Increased Macrosomia and Perinatal Morbidity Independent of Maternal Obesity and Advanced Age in Korean Women With GDM

Transcription

1 Pathophysiology/Complicatios N A L A R T I C L E Icreased Macrosomia ad Periatal Morbidity Idepedet of Materal Obesity ad Advaced Age i Korea Wome With GDM HAK C.JANG, MD NAM H. CHO, PHD YONG-KI MIN, MD IN K. HAN, MD KYU B. JUNG, MD BOYD E. METZGER, MD OBJECTIVE To examie the impact of gestatioal diabetes mellitus (GDM) o periatal outcome i a settig where iflueces of materal age ad obesity would be miimal. RESEARCH DESIGN AND METHODS A case-cotrol study was doe to compare the outcome of pregacy i wome with GDM ad wome with ormal carbohydrate metabolism matched for age, height, ad prepregacy weight. RESULTS The frequecies of preeclampsia ad primary cesarea sectios were higher ad delivery was earlier i pregacies complicated by GDM. Birth weight, symmetry idex, ad chest circumferece were greater, ad macrosomia ad eed for phototherapy were more commo i offsprig of mothers with GDM. Cord-serum C-peptide ad isuli cocetratios were higher i the ifats of mothers with GDM ad were strogly correlated with birth weight ad symmetry idex. However, materal age, prepregacy weight, ad prepregacy BM1 were ot correlated with birth weight. Postpradial glucose levels durig the first 2 week after diagosis of GDM had associatios with the ifat's birth weight, symmetry idex, ad cord isuli cocetratio i the diet-treated patiets with GDM. CONCLUSIO Atepartum materal glucose metabolism was sigificatly associated with fetal hyperisuliemia ad excessive fetal growth i relatively oobese Korea wome. These fidigs support a direct role for metabolic factors i the adverse outcomes i pregacies complicated by GDM. The Pederso hypothesis (1) is widely accepted as the pricipal mediator of excess fetal growth ad periatal morbidity i diabetic pregacies. It states that a icrease i materal utriets is rapidly traslated ito a icreased utriet milieu for the fetus. The fetal pacreas respods to glucose ad amio acid stimuli, ad fetal hyperisuliemia results. The fetal hyperisuliemia has a sigificat effect o adverse fetal outcomes such as macrosomia, eoatal hypoglycemia, ad other periatal morbidities. Periatal morbidities, especially macrosomia, are observed more ofte tha expected i ifats of mothers with gestatioal diabetes mellitus (GDM), eve though widespread screeig for ad itesive maagemet of GDM reduce overall morbidity (2). GDM may also have log-term implicatios for offsprig. The offsprig of mothers with pregestatioal From the Departmets of Medicie (H.C.J., Y.-K.M., I.K.H.) ad Obstetrics ad Gyecology (K.B.J.), Samsug Cheil Hospital, Seoul; the Departmet of Prevetive Medicie (N.H.C.), Ajou Uiversity Medical School, Suwo, Korea; ad the Ceter for Edocriology, Metabolism, ad Molecular Medicie (B.E.M.), Departmet of Medicie, Northwester Uiversity Medical School, Chicago, Illiois. Address correspodece ad reprit requests to Hak C.Jag, MD, Sugkyukwa Uiversity, College of Medicie, Samsug Cheil Hospital, Departmet of Medicie, 1-19, Mookchug-Dog, Choog-Ku, Seoul, Korea jaghak@samsug.co.kr. Received for publicatio 18 November 1996 ad accepted i revised form 3 Jue Abbreviatios: FPG, fastig plasma glucose; GDM, gestatioal diabetes mellitus; IBW, ideal body weight; LGA, large for gestatioal age; OGTT, oral glucose tolerace test; SGA, small for gestatioal age. diabetes ad gestatioal diabetes have higher frequecies of childhood obesity, impaired glucose tolerace, ad type 2 diabetes i adolescece or later (3-5) ad may be at risk for impairmet of itellectual ad motor developmet (6). Although macrosomia ad periatal morbidities are see with icreased frequecy i offsprig of gestatioal diabetic mothers, some studies have suggested that materal obesity ad advaced age, rather tha cocurret mild hyperglycemia, are primarily implicated (7-10). There have bee limited studies of GDM i ative Asia wome. We reported that the prevalece of GDM i Korea wome was similar to that i U.S. Caucasias, eve though the frequecy of obesity was much lower i Korea wome (11). However, studies o pregacy outcome i Korea wome with GDM have ot bee reported previously. The purpose of this study was to ivestigate the implicatios of GDM for periatal morbidities i a populatio with a low prevalece of materal obesity. We tried to idetify the effect of materal hyperglycemia o pregacy outcomes without ifluece of materal obesity ad age. We compared the periatal outcomes of wome with GDM ad cotrol subjects with ormal glucose tolerace matched i age, height, ad prepregacy weight. The data were collected prospectively i a largescale program of uiversal screeig for GDM i Seoul, Korea. RESEARCH DESIGN AND METHODS Screeig ad diagosis From Jauary 1991 to December 1992, all pregat wome receivig ateatal care at the Samsug Cheil Hospital i Seoul were screeed for glucose itolerace at weeks' gestatio. The scree cosisted of a veous plasma glucose measuremet 1 h after a 50-g oral glucose load admiistered without regard to time or amout of last meal, as recommeded by the Third Iter DIABETES CARE, VOLUME 20, NUMBER 10, OCTOBER 1997

