids.
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Figure 2. Fuel mediated teratogenesis. Short- and long-range implications on the offspring.
MATERNAL COMPARTMENT
The relationship between maternal plasma fuels and fetal growth is well-established. This is the easiest compartment to study and does not require any sophisticated invasive procedures to reach to it. Thus, our data base of knowledge on maternal metabolism (mainly carbohydrates) is extensive.
Glucose In the summary and recommendation of the Second International Workshop-Conference on Gestational Diabetes Mellitus,92it was stated that, even when dietary therapy alone is effective and maternal fasting and postprandial glucose levels are normalized, as many as 25% of infants of mothers with gestational diabetes mellitus (GDM) may have hypoglycemia, hypocalcemia, polycythemia, hyperbilirubinemia, and macro~omia.2~ During recent years, evidence has been presentedz9 documenting the influence of even subtle degrees of maternal hyperglycemia (levels below those that would clarify the patient as having GDM) on perinatal
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outcome and especially on macrosomia.* Several ~ t u d i e s ' ~33,,41~ reported ~, a high incidence of macrosomia (12% to 28%) in pregnant women with a positive glucose challenge test (GCT) and normal oral glucose tolerance test (OGTT). A surprising correlation was noted between the rate of macrosomia and the second-hour plasma glucose value during an OGTT.95Plasma glucose values of less than 5.6 mM, 5.6 to 6.6 mM, and 6.7 to 9.1 mM resulted in macrosomia rates of 9.9%, 15.5%, and 27.5%, respectively. Langel4O and Lindsay56 and coworkers studied women with one abnormal value on an OGTT and reported an incidence of macrosomia of 18% to 24% in comparison with a rate of 6.6% to 12% for controls. Thus, not only is classic GDM (at least two abnormal values on OGTT) associated with abnormal fetal growth but even milder degrees of glucose tolerance can lead to accelerated fetal growth. In 1989 Langer and coworkers4' attempted to determine the level of maternal glycemia at which perinatal morbidity could be reduced. The study demonstrated a relationship between the level of glycemic control and fetal growth. Thus, the low-mean blood glucose group (586 mg/ dL) had a high incidence of intrauterine growth retardation (20%), whereas the high-mean blood glucose (2105 mg/dL) group had a twofold increase in the incidence of large-for-gestational-age infants. The reported incidence of macrosomia in the 1970s and 1980s ranged from 10% to 32%, thus, representing the consensus in these years.t Twelve studies have reported the incidence of perinatal complication in GDM from 1990 to the present. The incidence of macrosomia has ranged from 7% to 30% and of large-for-gestational-age infants from 18% to Thus, despite tight metabolic control achieved in all of these studies, the incidence of neonatal morbidity and especially macrosomia in offspring of women with GDM has remained constant. Langer and coworkers" addressed this issue as a failure to achieve good glycemic control. They stated that the failure to demonstrate improved perinatal outcome may be explained, in part, by the management approach and by the retrospective design, missing data, and small sample size in these studies. In a prospective, population-based study, LangeP tested the hypothesis that intensified management of GDM, on the basis of stringent glycemic control, verified glucose data, and adherence to established criteria for insulin initiation, would result in enhanced perinatal outcome (macrosomia rates comparable with those for nondiabetic controls). The use of memory reflectance meters enabled this group to demonstrate a significant correlation between rates of large-for-gestational-age infants and macrosomia and glycemic Thus, despite years of meticulous study, a paucity of information exists regarding the optimal maternal glucose levels that should be *References 9, 10, 19, 20, 25, 29, 31, 33, 39, 4042, 49-51, 56, 66, 67, 72, 74, 78, 95, 97, and 99. tReferences 9, 10, 25, 31, 50, 66, 72, 74, 78, and 99.
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achieved to reduce embryonal, fetal, and perinatal morbidity and not cause any harm to intrauterine growth and development. Amino Acids The circulating maternal free amino acid pool is the primary source of nitrogen for the growing mammalian fetus. The fetus metabolizes its nitrogen source by synthesizing, oxidizing, and transaminating amino 53 Although it is well-established that placental transfer of glucose is directly proportional to the maternal blood glucose concentration, fetal amino acid uptake seems to be unrelated to the concentration of amino acids in maternal blood.64Although the flux of amino acids across the placenta is poorly understood, it is known that the placenta concentrates amino acids intracellularly and actively transports them to the fetus.3,101-103, Io5 Amino acids are essential for normal fetal growth and are supplied by the pregnant woman to the fetus via the blood stream and the intervillous space. Reduction of in utero placental blood flow or of the amount of available nutrients can cause impaired fetal growth.64,89 The techniques currently available for studying maternal-fetal processes of exchange are, for the most part, invasive, and risks to the mother and the fetus make them unsuitable for human research. The use of animals for the investigation of metabolic parameters and its application to the human situation are not always valid. Restrictions in the use of radioactive tracers in healthy humans prompted us to develop a convenient noninvasive stable isotope and gas chromatography-mass spectrometry technique to determine the nitrogen-15 (15N)enrichment of plasma amino acids.44, With this method, the rate of uptake of amino acids and the whole body pool of extracellular amino acid can be measured. This technique using 15Nglycine was 4M5, 47, 48, 85 including normal, diabetic, applied to several human studies28, 47 and hypertensive pregnancies.28, Isotope enrichment time decay curves following the rapid intravenous administration of 15Nglycine for three normal, eight diabetic, and four hypertensive pregnant women were linear within the first hour after administration. From the slopes of the intercepts of the least square lines describing the isotopic enrichment time decay curves, pool sizes and turnover rate constants are calculated. The metabolic clearance rate (mL/hour/kg body weight) from the circulating compartment is calculated by dividing amino acid flux by plasma concentration at time zero (Table 1). Measurement of I5N glycine kinetics in the women with GDM (diet-treated) showed significant differences in glycine pool sizes in comparison with the pre-GDM group (insulin-treated) (Table 1). The kinetic parameters summarized in Table 1 indicate no significant difference among normal pregnant women, those with pregnancyinduced hypertension, and women with GDM. However, significantly
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Table 1. DYNAMIC PARAMETERS OF GLYCINE VERSUS FETAL BIRTH WEIGHT ~~~~~
~
Group
(n)
Pool Size (pmol.kg-')
Normal (6) PIH (4) GDM (3) Pre-GDM (5)
75.9 ? 23.6 79.8 f 15.7 78.7 ? 19.0 134.6 f 21.6'
~
~
Disappearance Rate Constant Flux (h-j) (pmol*h-'.kg-')
2.5 f 0.3 2.1 f 0.1 2.3 2 0.2 2.2 2 0.2
Metabolic Clearance Rate (mL-h-l-kg-')
Birth Weight
181.7 f 57.0 1425.3 t476.7 164.5 f 19.8 1268.0f 148.8 176.3 ? 39.0 1220.0 t 205.7 299.2 f 35.2* 1494.4 & 209.8
3160 t 210 2015 ? 445t 3500 ? 500 4048 ? 350'
(9)
PIH = pregnancy-inducedhypertension; GDM = gestational diabetes mellitus. 'Pre-GDM versus normal pregnancy. PIH. and GDM, PcO.05 tPlH versus normal pregnancy, GDM, and pre-GDM, R 0 . 0 5
higher mean pool size levels of 134.0 pmol/kg body weight were calculated for the pre-GDM group (R0.05) compared with 78.7 p,mol/kg body weight for the women with GDM, 75.9 kmol/kg body weight for the normal pregnant women, and 79.8 pmol/kg body weight for the group with pregnancy-induced hypertension. Turnover rate constants of glycine were similar in all three groups and ranged from 2.1 to 2.5/hour (Table 1). Because significant changes of pool sizes were found only in the pre-GDM group, the resultant flux (pool size x turnover rate constant) was significantly higher only in the pre-GDM group (299.2 Fmol-h-'.kg-') than in the GDM (176.3 kmol*h-l.kg-'), PIH (164.5 kmol-h-'.kg-'), and normal pregnancy (181.7 prnol.h-'.kg-') groups. Insignificant differences of the glycine metabolic clearance rate (flux/plasma glycine level) were found between the normal group and all of the other groups. Fetal birth weight was significantly higher in the pre-GDM group (4048 g) in comparison with all of the other groups studied-3500 g in the women with GDM, 2015 g in the women with pregnancy-induced hypertension, and 3160 g in the normal pregnancy group. Mean neonatal birth weight in the hypertensive group (2015 g) was significantly lower than in all of the other groups studied. Pool size levels and fluxes in the pre-GDM group correlated strongly with fetal birth weight at delivery (Fig. 3). The isotope disappearance curves represent the hepatic uptake of glycine from the extracellular pool.'- 3, 4345,48,57,65, 85, lo2 The measured pool size represents the extracellular 65 The glycine kinetic parameters are determined in steady state. No evidence of any trace of 15Nglycine was found in the urine of the subjects studied.', 44, 65 Several reports have described plasma amino acid levels during pregnancy.52,53, lol Some amino acids, including those of glycine, are present in significantly lower levels in early gestation than the corresponding levels in nonpregnant women. In late pregnancy, only a few plasma amino acids are decreased or present in levels not significantly different from those determined in a nonpregnant control The cause of changes in amino acid levels is a subject of considerable controversy. A positive correlation has been observed between total maternal plasma amino acid levels in the last trimester and birth weight and cranial volume of infants at Correlation of maternal plasma
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Figure 3. Plasma glycine parameters compared to fetal birth weight. *Pre-GDM (birth weight) versus normal pregnancy, PIH, and GDM, P<0.05; tpre-GDM (pool size, flux) versus normal pregnancy, PIH, and GDM, R 0 . 0 5 .
