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Macrosomic infants of nondiabetic mothers and elevated C-peptide levels in cord blood
The Journal of Pediatrics Volume 127, Number 3
Akinbi and Gerdes
481
Macrosomic infants of nondiabetic mothers and elevated C-peptide levels in cord blood Henry T. Akinbi, MD, a n d Jeffrey S. G e r d e s , MD From the Section on Newborn Pediatrics, Pennsylvania Hospital, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia
C-peptide concentrations in the cord blood of 29 macrosomic neonates born of nondiabetic mothers were higher than in 23 control infants whose birth weight was appropriate for gestational age, and there was a significant direct correlation between birth weight and C-peptide concentration. Six of the macrosomic infants studied (20%) had hypoglycemia in the first 24 hours of life, compared with none of the infants born with appropriate weight. We conclude that chronic fetal hyperinsulinemia may be one of the causes of macrosomia and neonatal hypoglycemia in infants of nondiabetic mothers. (J PEDIATR1995;127:481-4) The Pedersen 1 hypothesis states that postnatal hypoglycemia and fetal macrosomia in infants of diabetic mothers are related to chronic fetal hyperinsulinemia as a response to fetal hyperglycemia. This hypothesis has been borne out by both direct and indirect evidence in animal models, as well as in human neonates. 2 In the immediate neonatal period, macrosomic infants of nondiabetic mothers are also at risk of hypoglycemia. We hypothesized that these infants also might have had hyperinsulinemia in utero. Up to 50% of insulin secreted by the pancreas may be metab01ized in the liver as it comes in via the portal circulation.3 Connecting peptide, a 31-amino acid residue of proteolytic cleavage of proinsulin in pancreatic B-cells, is cosecreted into the portal circulation in equimolar amount as insulin but, unlike insulin, is metabolized in the liver to only a minor extent. 4, 5 C-peptide has been found to be an accurate measure of insulin-secretory activity of pancreatic B-cells.5 Its values in the portal, peripheral venous, and arterial blood are strongly correlated. In this study, we measured C-peptide in the cord blood of macrosomic and control newbom infants whose Weight was appropriate for gestational age and related these values to glucose concentrations in the immediate neonatal period. METHODS Term singleton newborn babies bom in Pennsylvania Hospital from November 1992 to October 1993 were Supported in part by National Institutes of Health grant DK-19525. Submitted for publication Nov. 23, 1994; accepted April 21, 1995. Reprint requests: Jeffrey S. Gerdes, MD, Section on Newbom Pediatrics, Pennsylvania Hospital, 800 Spruce St., Philadelphia, PA 19107. Copyright © 1995 by Mosby-Year Book,Inc. 0022-3476/95/$5.00 + 0 9124165707
enrolled in the study if they weighed more than 4000 gm (>2 SD of the mean birth weight in the hospital) and if their condition was otherwise stable. For most of the macrosomic infants, the next parity- and gender-matched term singleton A G A infant was enrolled as a control subject. Infants were excluded if they had obvious congenital anomalies, a maternal history of diabetes, or an abnormal glucose tolerance test, if the mother had a history of macrosomic babies, or if the mother was receiving a medication that might cause hyperglycemia. All the mothers in this study had a normal 1-hour 50 gm glucose tolerance screening test early in the third trimester. AGA C-peptide IDM
Appropriatebirth weight for gestational age Connecting peptide Infants of diabetic mothers
At delivery 5 to 10 rnl of mixed arteriovenous blood was obtained from the double-clamped umbilical cord. Each sample was immediately separated by centrifugation. The resulting serum was mixed with aprotinin (Sigma Chemical Co., St. Louis, Mo., catalog No. A4529) to a concentration of 1 trypsin-inhibiting unit per milfiliter to inhibit proteolysis. Samples were subsequently stored at -80 ° C. All samples were analyzed in a single assay at the Radioimmunoassay Core Facility of the Diabetes Research Center of the University of Pennsylvania, with the use of a a modification of the method of Herding. 6 All reagents, including the primary and secondary antibodies, and the tracer were from Linco Research Inc. (St. Louis, Mo.). The primary antibody has less than 4% cross-reactivity with proinsulin. The assay was performed against a standard curve for human C-peptide. The latter curve covered a range of 0.05 to 6 hg/tal with a midpoint of 0.8 ng/ml. Assays were performed in duplicate. The intraassay coefficient of variation was less than 5%.