amino acid levels to fetal birth weight in GDM has been suggested. Consequently, it has been concluded that the abundance of amino acid building blocks is an important factor in fetal growth.*,58, 6o Recently, Kalkhoff and c o - ~ o r k e r shave ~ ~ shown a direct relationship between maternal amino acid concentrations and birth weight in infants of diabetic and nondiabetic women. Thus, measurements of amino acid fluxes in the maternal extracellular pool are of utmost importance. Static measurements of plasma amino acid levels reveal fragmentary information on dynamic changes of inflow or outflow but indicate that some changes have occurred which ought to be investigated. Thus, diagnosis based on changes of plasma amino acid levels is incomplete. Transplacental flux of nutrients from the maternal to fetal compartment may be affected by several factors, including nutrient concentration in maternal and fetal blood, uterine and umbilical blood flow and distribution, transplacental mode of transfer, and intraplacental metabolism.'o2,Io3, Io5 Amino acid uptake by the fetus depends on active transport by the placenta, maternal blood flow, and, to a lesser extent, on the maternal plasma amino acid concentration,22because most of the amino acids are delivered to the fetus in considerable excess. The uptake of nitrogen in the form of amino acids by the fetus is very large, 1.3 g of nitrogen/kg body weight per day. However, in a recent study using a mixture of I5Nlabeled L-alanine and L-valine in pregnant rabbits, alanine was found to be produced in the fetus in utero, and a possible mechanism of alanine production and alanine and valine transport from the maternal compartment to the fetal compartment was suggested.46
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Our studies regarding the dynamic parameters of amino acid metabolism suggest that fetal growth in pregnancies accompanied by disturbances in insulin homeostasis (GDM and pre-GDM) appears to be influenced by maternal metabolic derangement, although all treated patients were normoglycemic. A positive correlation has been observed between maternal hyperaminoacidemia, as expressed by the elevated pool size and fluxes in the insulin-treated diabetic pregnant women, and fetal birth weight. The increased pool size and fluxes in the insulin-treated group suggest maternal metabolic derangement in this group of diabetic women, which also may be caused by insulin, even with so-called "adequate" treatments as indicated by normal glucose levels. On the other hand, glycine pool size levels, turnover rate constants, and fluxes and metabolic clearance rates were not different among hypertensive pregnant women, normal pregnancies, and patients with GDM, although the group with pregnancy-induced hypertension delivered fetuses with significantly lower birth weights. This suggests that fetal growth in hypertensive pregnancy without any accompanying metabolic derangement appears to be influenced predominantly by uteroplacental blood flow or intraplacental metabolism rather than by the availability of glycine in the maternal extracellular compartment. As most amino acids are delivered in excess, it seems that the rate-limiting factor of fetal growth in these instances must be a reduced circulatory volume. The metabolic changes examined by assay with 15Nglycine in normal pregnancy and in pregnancy complicated by diabetes, hypertension, or other problems imposing a risk on fetal growth underscore the feasibility of using other isotopically labeled amino acids to gain more insight into the influence of maternal metabolic status on fetal growth. We anticipate that tracer methodologies will provide a powerful tool for clinical studies of maternal metabolism and fetal growth.
Lipids
Body fat of the term neonate represents a substantial percentage of body weight, 18%. During intrauterine growth, the fetus requires essential fatty acids (for growth support and brain development); nonessential lipids are important substrates during early postnatal life?l Changes in lipoprotein lipase activity throughout gestation combined with hepatic overproduction and enhanced absorption of lipids are responsible for the marked and progressive increase in maternal circulating triglycerides occurring during late gestation?', 93 There are conflicting reports regarding the correlation between maternal plasma levels of free fatty acids and birth weight in diabetic pregnancies. Several studies have reported a statistical correlation among free fatty triglycerides,32,94 and birth weight, whereas others21,35 have not been able to confirm this.
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PLACENTAL COMPARTMENT The placenta is a highly sophisticated organ that separates the maternal and fetal compartments and, thus, provides, uses, and modulates nutrient delivery from the pregnant woman to the growing fetus. Understanding placental function is essential for a more complete view of how this organ regulates nutrient transfer to the fetus and fetal growth in vitro.
Mechanisms of Transfer There are several specific transport systems across the placentas6 (see Fig. 1).
Diffusion Any molecule for which there is a maternal-fetal concentration difference tends to diffuse across the placenta. Net diffusional transfer depends on surface area, the permeability constant, and the maternalfetal concentration difference. There are two pathways available for differentiation: a hydrophilic route (lipid-insoluble molecular) and a lipophilic route.
Carrier-mediated Transport Carrier-mediated transport can be a purely passive process that depends on extraplacental-generated concentration gradients of the fuel (facilitated differentiation of glucose) or may require linkage to the energy supply within the trophoblast (active transport of amino acids).
Glucose Transfer Fetal plasma glucose concentrations are normally below those in maternal plasma, and the net transplacental flux is directly proportional to the maternal arterial concentration^.^^ Glucose transfer across the placenta is associated with all of the classic characteristics of a facilitated diffusion system-stereo-specific, natural, competitive, and independent of energy sources. Insulin has no direct effect on glucose transfer despite the existence of specific receptors for insulin on the trophoblast.6,32
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Amino Acid Transfer
Fetal plasma concentrations of most amino acids are significantly higher than the maternal concentration^.^^, 86, 88, *OZ, Io3 Placental tissue concentration of a few amino acids seems to be higher than in either maternal or fetal plasma because of a much higher syncytiotrophoblast concentration. Amino acid transport across the placenta is an active process requiring energy in their incorporation in the syncytiotrophoblast followed by a passive leak down the concentration gradient to the fetal plasma. Active transport mechanisms are operative early, as fetal plasma concentrations of amino acids are higher than in maternal plasma by 18 to 21 weeks of gestation. A defect in uptake or afflux components might be deleterious to fetal nutritionJ6,83,86 Lipid Transfer
The human placenta transports lipids at a rapid rate and produces the fattest of all newborns. Lipid stores in a term newborn account for approximately 18%of body weight.86,91, 98 Lipid transport across the placenta can occur by three different systems: 1. Direct transfer of free fatty acids by special transport proteins (carrier-mediated). 2. Synthesis within the placenta of complex lipids, followed by their release to the umbilical circulation. 3. Hydrolysis of complex lipids (triglycerides, lipoproteins, phospholipids) and release of free fatty acids to the umbilical circulation.
Regulation of fat synthesis in the fetus as well as fatty acid oxidation are poorly understood. Ketone body production by the fetus is generally low, but its oxidation may be rapid, thus, providing an alternate fuel during maternal ketonemia. Its influence on fetal nervous system development is contr~versial.~~ Transplacental Flux of Nutrients
At least six factors may affect the transplacental flux of nutrients.24*" Each compartment-maternal, placental, and fetal-is controlled by two of these factors. The placenta predominantly regulates fetal growth, not through the complicated regulation of fetal nutrition but most probably through the interaction of other mechanisms such as the secretion of human placental lactogen (HPl), insulin receptors, and other unknown factors.24It is not surprising that scant information is available as one
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moves from the maternal compartment (maternal substrate concentration and uterine blood flow) to the placental and fetal compartments. It seems that the placental compartment, regulated by its internal transfer mechanisms (architectural changes that underline the increase in placental transfer), and predominantly the internal placental metabolism (self-consumption of approximately 50% of total uterine glucose uptake and a huge concentration of amino acids) exerts a crucial role in fetal macronutrition and growth.24We can conclude that, with regard to the placental compartment and even more so for the fetal compartment (fetal intrauterine intermediary metabolism), our knowledge is very limited.