482
Akinbi and Gerdes
The Journal of Pediatrics September 1995
Table, Clinical data on macrosomic and control infants
Birth weight (gm) (_+SD) Gestational age (wk) (+SD) Maternal age (+SD) Proportion of male Maternal parity* Apgar score at 5 min* Mode of delivery (vaginal vs cesarean section) Cord blood C-peptide (ng/ml) (_+SD)
LGA (n = 29)
AGA (n = 23)
p
4258 (175) 39.5 (1.3) 30.9 (2.6)
3433 (316) 39.2 (.07) 30,1 (2,8)
0.0001 0.96 0,64
0.58 2 9 22/7 1.27 (0.7)
0.56 2 9 23.1 0.84 (0.5)
0.87 0.04 0.01
*Median score.
Blood sugar was measured by the hexokinase method with Chemstrip bG reagent strips (Boehringer Mannheim Corp., Indianapolis, Ind., catalog No. 0052) every 2 to 3 hours before feedings in macrosomic infants. In AGA infants, blood sugar was measured only before the first feeding or within the first 2 hours of life and was not repeated unless the value was borderline or low. All abnormal Chemstrip bG values were confmned with a plasma glucose level. Gestational age was confirmed by a combination of menstmal date, ultrasonography date (when available), and the Ballard score on newborn examination. Birth weight, gestational age, and records of mode of delivery, Chemstrip bG value, plasma glucose level, and morbidity during hòspital stay were extracted from hospital records. For the purpose of this study, macrosomia was defined as a birth weight of 4000 gm or greater. Neonatal hypoglycemia was defined as a Chemstrip glucose value less than 2.27 rnmol/L (40 mg/dl) and a plasma glucose value of less than 1.95 mmol/L (35 mg/dl) in the first 24 hours of life. All grouped data are reported as mean -+ SD unless otherwise noted. Differences between groups were analyzed with the Student t test, and correlation coefficients between birth weight and C-peptide levels were determined by Spearman rank correlation with the Abstat statistieal program (Anderson Bell Corp., Arvada, Colo.). This study was appmved by the institutional review board of Pennsylvania Hospital. Informed consent was obtained from the parents before enrollment.
RESULTS There was no difference between the mean gestational ages in the two groups (Table). Seven of the macrosornic infants (29%) were delivered by cesarean section, compared with one (4%) in the control group. The indications for cesarean section were cephalopelvic disproportion for four macrosomic infants and fetal distress in the remaining two and in the sole control infant. All infants were clinically well. The mean C-peptide concentration in macrosomic infants was significantly greater than that in A G A infants (Table).
Cesarean section was not a confounding variable, because there was also a significant difference in C-peptide between macrosomic and A G A infants delivered vaginally (1.27 +_ 0.7 ng/ml vs 0.86 -+ 0.8 ng/ml; p = 0.02). There was a significant correlation between birth weight and cord blood Cpeptide level (r = 0.68; p = 0.04) (Figure). Six of the macrosomic infants (20%) had neonatal hypoglycemia; two of these reqüired treatment in the intensive care nursery. None of the control infants had abnormal glucose values. Of the hypoglycemic infants, four had C-peptide levels greater than 1 SD above the mean for macrosomic infants and almost 2 SD above the mean for the whole study population.