Placental Size
A major factor affecting substrate flow to the fetus is the placental size and its functional capacity. Placental transport of fuels is a function of placental surface area. A linear relationship between fetal and placental weights has been documented in which small-for-gestational-age fetuses have a small placenta and large-for-gestational-age fetuses a large pla~enta.~, 24, 63, 69 On the other hand, severe histologic conditions may result in defective placental substrate transfer. The histologic changes related to smallfor-gestational-age fetuses include umbilical vascular thrombosis, edema, deposition of fibrinoid, thickening of the basement membrane, an increase in microvillous surface density, surface enlargement factor, and a reduction of the intermicrovillous space.24 The nonlinearity of the relationship among the flux in fuels, blood flow (from both sides-uterine and umbilical), and concentration (mainly fetal) makes it difficult to predict accurately the quantity of fuels crossing the placenta from the pregnant woman to the fetus and, thus, its influence on fetal growth. Moreover, the transport of different fuels may be affected to differing degrees in response to a given change in blood f l ~ ~ . ~ ~ , ~ , ~ Such absolute and relative changes in the flux of individual substrates across the placenta significantly complicate the understanding of the processes that produce abnormal fetal growth, either acceleration leading to macrosomia or deceleration resulting in growth retardation.
FETAL COMPARTMENT With the advent of techniques for sampling the human fetus by cordocentesis (umbilical blood ~ampling),3~ it has become possible to invade the fetal compartment and study fetal intermediary metabolisms.
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Amino Acids
Many studies have described the normal amino acid concentrations in the umbilical cord blood obtained at de1ive1-y.~. 54, 55, 76 A total alphaaminonitrogen difference of 6000 g/L was reported for appropriate for gestational age (AGA) infants and a lower value for small-for-gestational-age infants.76,lo4 Others55pointed out that the ratio of fetal amino acid concentration to maternal concentration was lower in infants born to hypertensive mothers, a ratio associated with intrauterine growth retardation. It also was suggested that the lower fetal/maternal ratios of branched chain amino acids might reflect decreased transport of these essential amino acids to the small-for-gestational-age f e t ~ s . 5 ~ At any given maternal concentration of amino acid, the fetal concentrations are lower in small-for-gestational-age infants in comparison with AGA infants, including the branched chain amino acid difference^.^ Fetal plasma amino acid concentrations, especially of the branched chain, are decreased in pregnancies in which the fetus is growth-retarded and umbilical artery blood flow is reduced.” In small-for-gestational-age fetuses, plasma concentrations and the fetal/maternal ratio of essential amino acids are decreased. This decrease is significantly correlated with the degree of fetal hypoxemia, thus, suggesting that uteroplacental insufficiency is accompanied by intrauterine ~tarvation.~ Glucose and Insulin
Reference ranges for fetal plasma insulin values have been reported for fetuses between 17 and 38 weeks of gestation. Umbilical venous plasma insulin concentrations and fetal insulin/glucose ratio increase exponentially with ge~tati0n.l~ Fetal plasma insulin concentrations correlate with the maternal insulin IeveI, a fact that probably reflects the good correlation between fetal and maternal glucose levels. Fetal hypoinsulinemia and hypoglycemia are found in small-for-gestational-age fetuses. Thus, the lower insulin/ glucose ratio found in small-for-gestational-agefetuses suggests a fetal pancreatic dysfunction leading to decreased glycogen and fat stores and resulting in impaired fetal growth.13 Salvesen and coworker^^^,^^ demonstrated high correlations between maternal and fetal blood glucose and between fetal glucose and blood pH; however, there was no significant association between the degree of acidemia and macrosomia. Further evidence of the interrelationship between maternal hyperglycemia and fetal hyperinsulinemia and acidemia was provided later.81 In pregnancies complicated by diabetes, fetal plasma insulin immunoreactivity is higher than in nondiabetic pregnancies by a magnitude that is greater than would be expected from the degree of hyperglycemia. The data suggest that the fetal insulin/glucose ratio provides an
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index of pancreatic beta-cell hyperplasia, which is the likely cause of macrosomia. Lipids
Fetal plasma triglycerides decrease exponentially with gestation, most probably as a result of increased use by the fetus for deposition into adipose looFetal tissues are capable of triglyceride synthesis from approximately 12 weeks' gestation; however deposition of adipose loo In small-for-gestationaltissue begins after week 24 of age fetuses, there is a correlation between hypertriglyceridation and hypoxemia, probably as a result of lipolysis of fetal fat stores.'* In AGA fetuses, the plasma triclyceride concentration decreases exponentially with gestation, probably reflecting increased uptake into adipose tissue.12 CONCLUSION
In recent years, it has become clear that fetal growth and development from the very first stages of intrauterine life are significantly influenced by the metabolic environment in which the conceptus develops. GDM, which occurs in 1% to 3% of all pregnancies, is viewed as an abnormality in carbohydrate homeostasis but recently has emerged as a disorder of all insulin-dependent fuels. Even the mildest forms of GDM are attended by significant alterations in maternal fuels, such as glucose,
Table 2. MATERNAL DISEASE STATE AND FETAL GROWTH ~
Maternal Disease Compartment Mother
Placenta
Effect
Diabetes
Hypertension
Basic defect Uterine blood flow Fuel mixture Fuels delivery to placenta Blood flow Size Fuels transfer
Impaired insulin action Normal Abnormal Augmented
Vasoconstriction I mpaired Normal Reduced
Normal Augmented Augmented
Reduced Reduced Reduced
,
.L
.L
Hyperalimentation
Undernutrition
1
Acceleration Fetus Neonate
1
Macrosomia LGA
Growth Size
IUGR = intrauterine growth retardation; LGA gestational age.
=
1
Delay
.1
IUGR SGA
large for gestational age; SGA = small for
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amino acids, and lipids, and are associated with abnormal fetal development", 73,75 (Table 2). Pregnancy-induced hypertension is a frequent complication of pregnancy that may impose a risk for the mother and fetus and may be associated with placental and uterovascular pathology.@89 There is a markedly reduced uteroplacental blood flow, and intrauterine growth retardation is of great significance and concern. There is also the possibility that a reduction in the availability of nutrients on the maternal side (expressed as plasma nutrient concentration) may limit fetal growth (Table 2). Both of these maternal disease states serve as excellent examples of the complexity of factors involved in normal and abnormal fetal growth, one representing mainly an impaired metabolic environment and the other, reduced uterine blood flow caused by vasoconstriction. Most probably, both pathophysiologic processes are entangled and cannot be separated at this stage.
References 1. Amir J, Reisner SH, Lapidot A Glycine turnover rates and pool sizes in neonates as determined by gas chromatography mass spectrometry and nitrogen 15. Pediatr Res 1411238-1249, 1980 2. Battaglia FC: The comparative physiology of fetal nutrition. Am J Obstet Gynecol 148:850-856, 1984 3. Battaglia FC, Meschia G: Substrate fetal metabolism. Physiol Rev 58499, 1978 4. Beaur R Morphometry of the placental exchange area. In Advances in Anatomy, Embryology and Cell Biology, vol 53. Berlin, Springer-Verlag, 1977, pp 5-65 5. Cetin I, Corbetta C, Sereni LP, et al: Umbilical amino acid concentrations in normal and growth-retarded fetuses sampled in utero by cordocentesis. Am J Obstet Gynecol 102~253-261,1990 6. Challier JC, et al: Effect of insulin on glucose uptake and metabolism in the human placenta. J Clin Endocrinol Metab 63:803, 1986 7. Cockburn F, Blagden A, Michie EA, et al: The influence of preeclampsia and diabetes mellitus on plasma free amino acids in maternal umbilical vein and infants blood. J Obstet Gynaecol Br Commonw 78:215-231, 1971 8. Corliss LE: Patten's Human Embryology: Elements of Clinical Development. New York, McCraw-Hill, 1976 9. Coustan DR, Imarah J: Prophylactic insulin treatment of gestational diabetes reduces the incidence of macrosomia, operative delivery, and birth trauma. Am J Obstet Cynecol 150:836-842, 1984 10. Coustan DR, Lewis SB: Insulin therapy for gestational diabetes. Obstet Gynecol 51:306-310, 1978 11. Diamant YZ, Metzger BE, Freinkel N, et a 1 Placental lipid and glycogen content in human and experimental diabetes mellitus. Am J Obstet Gynecol 144:5-11, 1982 12. Economides DL, Crook D, Nicolaides KH: Hypertriglyceridemia and hypoxemia in SGA fetuses. Am J Obstet Gynecol 162382-386, 1990 13. Economides DL, Proudler A, Nicolaides K H Plasma insulin in AGA and SGA fetuses. Am J Obstet Cynecol 160:1091-1094, 1989 14. Freinkel N The Banting lecture of pregnancy and progeny. Diabetes 29:1023-1035, 1980 15. Freinkel N Gestational diabetes 1979: Philosophical and practical aspects of a major public health problem. Diabetes Care 3:399-401, 1980