DISCUSSION Insufin is but one of the several hormones/growth factors that modulate fetal growth. The importance of insufin as a major anabolic hormone in fetal life has been shown in rhesus monkeys, 7 in rabbits, 8 and in human beings. 9, 10 A linear correlation between fetal weight and fetal insulinemia was demonstrated by Metzger and Brachet. 11 Both cord blood free immunoreactive insulin and C-peptide were found to be more elevated in IDMs with both macrosomia and hypoglycemia than in those with either isolated macrosomia or hypoglycemia.10 Susa et al. 7 showed that fetal hyperinsulinemia in the presence of maternal euglycemia led to fetal macrosomia in monkeys, and an increased cord blood C-peptide level has been shown to correlate with macrosomia and neonatal hypoglycemia in IDMs. 2 These studies demonstrated a causal relationship between fetal hyperinsnlinemia and macrosomia, but they all studied insulin-C-peptide dynamics exclusively in IDMs. In this study, we extended the Pedersen hypothesis 1 to macrosomic infants of nondiabetic mothers becanse of their vulnerability to neonatal hypoglycemia. We did not find any evidence of maternal or fetal hyperglycemia in our macrosomic infants. However, attempts at maintaining strict euglycemia in diabetic mothers have not consistently prevented fetal macrosomia or neonatal hypoglycemia. Furthermore, the severity of diabetes, based on the White classification,
The Journal of Pediatrics Volume 127, Number 3
Akinbi and Gerdes
483
3.5 Y = -2.181 + .001X; r = 0.68, p = 0.04
3
0 A G A Controls • Macrosomic Newborns 0,~ Hypoglycemic Newborns
~=~4D D,-•
2.5
~
•
1.5
oO 1
o
*G e
.~-~~"
0
00 00
.~
~ . /
• 2800 .
o.,~.'~o
o--
oo
. 3 0 00 . " 3200 . " 3400
• O
o
*
oo
3600 " 3 ; 0 0 " 4 ; 0 0 " 420 0
4400 ' '" 4 ; 00
'
B i r t h W t (g) Figure. C-peptide levels in cord blood of macrosomic neonates with and without hypoglycemia, and in AGA control infants.
does not predict the occurrence of these two comptications.]° The C-peptide levels in our study population are in agreement with the levels reported by Caballero et al.12 in their macrosomic, AGA, and small-for-gestational-ageinfants. In out population, two thirds of the macrosomic infants with neonatal hypoglycemia had C-peptide levels greater than 2 SD above the mean for the whole group. This is in agreement with the finding in IDMs, 1° although the small sample size and the use of Chemstrip bG reagent strips as a less than ideal screen in our study preclude any further extrapolation. The two findings in this study--significantly increased cord blood C-peptide levels in macrosomic infants compared with A G A infants and a correlation between birth weight and C-peptide levels--support our hypothesis that macrosomia may be related to chronic fetal hyperinsulinemia. Alternatively, macrosomia could stem from increased sensitivity to insulin in utero, or hyperinsulinemia may be a marker of increased substrate delivery from mother to fetus. The contribution of Substrates other than glucose may also be important. 13 Out smdy could not rule out these additional etiologic
factors. It is possible that current obstetric surveillance may not be sensitive enough or performed frequently enough to detect subtle or intermittent maternal hyperglycemia. Subtle maternal hyperglycemia as a cause of fetal hyperinsulinemia, macrosomia, and neonatal hypoglycemia will be better addressed by a prospective study that includes maternal hemoglobin Alc. We conclude that some macrosomic infants of nondiabetic mothers have elevated cord blood C-peptide levels. The combination of macrosomia and neonatal hypoglycemia may be explalned in part by chronic fetal hyperinsulinism. We gratefully acknowledge the assistance of Dr. Jeanne L. Ballard, who critically reviewed the manuscript. We thank Ms. Mary Grous, Chris Dalin, and Dr. Leslie Hansen for their help in data acquisition. REFERENCES
1. Pedersen J. Weight and length at birth of iräants of diabetic mothers. Acta Endocrinol 1954;16:330-42.
484
Akinbi and Gerdes
The Journal of Pediatrics September 1995
2. Kaden M, Harding P, Field JB. Effects of intraduodenalglucose administration on hepatic extraction of insulin in the anesthetized dog. J Clin Invest 1973;52:2016-28. 3. Faber OK, Kehlet H, Madsbad S, Binder C. Kinetics of human C- peptide in man. Diabetes 1978; 27:207-9. 4. Horwitz DL, Starr JI, Mako ME, Backard WG, RubinsteinAH. Proinsulin, insulin and C-peptide in human portal and peripheral blood. J Clin Invest 1975;55:1278-83. 5. Heding LG. Radioimmunological determination of human Cpeptide in serum. Diabetologia 1975;11:541-8. 6. Susa JB, Widness JA, Hintz R, Liu F, Sehgal P, Schwartz R. Somatomedins and insulin in diabetic pregnancies: effects of fetal macrosomia in human and rhesus monkey. J Clin Endocrinol Metabol 1984;58:1099-104. 7. Fletcher JM, Falconer J, Basset JM. The relationship of body and placental weight to plasma levels of insulin and other hormones during development of fetal rabbits. Diabetologia 1982;23:124-8.
8. Berk MA, Mimouni F, Miodovnik M, Hertzberg V, Valuck J. Macrosomia in infants of insulin-dependentmothers. Pediatrics 1989;83:1029-34. 9. Knip M, Lautala P, Leppaluoto J, Akerblom HK, Kouvalainen K. Relation of enteroinsular hormones at birth to macrosomia and neonatal hypoglycemia in infants of diabetic mothers. J PEOIATR1983;103:603-11. 10. Metzger P, Brachet E. The rabbit in the last third of gestation: data concerning whole fetus, its diaphragm and brown adipose tissue. Biol Neonate 1978;33:297-303. 11. Caballero CM, Gomez JR, Duo GA, et al. C-pepfide in cord blood of macrosomic and low birthweight infants. Anales Espafioles de Pediatria 1993;39:29-32. 12. FreinkelN.Ofpregnancyandprogeny.Diabetes1980;29:102335.
1-800-55-MOSBY This number links you to the full text of articles published in more than 25,000 journals, including all Mosby journals. M O S B Y Document Express ®, a rapid response information retrieval service, provides quick turnaround, 24-hour availability, and speedy delivery methods. For inquiries and pricing information, call our toll-free, 24-hour order tine: 1-800-55-MOSBY; outside the United States: 415-259-5046; fax: 415-259-5019; E-mail: [email protected]. MOSBY Document Express® is offered in cooperation with Dynamie Information Corp.
Akinbi and Gerdes
481
Macrosomic infants of nondiabetic mothers and elevated C-peptide levels in cord blood Henry T. Akinbi, MD, a n d Jeffrey S. G e r d e s , MD From the Section on Newborn Pediatrics, Pennsylvania Hospital, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia
C-peptide concentrations in the cord blood of 29 macrosomic neonates born of nondiabetic mothers were higher than in 23 control infants whose birth weight was appropriate for gestational age, and there was a significant direct correlation between birth weight and C-peptide concentration. Six of the macrosomic infants studied (20%) had hypoglycemia in the first 24 hours of life, compared with none of the infants born with appropriate weight. We conclude that chronic fetal hyperinsulinemia may be one of the causes of macrosomia and neonatal hypoglycemia in infants of nondiabetic mothers. (J PEDIATR1995;127:481-4) The Pedersen 1 hypothesis states that postnatal hypoglycemia and fetal macrosomia in infants of diabetic mothers are related to chronic fetal hyperinsulinemia as a response to fetal hyperglycemia. This hypothesis has been borne out by both direct and indirect evidence in animal models, as well as in human neonates. 2 In the immediate neonatal period, macrosomic infants of nondiabetic mothers are also at risk of hypoglycemia. We hypothesized that these infants also might have had hyperinsulinemia in utero. Up to 50% of insulin secreted by the pancreas may be metab01ized in the liver as it comes in via the portal circulation.3 Connecting peptide, a 31-amino acid residue of proteolytic cleavage of proinsulin in pancreatic B-cells, is cosecreted into the portal circulation in equimolar amount as insulin but, unlike insulin, is metabolized in the liver to only a minor extent. 4, 5 C-peptide has been found to be an accurate measure of insulin-secretory activity of pancreatic B-cells.5 Its values in the portal, peripheral venous, and arterial blood are strongly correlated. In this study, we measured C-peptide in the cord blood of macrosomic and control newbom infants whose Weight was appropriate for gestational age and related these values to glucose concentrations in the immediate neonatal period. METHODS Term singleton newborn babies bom in Pennsylvania Hospital from November 1992 to October 1993 were Supported in part by National Institutes of Health grant DK-19525. Submitted for publication Nov. 23, 1994; accepted April 21, 1995. Reprint requests: Jeffrey S. Gerdes, MD, Section on Newbom Pediatrics, Pennsylvania Hospital, 800 Spruce St., Philadelphia, PA 19107. Copyright © 1995 by Mosby-Year Book,Inc. 0022-3476/95/$5.00 + 0 9124165707