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16. Freinkel N, Dooley SL, Metzger BE: Care of the pregnant woman with insulindependent diabetes mellitus. N Engl J Med 313:96-101, 1985 17. Freinkel N, Metzger BE Pregnancy as a tissue culture experience: The critical implications of maternal metabolism for fetal development. In Pregnancy Metabolism, Diabetes and the Fetus. CIBA Foundation Symposium No. 63. Amsterdam, Excerpta Medica, 1979, pp 3-23 18. Freinkel N, Metzger BE: Emerging challenges in diabetes and pregnancy: Diabetic embryopathy and gestational diabetes. In Alberti KGMM, Krall LP (eds): The Diabetes Annual/4. Amsterdam, Elsevier, 1988, pp 18S201 19. Frisoli G, Naranjo L, Shehab N Glycohemoglobins in normal and diabetic pregnancy. Am J Perinatol 2:18>188, 1985 20. Gabbe S, Mestman JH, Freeman RK, et a1 Management and outcome of class A diabetes mellitus. Am J Obstet Gynecol 127465469, 1977 21. Gillmer MD, Beard RW, Oakley NW, et al: Diurnal plasma free fatty acid profiles in normal and diabetic pregnancies. BMJ 2670-673, 1977 22. Glendenning MB, Margolis AJ, Page EW Amino acid concentrations in fetal and maternal plasma. Am J Obstet Gynecol 81:591-594, 1961 23. Haugel S, et a1 Glucose uptake, utilization, and transfer by the human placenta as functions of maternal glucose concentration. Pediatr Res 20269, 1986 24. Hay WW Jr: The placenta. Not just a conduit for maternal fuels. Diabetes 4O(suppl 2):44-59, 1991 25. Heckberg SR, Stephens CR, Daling JR: Diabetes in pregnancy: Maternal and infant outcome. Paediatr Perinatol Epidemiol2:314-326, 1988 26. Hill PM, Young M: Net placental transfer of free amino acids against varying concentrations. J Physiol235:1092-1095, 1973 27. Hod M, Diamant YZ: The offspring of a diabetic mother-short- and long-range implications. Isr J Med Sci 28:81-86, 1992 28. Hod M, Dorsman M, Friedman S, et al: Dynamic parameters of glycine metabolism in diabetic human pregnancy measured by Ii5N]glycine and GCMS. Isr J Med Sci 27462468,1991 29. Hod M, Merlob B, Friedman S: GDM-a survey of perinatal complications in the 1980s. Diabetes 49(suppl 2):74-78, 1991 30. Hod M, Star S, Passonneau JV,et al: Effect of hyperglycemia on sorbitol and myoinositol content of cultured rat conceptus: Failure of ARI’s to modify myo-inositol depletion and dysmorphogenesis. Biochem Biophys Res Commun 140:974-980,1986 31. Jacobson JD, Cousins L A population-based study of maternal and perinatal outcome in patients with gestational diabetes. Am J Obstet Gynecol 161:981-986, 1989 32. Johnson LW, Smith CH: Monosaccharide transport across microvillous membrane of human placenta. Am J Physiol 238C160,1980 33. Jovanovic L, Peterson CM: Screening for gestational diabetes: Optimum timing and criteria for retesting. Diabetes 34(suppl 2):21-23, 1985 34. Kalkhoff RK: Impact of maternal fuels and nutritional state on fetal growth. Diabetes 4O(suppl 2):61-65, 1991 35. Kalkhoff RK, Kandaraki E, Mitchell T, et al: Maternal plasma fuel disturbances in mild nonobese and obese gestational diabetes mellitus: Relationship to fetal birthweight. In Proceedings of the Third International Workshop-Conference on Gestational Diabetes Mellitus, Chicago, November 9, 1990 36. Kalkhoff RK, Kandaraki E, Morrow AG, et al: Relationship between neonatal birth weight and maternal plasma amino acid profiles in lean and obese nondiabetic women and in type 1 diabetic pregnant women. Metabolism 37234-239, 1988 37. Kamoon P, Droin V, Forestier F, et al: Free amino acids in human fetal plasma. Clin Chim Acta 150227-230, 1985 38. Knopp RH, Magee S Larson ME’, et al: Alternative screening tests and birth weight associations in pregnant women with abnormal glucose screening [abstract]. Diabetes 37(suppl l):llOA, 1988 39. Landon MB, Gabbe SG: Anteparturn fetal surveillance in gestational diabetes mellitus. Diabetes 34(suppl 2):50-54, 1985 40. Langer 0, Brustman L, Anyaegbunam A: The significance of one abnormal glucose
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tolerance test value on adverse outcome in pregnancy. Am J Obstet Gynecol 157758763, 1987 41. Langer 0, Levy S, Brustman L, et al: Glycemic control in GDM: How tight is tight enough. Small for gestational age versus large for gestational age? Am J Obstet Gynecol 161:646453, 1989 42. Langer 0, Rodriguez DA, Xenakis EMJ, et al: Intensified versus conventional management of GDM. Am J Obstet Gynecol 170:103&1047, 1994 43. Lapidot A, Nissim I Application of nitrogen-15 and GCMS in metabolic studies of amino acids in man. Adv Mass Spectrum 113:1142, 1980 44. Lapidot A, Nissim I: Regulation of pool sizes and turnover rates of amino acids in humans, 15N glycine and 15N alanine single dose experiments using gas chromatography-mass spectrometry analysis. Metabolism 29:230-239, 1979 45. Lapidot A, Amir J, Reisner SH: Dynamic aspect of amino acids in neonates, probed by nitrogen-15 and BC-MS. Analytical Chemistry Symposium Series. Amsterdam, Elsevier Publishers, 1982, p 331 46. Lapidot A, Emudianughe TS, Kalderon B: Estimation of maternal fetal amino acids transport and alanine production in the fetus, with stable tracer I-[15N]alanine and L-[15N]valine. In Lubec G, Rosental GE (eds): Amino Acid. Escon Science Publishers 1992 47. Lapidot A, Hob M, Amir J: Dynamic parameters of glycine metabolism in norrnotensive human pregnancy and in hypertensive pregnancy with IUGR. Clin Exp Hypertens Pregnancy [B] 9(3):323-337, 1990 48. Lapidot A, Nissim I, Shaklai M, et al: Glycine pool and turnover rates in leukemia patients measured with [N15N] glycine. Clin Sci 66:147-154, 1984 49. Lavin JP, Lovelace DT, Lovelace L, et al: Clinical experience with 107 diabetic pregnancies. Am J Obstet Gynecol 147742-752, 1983 50. Leikin E, Jenkins JG, Granes W L Prophylactic insulin in gestational diabetes. Obstet Gynecol 70587-592, 1987 51. Leikin EL, Jenkins JH, Pomerantz GA, et al: Abnormal glucose screening tests in pregnancy: A risk factor for fetal macrosomia. Obstet Gynecol 569:570-573, 1987 52. Lemons JA: Fetal-placental nitrogen metabolism. Semin Perinatol 3:177-182, 1979 53. Lemons JA, Adcock EW, Jones MD, et a1 Umbilical uptake of amino acids in the unstressed fetal lamb. J Clin Invest 58:1428-1435, 1976 54. Lindblad BS, Baldesten A: The normal plasma free amino acid levels of nonpregnant women and of mother and child during delivery. Acta Paediatr Scand 56:37-38, 1967 55. Lindblad BS, Zetterstrom R: The venous plasma free amino acid levels of mother and child during delivery. II. After short gestation and gestation complicated by hypertension with special reference to the small for dates syndrome. Acta Paediatr Scand 57195-204, 1968 56. Lindsay MK, Graves W, Klein L The relationship of one abnormal glucose tolerance test value and pregnancy complications. Obstet Gynecol 73:10%106, 1989 57. Martin C : Physiological changes during pregnancy: The mother. In Quilligan EJ, Kretcher N (eds): Fetal and Maternal Medicine. New York, Wiley, 1980, p 170 58. McClain PE, Metcoff J: Relationship of maternal amino acid profiles of 24 weeks of gestation to fetal growth. Clin Res 24502A, 1976 59. McIntosh N: Plasma amino acids of the mid-trimester human fetus. Biol Neonate 45:218, 1984 60. Metzger BE, Phelps RL, Freinkel N Correlation of plasms amino acids with fetal macrosomia in gestational diabetes. Clin Res 24:502A, 1976 61. Metzger BE, Phelps RL, Freinkel N, et a1 Effects of gestational diabetes on diurnal profiles of plasma glucose, lipids and individual amino acids. Diabetes Care 3402409,1980 62. Moghissi MS, Cherchill JA, Kure D Relationship of maternal amino acids and proteins to fetal growth and mental development. Am J Obstet Gynecol 123:398, 1975 63. Molteni RA, Stys SF, Battaglia FC: Relationship of fetal and placental weight in human beings: Fetal/placental weight ratios at various gestational ages and birth weight distributions. J Reprod Med 21:327-334,1978
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64. Morris FH: Placental factors conditioning fetal nutrition and growth. Am J Clin Nutr 34.760-766, 1981 65. Nissim I, Lapidot A Plasma amino turnover rates and pools in rabbits: In vivo studies using stable isotopes. Am J Physiol 237:E418, 1979 66. Oppermann W, Gugliucci C, OSullivan MH, et a1 Gestational diabetes and macrosomia. In Camerini-Cavalos RA, Cole HS (eds): Early Diabetes in Early Life. New York, Academic, 1975, pp 455468 67. OSullivan JB: Prospective study of gestational diabetes and its treatment. In Sutherland HW, Stowers JM (eds): Carbohydrate Metabolism in Pregnancy and the Newborn. New York, Churchill Livingstone, 1975, pp 195-204 68. Ounsted M, Moar V, Scott W A Perinatal morbidity and mortality in small-fordates babies: The relative importance of some maternal factors. Early Hum Dev 5367-371, 1981 69. Owens JA, Falconer J, Robinson J S Effect of restriction of placental growth on fetal and utero-placenta metabolism. J Dev Physiol (Oxf) 9:225-238, 1987 70. Pedersen J: Weight and length at births of infants of diabetic mothers. Acta Endocrinol 16342-347, 1954 71. Pedersen J, Bohsen-Moller B, Poulsen H Blood sugar in newborn infants of diabetic mothers. Acta Endocrinol 15:671-676, 1954 72. Persson B, Stangenberg M, Hansson U, et al: Gestational diabetes mellitus (GDM): Comparative evaluation of two treatment regimens, diet versus insulin and diet. Diabetes 34(suppl 2):lOl-105, 1985 73. Phelps RL, Metzger BE, Freinkel N Diurnal profiles of plasma glucose, insulin, free fatty acids, triglycerides, cholesterol and individual amino acids in late normal pregnancy. Am J Obstet Gynecol 140:730-736,1981 74. Philipson EH, Kalhan SC, Rosen MG, et a1 Gestational diabetes mellitus: Is future improvement necessary? Diabetes 34(suppl 2):55-69, 1985 75. Potter JM, Reckless JP, Cullen DR Diurnal variations in blood intermediary metabolites in midgestational diabetic patients and the effect of a carbohydrate-restricted diet. Diabetologia 2268-72, 1982 76. Prenton MA, Young M Umbilical vein-artery and uterine arteriovenous plasma amino acid differences. J Obstet Gynaecol Br Commonw 76404-411, 1969 77. Reece EA, Homko C, Wiznitzer A: Metabolic changes in diabetic and nondiabetic subjects during pregnancy. Obstet Gynecol Surv 4964-71, 1994 78. Roversi GD, Gargiulo M, Nicolini U, et al: Maximal tolerated insulin therapy in gestational diabetes. Diabetes Care 3:489494, 1980 79. Salvesen DR, Brudenell JM, Ireland R, et al: Fetal plasma erythropoietin in pregnancies complicated by maternal diabetes mellitus. Am J Obstet Gynecol 168:8%94, 1993 80. Salvesen DR, Brudenell JM, Nicolaides K H Fetal polycythemia and thrombocytopenia in pregnancies complicated by maternal diabetes mellitus. Am J Obstet Gynecol 166:1287-1293, 1992 81. Salvesen DR, Brudenell JM, Provoler AJ, et a1 Fetal pancreatic B-cell function in pregnancies complicated by maternal diabetes: Relationship to fetal acidemia and macrosomia. Am J Obstet Gynecol 1081363-1369, 1993 82. Schneider H, Dancis J: Amino acid transport in human placental slices. Am J Obstet Gynecol 120:1092-1095, 1974 83. Schwartz R Hyperinsulinemia and macrosomia [editorial]. N Engl J Med 323:340342, 1990 84. Scriver CR, Rosenberg LE (eds): Amino Acid Metabolism and Its Disorders. Philadelphia, WB Saunders, 1973, pp 39-60 85. Shoenheimer R, Ratner S Studies in protein metabolism. 11. Synthesis of amino acid containing isotopic nitrogen. J Biol Chem 127:301-308, 1983 86. Sibley CP, Boyd RDH: Mechanisms of transfer across the placenta. In Polin RA, Fox WW (eds): Fetal and Neonatal Physiology. Philadelphia, WB Saunders, 1992, pp 62-74 87. Skryten A, Johnson P, Samsioe G, et al: Studies in diabetic pregnancy. I. Serum lipids. Acta Obstet Gynaecol Scand 55211-215, 1976 88. Soltesz G, et al: The metabolic and endocrine milieu of the human fetus and mother at 18-21 weeks of gestation. I. Plasma amino acid concentrations. Pediatr Res 19:91,1985
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89. Sparks JW. Human intrauterine growth and nutrient secretion. Semin Perinatol87493, 1984 90. Sparks JW,Cetin I: Polin and Fox Fetal and Neonatal Physiology: Intrauterine Growth and Nutrition. Philadelphia, WB Saunders, 1992, pp 179-197 91. Sparks JW, Girand J, Battaglia FC: An estimate of the caloric requirements of the human fetus. Biol Neonate 38:11%119, 1980 92. Summary and recommendations of the Second International Workshop-Conference on GDM. Diabetes 34(suppl 2):123-126, 1985 93. Szabo AJ, De Lellis R, Grimaldo RD: Triglyceride synthesis by the human placenta. I. Incorporation of labeled palmitate into placental triglycerides. Am J Obstet Gynecol 115:257-262, 1973 94. Szabo AJ, Oppermann W, Hanover B, et al: Fetal adipose tissue development: Relationship to maternal free fatty acid levels. In Camerini-Davalos RA, Cole HS (eds): Early Diabetes in Early Life. New York, Academic, 1975, pp 67-176 95. Tallarigo L, Giampietro 0, Penno G, et a1 Relation of glucose tolerance to complications of pregnancy in nondiabetic women. N Engl J Med 315:989-992, 1986 96. Tsang R, Glueck J, Evans G, et al: Cord blood hypertriglyceridemia. Am J Dis Child 1277-2, 1974 97. Weiner CP: Effect of varying degrees of normal glucose metabolism on maternal and perinatal outcome. Am J Obstet Gynecol 159:862-870, 1988 98. Widdowson E M Changes in body proportion and composition during growth. In David JA, Dobbing J (eds): Scientific Foundations of Pediatrics. Philadelphia, WB Saunders, 1974, pp 44-45 99. Widness JA, Cowett RM, Coustan DR, et al: Neonatal morbidities in infants of mothers with glucose intolerance in pregnancy. Diabetes 34(suppl2):61-65, 1985 100. Yoshioka T, Roux J F In vitro metabolism of plamitic acid in human fetal tissues. Pediatr Res 6:675-681, 1972 101. Young M: The accumulation of protein by the fetus. In Beard RW, Nathaniez PW (eds): Fetal Physiology and Medicine. Philadelphia, WB Saunders, 1976, pp 59-79 102. Young M: In Chamberlain BP, Wilkinson AW (eds): Placental Transfer. London, Pitman, 1979, pp 142-158 103. Young M, McFadyen IR Placental transfer and fetal uptake of amino acids in the pregnant ewe. J Perinat Med 1:174, 1973 104. Young M, Prenton MA: Maternal and fetal plasma amino acid concentrations during gestation and in retarded fetal growth. J Obstet Gynaecol Br Commonw 76333-344, 1969 105. Yudilevich DL, Sveiry J H Transport of amino acid in placenta. Biochem Biophys Acta 169:822, 1979
Address reprint requests to Moshe Hod, MD Department of Obstetrics and Gynecology Beilinson Medical Center Petah Tiqva 49100 Israel
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FUEL METABOLISM IN DEVIANT FETAL GROWTH IN OFFSPRING OF DIABETIC WOMEN Moshe Hod, MD, and Oded Langer, MD
Pregnancy is a unique metabolic state in which the woman must provide substrates and fuels not only for her own energy needs but also for the growth and metabolic requirements of the conceptus. Human fetal growth results from an interplay of maternal, placental, and fetal factors. The nutritional supply to the fetus provided by the uteroplacental circulation and the transfer of substrates across the placenta are probably the major contributors to the complicated process that regulates fetal 90 Significant correlation exists between the levels of maternal plasma glucose, amino acids, free fatty acids, and triglycerides and the newborn birth weight in different maternal disease states.%, n, The relative influence of each abnormality combined with other factors such as maternal and fetal substrate concentration, uterine blood flow, and placental size and function remains controversial, thus, requiring more investigation in humans. Human intrauterine growth has received considerable attention in recent years, mainly because, from an obstetric viewpoint, it remains the most important sign of fetal well-being with short- and long-term implications for the rest of life. The human conceptus begins life as a single large cell (0.1 mm in diameter), and, during the 266 days of gestation following fertilization,
From the Perinatal Division, Department of Obstetrics and Gynecology, Beilinson Medical Center, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv University, Israel (MH); and the Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (OL)
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it increases in size, weight, and surface area in a rapid and markedly nonlinear fashion.8 The fertilized egg divides and differentiates into more than 200 different cell types. From fertilization to delivery, the length of the conceptus increases by a factor of 5000, surface area by a factor of 61 X lo6, and weight by a factor of nearly 6 x 1012.s The organization, orchestration, and specialization in cellular function of this delicate and complex process require control mechanisms. Collection of information to define these mechanisms is ongoing. In this article, we review the processes that are involved in abnormal fetal growth that are caused by abnormalities in maternal metabolic environment. To present the data regarding studies of the various fields involved in normal and abnormal metabolism in human pregnancy, the review is divided according to the three compartments (maternal, placental, and fetal) that, as a whole, represent the pregnant state.