enrolled in the study if they weighed more than 4000 gm (>2 SD of the mean birth weight in the hospital) and if their condition was otherwise stable. For most of the macrosomic infants, the next parity- and gender-matched term singleton A G A infant was enrolled as a control subject. Infants were excluded if they had obvious congenital anomalies, a maternal history of diabetes, or an abnormal glucose tolerance test, if the mother had a history of macrosomic babies, or if the mother was receiving a medication that might cause hyperglycemia. All the mothers in this study had a normal 1-hour 50 gm glucose tolerance screening test early in the third trimester. AGA C-peptide IDM
Appropriatebirth weight for gestational age Connecting peptide Infants of diabetic mothers
At delivery 5 to 10 rnl of mixed arteriovenous blood was obtained from the double-clamped umbilical cord. Each sample was immediately separated by centrifugation. The resulting serum was mixed with aprotinin (Sigma Chemical Co., St. Louis, Mo., catalog No. A4529) to a concentration of 1 trypsin-inhibiting unit per milfiliter to inhibit proteolysis. Samples were subsequently stored at -80 ° C. All samples were analyzed in a single assay at the Radioimmunoassay Core Facility of the Diabetes Research Center of the University of Pennsylvania, with the use of a a modification of the method of Herding. 6 All reagents, including the primary and secondary antibodies, and the tracer were from Linco Research Inc. (St. Louis, Mo.). The primary antibody has less than 4% cross-reactivity with proinsulin. The assay was performed against a standard curve for human C-peptide. The latter curve covered a range of 0.05 to 6 hg/tal with a midpoint of 0.8 ng/ml. Assays were performed in duplicate. The intraassay coefficient of variation was less than 5%.
482
Akinbi and Gerdes
The Journal of Pediatrics September 1995
Table, Clinical data on macrosomic and control infants
Birth weight (gm) (_+SD) Gestational age (wk) (+SD) Maternal age (+SD) Proportion of male Maternal parity* Apgar score at 5 min* Mode of delivery (vaginal vs cesarean section) Cord blood C-peptide (ng/ml) (_+SD)
LGA (n = 29)
AGA (n = 23)
p
4258 (175) 39.5 (1.3) 30.9 (2.6)
3433 (316) 39.2 (.07) 30,1 (2,8)
0.0001 0.96 0,64
0.58 2 9 22/7 1.27 (0.7)
0.56 2 9 23.1 0.84 (0.5)
0.87 0.04 0.01
*Median score.
Blood sugar was measured by the hexokinase method with Chemstrip bG reagent strips (Boehringer Mannheim Corp., Indianapolis, Ind., catalog No. 0052) every 2 to 3 hours before feedings in macrosomic infants. In AGA infants, blood sugar was measured only before the first feeding or within the first 2 hours of life and was not repeated unless the value was borderline or low. All abnormal Chemstrip bG values were confmned with a plasma glucose level. Gestational age was confirmed by a combination of menstmal date, ultrasonography date (when available), and the Ballard score on newborn examination. Birth weight, gestational age, and records of mode of delivery, Chemstrip bG value, plasma glucose level, and morbidity during hòspital stay were extracted from hospital records. For the purpose of this study, macrosomia was defined as a birth weight of 4000 gm or greater. Neonatal hypoglycemia was defined as a Chemstrip glucose value less than 2.27 rnmol/L (40 mg/dl) and a plasma glucose value of less than 1.95 mmol/L (35 mg/dl) in the first 24 hours of life. All grouped data are reported as mean -+ SD unless otherwise noted. Differences between groups were analyzed with the Student t test, and correlation coefficients between birth weight and C-peptide levels were determined by Spearman rank correlation with the Abstat statistieal program (Anderson Bell Corp., Arvada, Colo.). This study was appmved by the institutional review board of Pennsylvania Hospital. Informed consent was obtained from the parents before enrollment.