IMPLICATIONS FOR THE FETUS-FUEL-MEDIATED TERATOGENESIS
In 1954 Pedersen and coworkers70,71 hypothesized that maternal hyperglycemia leads to fetal hyperinsulinemia. This concept was later expanded, and evidence was presented83 that fetal hyperinsulinemia suppresses the production of surfactant, promotes various growth factors, and induces relative fetal hypoxemia, thus, leading to various neonatal morbidities (Figs. 1 and 2). In 1979 Freinkel and coworkers1"18, 30 suggested that pregnancy constitutes a "tissue culture experience'' in which normal nutrients during intrauterine development may also act as pharmacologic agents above and beyond their simple nutritive function. They pointed out that most major fuels in the pregnant woman have an easy access to the fetus in a concentration-dependent fashion, thus, delimiting the incubation medium in which fetal cells arise and undergo organization, differentiation, function, and maturation. Freinkel designated these potentially pharmacologic actions of maternal metabolites as "fuel-mediated teratogenesis."lP1s, 30 This phenomenon can occur at any time during pregnancy. If it appears very early in pregnancy, at the time of ongoing organogenesis (between 2 and 6 weeks' postimplantation), it can exert a teratogenic effect that will result in early fetal loss and growth delay, with or without malformations. Later during the second and third trimesters, it will result in behavioral, anthropometric, and metabolic abnormalities, such as macrosomia, nervous system development delay, birth trauma, and various neonatal complications (organic, metabolic, and hematologic) (see Fig. 2)?7
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Figure 1. Maternal metabolic environment and its effect on placental and fetal compartments. HPL = human placental lactogen; FFA = free fatty acids.
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Figure 2. Fuel mediated teratogenesis. Short- and long-range implications on the offspring.
MATERNAL COMPARTMENT
The relationship between maternal plasma fuels and fetal growth is well-established. This is the easiest compartment to study and does not require any sophisticated invasive procedures to reach to it. Thus, our data base of knowledge on maternal metabolism (mainly carbohydrates) is extensive.
Glucose In the summary and recommendation of the Second International Workshop-Conference on Gestational Diabetes Mellitus,92it was stated that, even when dietary therapy alone is effective and maternal fasting and postprandial glucose levels are normalized, as many as 25% of infants of mothers with gestational diabetes mellitus (GDM) may have hypoglycemia, hypocalcemia, polycythemia, hyperbilirubinemia, and macro~omia.2~ During recent years, evidence has been presentedz9 documenting the influence of even subtle degrees of maternal hyperglycemia (levels below those that would clarify the patient as having GDM) on perinatal
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outcome and especially on macrosomia.* Several ~ t u d i e s ' ~33,,41~ reported ~, a high incidence of macrosomia (12% to 28%) in pregnant women with a positive glucose challenge test (GCT) and normal oral glucose tolerance test (OGTT). A surprising correlation was noted between the rate of macrosomia and the second-hour plasma glucose value during an OGTT.95Plasma glucose values of less than 5.6 mM, 5.6 to 6.6 mM, and 6.7 to 9.1 mM resulted in macrosomia rates of 9.9%, 15.5%, and 27.5%, respectively. Langel4O and Lindsay56 and coworkers studied women with one abnormal value on an OGTT and reported an incidence of macrosomia of 18% to 24% in comparison with a rate of 6.6% to 12% for controls. Thus, not only is classic GDM (at least two abnormal values on OGTT) associated with abnormal fetal growth but even milder degrees of glucose tolerance can lead to accelerated fetal growth. In 1989 Langer and coworkers4' attempted to determine the level of maternal glycemia at which perinatal morbidity could be reduced. The study demonstrated a relationship between the level of glycemic control and fetal growth. Thus, the low-mean blood glucose group (586 mg/ dL) had a high incidence of intrauterine growth retardation (20%), whereas the high-mean blood glucose (2105 mg/dL) group had a twofold increase in the incidence of large-for-gestational-age infants. The reported incidence of macrosomia in the 1970s and 1980s ranged from 10% to 32%, thus, representing the consensus in these years.t Twelve studies have reported the incidence of perinatal complication in GDM from 1990 to the present. The incidence of macrosomia has ranged from 7% to 30% and of large-for-gestational-age infants from 18% to Thus, despite tight metabolic control achieved in all of these studies, the incidence of neonatal morbidity and especially macrosomia in offspring of women with GDM has remained constant. Langer and coworkers" addressed this issue as a failure to achieve good glycemic control. They stated that the failure to demonstrate improved perinatal outcome may be explained, in part, by the management approach and by the retrospective design, missing data, and small sample size in these studies. In a prospective, population-based study, LangeP tested the hypothesis that intensified management of GDM, on the basis of stringent glycemic control, verified glucose data, and adherence to established criteria for insulin initiation, would result in enhanced perinatal outcome (macrosomia rates comparable with those for nondiabetic controls). The use of memory reflectance meters enabled this group to demonstrate a significant correlation between rates of large-for-gestational-age infants and macrosomia and glycemic Thus, despite years of meticulous study, a paucity of information exists regarding the optimal maternal glucose levels that should be *References 9, 10, 19, 20, 25, 29, 31, 33, 39, 4042, 49-51, 56, 66, 67, 72, 74, 78, 95, 97, and 99. tReferences 9, 10, 25, 31, 50, 66, 72, 74, 78, and 99.
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achieved to reduce embryonal, fetal, and perinatal morbidity and not cause any harm to intrauterine growth and development. Amino Acids The circulating maternal free amino acid pool is the primary source of nitrogen for the growing mammalian fetus. The fetus metabolizes its nitrogen source by synthesizing, oxidizing, and transaminating amino 53 Although it is well-established that placental transfer of glucose is directly proportional to the maternal blood glucose concentration, fetal amino acid uptake seems to be unrelated to the concentration of amino acids in maternal blood.64Although the flux of amino acids across the placenta is poorly understood, it is known that the placenta concentrates amino acids intracellularly and actively transports them to the fetus.3,101-103, Io5 Amino acids are essential for normal fetal growth and are supplied by the pregnant woman to the fetus via the blood stream and the intervillous space. Reduction of in utero placental blood flow or of the amount of available nutrients can cause impaired fetal growth.64,89 The techniques currently available for studying maternal-fetal processes of exchange are, for the most part, invasive, and risks to the mother and the fetus make them unsuitable for human research. The use of animals for the investigation of metabolic parameters and its application to the human situation are not always valid. Restrictions in the use of radioactive tracers in healthy humans prompted us to develop a convenient noninvasive stable isotope and gas chromatography-mass spectrometry technique to determine the nitrogen-15 (15N)enrichment of plasma amino acids.44, With this method, the rate of uptake of amino acids and the whole body pool of extracellular amino acid can be measured. This technique using 15Nglycine was 4M5, 47, 48, 85 including normal, diabetic, applied to several human studies28, 47 and hypertensive pregnancies.28, Isotope enrichment time decay curves following the rapid intravenous administration of 15Nglycine for three normal, eight diabetic, and four hypertensive pregnant women were linear within the first hour after administration. From the slopes of the intercepts of the least square lines describing the isotopic enrichment time decay curves, pool sizes and turnover rate constants are calculated. The metabolic clearance rate (mL/hour/kg body weight) from the circulating compartment is calculated by dividing amino acid flux by plasma concentration at time zero (Table 1). Measurement of I5N glycine kinetics in the women with GDM (diet-treated) showed significant differences in glycine pool sizes in comparison with the pre-GDM group (insulin-treated) (Table 1). The kinetic parameters summarized in Table 1 indicate no significant difference among normal pregnant women, those with pregnancyinduced hypertension, and women with GDM. However, significantly
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Table 1. DYNAMIC PARAMETERS OF GLYCINE VERSUS FETAL BIRTH WEIGHT ~~~~~
~
Group
(n)
Pool Size (pmol.kg-')
Normal (6) PIH (4) GDM (3) Pre-GDM (5)
75.9 ? 23.6 79.8 f 15.7 78.7 ? 19.0 134.6 f 21.6'
~
~
Disappearance Rate Constant Flux (h-j) (pmol*h-'.kg-')
2.5 f 0.3 2.1 f 0.1 2.3 2 0.2 2.2 2 0.2
Metabolic Clearance Rate (mL-h-l-kg-')
Birth Weight
181.7 f 57.0 1425.3 t476.7 164.5 f 19.8 1268.0f 148.8 176.3 ? 39.0 1220.0 t 205.7 299.2 f 35.2* 1494.4 & 209.8
3160 t 210 2015 ? 445t 3500 ? 500 4048 ? 350'
(9)
PIH = pregnancy-inducedhypertension; GDM = gestational diabetes mellitus. 'Pre-GDM versus normal pregnancy. PIH. and GDM, PcO.05 tPlH versus normal pregnancy, GDM, and pre-GDM, R 0 . 0 5
higher mean pool size levels of 134.0 pmol/kg body weight were calculated for the pre-GDM group (R0.05) compared with 78.7 p,mol/kg body weight for the women with GDM, 75.9 kmol/kg body weight for the normal pregnant women, and 79.8 pmol/kg body weight for the group with pregnancy-induced hypertension. Turnover rate constants of glycine were similar in all three groups and ranged from 2.1 to 2.5/hour (Table 1). Because significant changes of pool sizes were found only in the pre-GDM group, the resultant flux (pool size x turnover rate constant) was significantly higher only in the pre-GDM group (299.2 Fmol-h-'.kg-') than in the GDM (176.3 kmol*h-l.kg-'), PIH (164.5 kmol-h-'.kg-'), and normal pregnancy (181.7 prnol.h-'.kg-') groups. Insignificant differences of the glycine metabolic clearance rate (flux/plasma glycine level) were found between the normal group and all of the other groups. Fetal birth weight was significantly higher in the pre-GDM group (4048 g) in comparison with all of the other groups studied-3500 g in the women with GDM, 2015 g in the women with pregnancy-induced hypertension, and 3160 g in the normal pregnancy group. Mean neonatal birth weight in the hypertensive group (2015 g) was significantly lower than in all of the other groups studied. Pool size levels and fluxes in the pre-GDM group correlated strongly with fetal birth weight at delivery (Fig. 3). The isotope disappearance curves represent the hepatic uptake of glycine from the extracellular pool.'- 3, 4345,48,57,65, 85, lo2 The measured pool size represents the extracellular 65 The glycine kinetic parameters are determined in steady state. No evidence of any trace of 15Nglycine was found in the urine of the subjects studied.', 44, 65 Several reports have described plasma amino acid levels during pregnancy.52,53, lol Some amino acids, including those of glycine, are present in significantly lower levels in early gestation than the corresponding levels in nonpregnant women. In late pregnancy, only a few plasma amino acids are decreased or present in levels not significantly different from those determined in a nonpregnant control The cause of changes in amino acid levels is a subject of considerable controversy. A positive correlation has been observed between total maternal plasma amino acid levels in the last trimester and birth weight and cranial volume of infants at Correlation of maternal plasma
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Figure 3. Plasma glycine parameters compared to fetal birth weight. *Pre-GDM (birth weight) versus normal pregnancy, PIH, and GDM, P<0.05; tpre-GDM (pool size, flux) versus normal pregnancy, PIH, and GDM, R 0 . 0 5 .
amino acid levels to fetal birth weight in GDM has been suggested. Consequently, it has been concluded that the abundance of amino acid building blocks is an important factor in fetal growth.*,58, 6o Recently, Kalkhoff and c o - ~ o r k e r shave ~ ~ shown a direct relationship between maternal amino acid concentrations and birth weight in infants of diabetic and nondiabetic women. Thus, measurements of amino acid fluxes in the maternal extracellular pool are of utmost importance. Static measurements of plasma amino acid levels reveal fragmentary information on dynamic changes of inflow or outflow but indicate that some changes have occurred which ought to be investigated. Thus, diagnosis based on changes of plasma amino acid levels is incomplete. Transplacental flux of nutrients from the maternal to fetal compartment may be affected by several factors, including nutrient concentration in maternal and fetal blood, uterine and umbilical blood flow and distribution, transplacental mode of transfer, and intraplacental metabolism.'o2,Io3, Io5 Amino acid uptake by the fetus depends on active transport by the placenta, maternal blood flow, and, to a lesser extent, on the maternal plasma amino acid concentration,22because most of the amino acids are delivered to the fetus in considerable excess. The uptake of nitrogen in the form of amino acids by the fetus is very large, 1.3 g of nitrogen/kg body weight per day. However, in a recent study using a mixture of I5Nlabeled L-alanine and L-valine in pregnant rabbits, alanine was found to be produced in the fetus in utero, and a possible mechanism of alanine production and alanine and valine transport from the maternal compartment to the fetal compartment was suggested.46
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Our studies regarding the dynamic parameters of amino acid metabolism suggest that fetal growth in pregnancies accompanied by disturbances in insulin homeostasis (GDM and pre-GDM) appears to be influenced by maternal metabolic derangement, although all treated patients were normoglycemic. A positive correlation has been observed between maternal hyperaminoacidemia, as expressed by the elevated pool size and fluxes in the insulin-treated diabetic pregnant women, and fetal birth weight. The increased pool size and fluxes in the insulin-treated group suggest maternal metabolic derangement in this group of diabetic women, which also may be caused by insulin, even with so-called "adequate" treatments as indicated by normal glucose levels. On the other hand, glycine pool size levels, turnover rate constants, and fluxes and metabolic clearance rates were not different among hypertensive pregnant women, normal pregnancies, and patients with GDM, although the group with pregnancy-induced hypertension delivered fetuses with significantly lower birth weights. This suggests that fetal growth in hypertensive pregnancy without any accompanying metabolic derangement appears to be influenced predominantly by uteroplacental blood flow or intraplacental metabolism rather than by the availability of glycine in the maternal extracellular compartment. As most amino acids are delivered in excess, it seems that the rate-limiting factor of fetal growth in these instances must be a reduced circulatory volume. The metabolic changes examined by assay with 15Nglycine in normal pregnancy and in pregnancy complicated by diabetes, hypertension, or other problems imposing a risk on fetal growth underscore the feasibility of using other isotopically labeled amino acids to gain more insight into the influence of maternal metabolic status on fetal growth. We anticipate that tracer methodologies will provide a powerful tool for clinical studies of maternal metabolism and fetal growth.
Lipids
Body fat of the term neonate represents a substantial percentage of body weight, 18%. During intrauterine growth, the fetus requires essential fatty acids (for growth support and brain development); nonessential lipids are important substrates during early postnatal life?l Changes in lipoprotein lipase activity throughout gestation combined with hepatic overproduction and enhanced absorption of lipids are responsible for the marked and progressive increase in maternal circulating triglycerides occurring during late gestation?', 93 There are conflicting reports regarding the correlation between maternal plasma levels of free fatty acids and birth weight in diabetic pregnancies. Several studies have reported a statistical correlation among free fatty triglycerides,32,94 and birth weight, whereas others21,35 have not been able to confirm this.
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PLACENTAL COMPARTMENT The placenta is a highly sophisticated organ that separates the maternal and fetal compartments and, thus, provides, uses, and modulates nutrient delivery from the pregnant woman to the growing fetus. Understanding placental function is essential for a more complete view of how this organ regulates nutrient transfer to the fetus and fetal growth in vitro.
Mechanisms of Transfer There are several specific transport systems across the placentas6 (see Fig. 1).
Diffusion Any molecule for which there is a maternal-fetal concentration difference tends to diffuse across the placenta. Net diffusional transfer depends on surface area, the permeability constant, and the maternalfetal concentration difference. There are two pathways available for differentiation: a hydrophilic route (lipid-insoluble molecular) and a lipophilic route.
Carrier-mediated Transport Carrier-mediated transport can be a purely passive process that depends on extraplacental-generated concentration gradients of the fuel (facilitated differentiation of glucose) or may require linkage to the energy supply within the trophoblast (active transport of amino acids).