RESULTS There was no difference between the mean gestational ages in the two groups (Table). Seven of the macrosornic infants (29%) were delivered by cesarean section, compared with one (4%) in the control group. The indications for cesarean section were cephalopelvic disproportion for four macrosomic infants and fetal distress in the remaining two and in the sole control infant. All infants were clinically well. The mean C-peptide concentration in macrosomic infants was significantly greater than that in A G A infants (Table).
Cesarean section was not a confounding variable, because there was also a significant difference in C-peptide between macrosomic and A G A infants delivered vaginally (1.27 +_ 0.7 ng/ml vs 0.86 -+ 0.8 ng/ml; p = 0.02). There was a significant correlation between birth weight and cord blood Cpeptide level (r = 0.68; p = 0.04) (Figure). Six of the macrosomic infants (20%) had neonatal hypoglycemia; two of these reqüired treatment in the intensive care nursery. None of the control infants had abnormal glucose values. Of the hypoglycemic infants, four had C-peptide levels greater than 1 SD above the mean for macrosomic infants and almost 2 SD above the mean for the whole study population.
DISCUSSION Insufin is but one of the several hormones/growth factors that modulate fetal growth. The importance of insufin as a major anabolic hormone in fetal life has been shown in rhesus monkeys, 7 in rabbits, 8 and in human beings. 9, 10 A linear correlation between fetal weight and fetal insulinemia was demonstrated by Metzger and Brachet. 11 Both cord blood free immunoreactive insulin and C-peptide were found to be more elevated in IDMs with both macrosomia and hypoglycemia than in those with either isolated macrosomia or hypoglycemia.10 Susa et al. 7 showed that fetal hyperinsulinemia in the presence of maternal euglycemia led to fetal macrosomia in monkeys, and an increased cord blood C-peptide level has been shown to correlate with macrosomia and neonatal hypoglycemia in IDMs. 2 These studies demonstrated a causal relationship between fetal hyperinsnlinemia and macrosomia, but they all studied insulin-C-peptide dynamics exclusively in IDMs. In this study, we extended the Pedersen hypothesis 1 to macrosomic infants of nondiabetic mothers becanse of their vulnerability to neonatal hypoglycemia. We did not find any evidence of maternal or fetal hyperglycemia in our macrosomic infants. However, attempts at maintaining strict euglycemia in diabetic mothers have not consistently prevented fetal macrosomia or neonatal hypoglycemia. Furthermore, the severity of diabetes, based on the White classification,
The Journal of Pediatrics Volume 127, Number 3
Akinbi and Gerdes
483
3.5 Y = -2.181 + .001X; r = 0.68, p = 0.04
3
0 A G A Controls • Macrosomic Newborns 0,~ Hypoglycemic Newborns
~=~4D D,-•
2.5
~
•
1.5
oO 1
o
*G e
.~-~~"
0
00 00
.~
~ . /
• 2800 .
o.,~.'~o
o--
oo
. 3 0 00 . " 3200 . " 3400
• O
o
*
oo
3600 " 3 ; 0 0 " 4 ; 0 0 " 420 0
4400 ' '" 4 ; 00
'
B i r t h W t (g) Figure. C-peptide levels in cord blood of macrosomic neonates with and without hypoglycemia, and in AGA control infants.
does not predict the occurrence of these two comptications.]° The C-peptide levels in our study population are in agreement with the levels reported by Caballero et al.12 in their macrosomic, AGA, and small-for-gestational-ageinfants. In out population, two thirds of the macrosomic infants with neonatal hypoglycemia had C-peptide levels greater than 2 SD above the mean for the whole group. This is in agreement with the finding in IDMs, 1° although the small sample size and the use of Chemstrip bG reagent strips as a less than ideal screen in our study preclude any further extrapolation. The two findings in this study--significantly increased cord blood C-peptide levels in macrosomic infants compared with A G A infants and a correlation between birth weight and C-peptide levels--support our hypothesis that macrosomia may be related to chronic fetal hyperinsulinemia. Alternatively, macrosomia could stem from increased sensitivity to insulin in utero, or hyperinsulinemia may be a marker of increased substrate delivery from mother to fetus. The contribution of Substrates other than glucose may also be important. 13 Out smdy could not rule out these additional etiologic
factors. It is possible that current obstetric surveillance may not be sensitive enough or performed frequently enough to detect subtle or intermittent maternal hyperglycemia. Subtle maternal hyperglycemia as a cause of fetal hyperinsulinemia, macrosomia, and neonatal hypoglycemia will be better addressed by a prospective study that includes maternal hemoglobin Alc. We conclude that some macrosomic infants of nondiabetic mothers have elevated cord blood C-peptide levels. The combination of macrosomia and neonatal hypoglycemia may be explalned in part by chronic fetal hyperinsulinism. We gratefully acknowledge the assistance of Dr. Jeanne L. Ballard, who critically reviewed the manuscript. We thank Ms. Mary Grous, Chris Dalin, and Dr. Leslie Hansen for their help in data acquisition. REFERENCES
1. Pedersen J. Weight and length at birth of iräants of diabetic mothers. Acta Endocrinol 1954;16:330-42.
484
Akinbi and Gerdes
The Journal of Pediatrics September 1995
2. Kaden M, Harding P, Field JB. Effects of intraduodenalglucose administration on hepatic extraction of insulin in the anesthetized dog. J Clin Invest 1973;52:2016-28. 3. Faber OK, Kehlet H, Madsbad S, Binder C. Kinetics of human C- peptide in man. Diabetes 1978; 27:207-9. 4. Horwitz DL, Starr JI, Mako ME, Backard WG, RubinsteinAH. Proinsulin, insulin and C-peptide in human portal and peripheral blood. J Clin Invest 1975;55:1278-83. 5. Heding LG. Radioimmunological determination of human Cpeptide in serum. Diabetologia 1975;11:541-8. 6. Susa JB, Widness JA, Hintz R, Liu F, Sehgal P, Schwartz R. Somatomedins and insulin in diabetic pregnancies: effects of fetal macrosomia in human and rhesus monkey. J Clin Endocrinol Metabol 1984;58:1099-104. 7. Fletcher JM, Falconer J, Basset JM. The relationship of body and placental weight to plasma levels of insulin and other hormones during development of fetal rabbits. Diabetologia 1982;23:124-8.
8. Berk MA, Mimouni F, Miodovnik M, Hertzberg V, Valuck J. Macrosomia in infants of insulin-dependentmothers. Pediatrics 1989;83:1029-34. 9. Knip M, Lautala P, Leppaluoto J, Akerblom HK, Kouvalainen K. Relation of enteroinsular hormones at birth to macrosomia and neonatal hypoglycemia in infants of diabetic mothers. J PEOIATR1983;103:603-11. 10. Metzger P, Brachet E. The rabbit in the last third of gestation: data concerning whole fetus, its diaphragm and brown adipose tissue. Biol Neonate 1978;33:297-303. 11. Caballero CM, Gomez JR, Duo GA, et al. C-pepfide in cord blood of macrosomic and low birthweight infants. Anales Espafioles de Pediatria 1993;39:29-32. 12. FreinkelN.Ofpregnancyandprogeny.Diabetes1980;29:102335.
1-800-55-MOSBY This number links you to the full text of articles published in more than 25,000 journals, including all Mosby journals. M O S B Y Document Express ®, a rapid response information retrieval service, provides quick turnaround, 24-hour availability, and speedy delivery methods. For inquiries and pricing information, call our toll-free, 24-hour order tine: 1-800-55-MOSBY; outside the United States: 415-259-5046; fax: 415-259-5019; E-mail: [email protected]. MOSBY Document Express® is offered in cooperation with Dynamie Information Corp.