Glucose Transfer Fetal plasma glucose concentrations are normally below those in maternal plasma, and the net transplacental flux is directly proportional to the maternal arterial concentration^.^^ Glucose transfer across the placenta is associated with all of the classic characteristics of a facilitated diffusion system-stereo-specific, natural, competitive, and independent of energy sources. Insulin has no direct effect on glucose transfer despite the existence of specific receptors for insulin on the trophoblast.6,32
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Amino Acid Transfer
Fetal plasma concentrations of most amino acids are significantly higher than the maternal concentration^.^^, 86, 88, *OZ, Io3 Placental tissue concentration of a few amino acids seems to be higher than in either maternal or fetal plasma because of a much higher syncytiotrophoblast concentration. Amino acid transport across the placenta is an active process requiring energy in their incorporation in the syncytiotrophoblast followed by a passive leak down the concentration gradient to the fetal plasma. Active transport mechanisms are operative early, as fetal plasma concentrations of amino acids are higher than in maternal plasma by 18 to 21 weeks of gestation. A defect in uptake or afflux components might be deleterious to fetal nutritionJ6,83,86 Lipid Transfer
The human placenta transports lipids at a rapid rate and produces the fattest of all newborns. Lipid stores in a term newborn account for approximately 18%of body weight.86,91, 98 Lipid transport across the placenta can occur by three different systems: 1. Direct transfer of free fatty acids by special transport proteins (carrier-mediated). 2. Synthesis within the placenta of complex lipids, followed by their release to the umbilical circulation. 3. Hydrolysis of complex lipids (triglycerides, lipoproteins, phospholipids) and release of free fatty acids to the umbilical circulation.
Regulation of fat synthesis in the fetus as well as fatty acid oxidation are poorly understood. Ketone body production by the fetus is generally low, but its oxidation may be rapid, thus, providing an alternate fuel during maternal ketonemia. Its influence on fetal nervous system development is contr~versial.~~ Transplacental Flux of Nutrients
At least six factors may affect the transplacental flux of nutrients.24*" Each compartment-maternal, placental, and fetal-is controlled by two of these factors. The placenta predominantly regulates fetal growth, not through the complicated regulation of fetal nutrition but most probably through the interaction of other mechanisms such as the secretion of human placental lactogen (HPl), insulin receptors, and other unknown factors.24It is not surprising that scant information is available as one
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moves from the maternal compartment (maternal substrate concentration and uterine blood flow) to the placental and fetal compartments. It seems that the placental compartment, regulated by its internal transfer mechanisms (architectural changes that underline the increase in placental transfer), and predominantly the internal placental metabolism (self-consumption of approximately 50% of total uterine glucose uptake and a huge concentration of amino acids) exerts a crucial role in fetal macronutrition and growth.24We can conclude that, with regard to the placental compartment and even more so for the fetal compartment (fetal intrauterine intermediary metabolism), our knowledge is very limited.
Placental Size
A major factor affecting substrate flow to the fetus is the placental size and its functional capacity. Placental transport of fuels is a function of placental surface area. A linear relationship between fetal and placental weights has been documented in which small-for-gestational-age fetuses have a small placenta and large-for-gestational-age fetuses a large pla~enta.~, 24, 63, 69 On the other hand, severe histologic conditions may result in defective placental substrate transfer. The histologic changes related to smallfor-gestational-age fetuses include umbilical vascular thrombosis, edema, deposition of fibrinoid, thickening of the basement membrane, an increase in microvillous surface density, surface enlargement factor, and a reduction of the intermicrovillous space.24 The nonlinearity of the relationship among the flux in fuels, blood flow (from both sides-uterine and umbilical), and concentration (mainly fetal) makes it difficult to predict accurately the quantity of fuels crossing the placenta from the pregnant woman to the fetus and, thus, its influence on fetal growth. Moreover, the transport of different fuels may be affected to differing degrees in response to a given change in blood f l ~ ~ . ~ ~ , ~ , ~ Such absolute and relative changes in the flux of individual substrates across the placenta significantly complicate the understanding of the processes that produce abnormal fetal growth, either acceleration leading to macrosomia or deceleration resulting in growth retardation.
FETAL COMPARTMENT With the advent of techniques for sampling the human fetus by cordocentesis (umbilical blood ~ampling),3~ it has become possible to invade the fetal compartment and study fetal intermediary metabolisms.
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Amino Acids
Many studies have described the normal amino acid concentrations in the umbilical cord blood obtained at de1ive1-y.~. 54, 55, 76 A total alphaaminonitrogen difference of 6000 g/L was reported for appropriate for gestational age (AGA) infants and a lower value for small-for-gestational-age infants.76,lo4 Others55pointed out that the ratio of fetal amino acid concentration to maternal concentration was lower in infants born to hypertensive mothers, a ratio associated with intrauterine growth retardation. It also was suggested that the lower fetal/maternal ratios of branched chain amino acids might reflect decreased transport of these essential amino acids to the small-for-gestational-age f e t ~ s . 5 ~ At any given maternal concentration of amino acid, the fetal concentrations are lower in small-for-gestational-age infants in comparison with AGA infants, including the branched chain amino acid difference^.^ Fetal plasma amino acid concentrations, especially of the branched chain, are decreased in pregnancies in which the fetus is growth-retarded and umbilical artery blood flow is reduced.” In small-for-gestational-age fetuses, plasma concentrations and the fetal/maternal ratio of essential amino acids are decreased. This decrease is significantly correlated with the degree of fetal hypoxemia, thus, suggesting that uteroplacental insufficiency is accompanied by intrauterine ~tarvation.~ Glucose and Insulin
Reference ranges for fetal plasma insulin values have been reported for fetuses between 17 and 38 weeks of gestation. Umbilical venous plasma insulin concentrations and fetal insulin/glucose ratio increase exponentially with ge~tati0n.l~ Fetal plasma insulin concentrations correlate with the maternal insulin IeveI, a fact that probably reflects the good correlation between fetal and maternal glucose levels. Fetal hypoinsulinemia and hypoglycemia are found in small-for-gestational-age fetuses. Thus, the lower insulin/ glucose ratio found in small-for-gestational-agefetuses suggests a fetal pancreatic dysfunction leading to decreased glycogen and fat stores and resulting in impaired fetal growth.13 Salvesen and coworker^^^,^^ demonstrated high correlations between maternal and fetal blood glucose and between fetal glucose and blood pH; however, there was no significant association between the degree of acidemia and macrosomia. Further evidence of the interrelationship between maternal hyperglycemia and fetal hyperinsulinemia and acidemia was provided later.81 In pregnancies complicated by diabetes, fetal plasma insulin immunoreactivity is higher than in nondiabetic pregnancies by a magnitude that is greater than would be expected from the degree of hyperglycemia. The data suggest that the fetal insulin/glucose ratio provides an
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index of pancreatic beta-cell hyperplasia, which is the likely cause of macrosomia. Lipids
Fetal plasma triglycerides decrease exponentially with gestation, most probably as a result of increased use by the fetus for deposition into adipose looFetal tissues are capable of triglyceride synthesis from approximately 12 weeks' gestation; however deposition of adipose loo In small-for-gestationaltissue begins after week 24 of age fetuses, there is a correlation between hypertriglyceridation and hypoxemia, probably as a result of lipolysis of fetal fat stores.'* In AGA fetuses, the plasma triclyceride concentration decreases exponentially with gestation, probably reflecting increased uptake into adipose tissue.12 CONCLUSION
In recent years, it has become clear that fetal growth and development from the very first stages of intrauterine life are significantly influenced by the metabolic environment in which the conceptus develops. GDM, which occurs in 1% to 3% of all pregnancies, is viewed as an abnormality in carbohydrate homeostasis but recently has emerged as a disorder of all insulin-dependent fuels. Even the mildest forms of GDM are attended by significant alterations in maternal fuels, such as glucose,
Table 2. MATERNAL DISEASE STATE AND FETAL GROWTH ~
Maternal Disease Compartment Mother
Placenta
Effect
Diabetes
Hypertension
Basic defect Uterine blood flow Fuel mixture Fuels delivery to placenta Blood flow Size Fuels transfer
Impaired insulin action Normal Abnormal Augmented
Vasoconstriction I mpaired Normal Reduced
Normal Augmented Augmented
Reduced Reduced Reduced
,
.L
.L
Hyperalimentation
Undernutrition
1
Acceleration Fetus Neonate
1
Macrosomia LGA
Growth Size
IUGR = intrauterine growth retardation; LGA gestational age.
=
1
Delay
.1
IUGR SGA
large for gestational age; SGA = small for
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273
amino acids, and lipids, and are associated with abnormal fetal development", 73,75 (Table 2). Pregnancy-induced hypertension is a frequent complication of pregnancy that may impose a risk for the mother and fetus and may be associated with placental and uterovascular pathology.@89 There is a markedly reduced uteroplacental blood flow, and intrauterine growth retardation is of great significance and concern. There is also the possibility that a reduction in the availability of nutrients on the maternal side (expressed as plasma nutrient concentration) may limit fetal growth (Table 2). Both of these maternal disease states serve as excellent examples of the complexity of factors involved in normal and abnormal fetal growth, one representing mainly an impaired metabolic environment and the other, reduced uterine blood flow caused by vasoconstriction. Most probably, both pathophysiologic processes are entangled and cannot be separated at this stage.
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Address reprint requests to Moshe Hod, MD Department of Obstetrics and Gynecology Beilinson Medical Center Petah Tiqva 49100 Israel