2 Jag ad Associates atioal Workshop-Coferece o Gestatioal Diabetes Mellitus, with mior modificatios (12). Wome with plasma glucose levels >7.2 mmol/l (130 mg/dl) were recalled for a 3-h 100-g oral glucose tolerace test (OGTT) performed after a overight fast of at least 8 h but o more tha 14 h. The tests were carried out i the outpatiet departmet after 3 days of 150 g of carbohydrate i the diet ad urestricted physical activities. Patiets were cosidered to have GDM if at least two values reached or exceeded the followig: 5.8 mmol/l (105 mg/dl) at fastig, 10.6 mmol/l (190 mg/dl) at 1 h, 9.2 mmol/l (1 mg/dl) at 2 h, ad 8.1 mmol/l (145 mg/dl) at 3 h (13). Subjects Periatal outcomes were studied i pregacies i which a sigleto ifat was delivered at the Samsug Cheil Hospital durig the study period. Pregacies complicated by coditios that might affect the outcomes of pregacy (chroic hypertesio, thyroid disease, real disease, asthma, chroic ifectious disease, ad smokig) were excluded from the study before data collectio. The study protocol was approved by the Samsug Cheil Hospital research ad ethics committee, ad iformed coset was obtaied from all subjects. Our objective was to select three cotrol subjects for each subject with GDM, specifically usig those matchig by age ± 3 years, prepregacy weight ± 2 kg, ad height ± 3 cm with screeig dates closest to the patiets with GDM. However, subjects with GDM were older ad heavier tha the populatio average. Thus, the fial matchig of all cotrol subjects of eligible weights ad ages yielded a ratio of 2.4:1 rather tha 3:1. The cotrol group was selected from those with ormal glucose tolerace; however, to assure a represetative sample, it was ot madated that the glucose value from the screeig test should be <7.2 mmol/l. Thus, i the cotrol group of wome, 128 had a egative scree (84%) ad 25 had a positive scree but a ormal glucose tolerace test (16%). Cliical maagemet protocol A team approach was used i the maagemet of GDM. The team, icludig physicias, urse educators, ad dietitias, provided idividualized diabetes care. Diet was composed of 50-60% carbohydrate, 20% fat, ad 20-30% protei, divided ito three meals ad two or three sacks per day. Noobese patiets were put o a diet of 35 kcal/kg ideal body weight (IBW) per day, ad obese patiets were put o a diet with mild caloric restrictio of 30 kcal/kg IBW per day. Patiets with a prepregacy BMI of ^27.3 kg/m 2 were classified as obese. It was recommeded that patiets walk for mi twice daily after meals. Total calorie itake ad calorie distributio were evaluated by 24-h diet recall. Glycemic cotrol was moitored by fastig ad 2-h postpradial veous blood glucose measuremets at weekly outpatiet visits i patiets maaged with diet ad exercise. Patiets requirig isuli therapy moitored their fastig, 2-h postpradial (three times a day), ad bedtime capillary blood glucose levels at home, ad their 2-h postpradial veous blood glucose values were measured at each outpatiet visit. The goals for glycemic cotrol were fastig blood glucose levels of mmol/l ad 2-h postpradial levels of ^6.7 mmol/l. Isuli therapy was added (twice daily mixed regular ad NPH isuli) whe a patiet had a fastig blood glucose level >5.8 mmol/l or a 2-h postpradial blood glucose level >6.7 mmol/l o two cosecutive weekly visits. If a patiets diagostic OGTT fastig plasma glucose (FPG) level was ^6.1 mmol/l, isuli therapy was started immediately The isuli dosage was adjusted to the results of blood glucose tests at weekly follow-up visits, ad total calories i the diet ad duratio of exercise were also adjusted to the patiets blood glucose levels ad rate of weight gai. Obstetric surveillace Subjects were certai of the date of their last mestrual period, or they had obstetric datig from a ultrasoud examiatio. Cliical estimates of gestatioal age were used if they were withi the rage of the ultrasoud estimates. If there were icosistecies betwee the ultrasoud ad cliical estimates of gestatioal age, the ultrasoud estimate was used if it had bee obtaied before 20 weeks' gestatio. Atepartum surveillace i pregat wome with GDM icluded serial ultrasouds ad biophysical profiles every 2-4 weeks after diagosis of GDM ad ostress tests ad amiotic fluid idex measuremets weekly after 34 weeks' gestatio. Labor was iduced after 40 weeks' gestatio if spotaeous labor had ot occurred. If the fetus was estimated by ultrasoud to weigh >4,000 g at 38 weeks' gestatio, delivery by primary cesarea sectio was recommeded uless the patiets were multigravida. I accord with Korea Medical Practice Guidelies, the primigravidas who were >35 years of age were delivered by primary cesarea sectio. Preeclampsia was defied as persistetly elevated blood pressure (systolic blood pressure ^140 mmhg ad/or diastolic blood pressure ^90 mmhg o more tha two measuremets ^6 h apart) ad proteiuria (si 4- i a urie protei test) i the 2d or 3rd trimester. The diagosis of polyhydramios was made by ultrasoud. At the begiig of labor, a itraveous ifusio of ormal salie was started uless the blood glucose level fell to <3.9 mmol/l (70 mg/dl). The goal of glycemic cotrol durig labor was a blood glucose level of mmol/l (70-90 mg/dl). If the blood glucose level was <3.9 mmol/l, ormal salie was chaged to 5% dextrose. Blood glucose cocetratio was moitored hourly. Neoatal assessmet All ewbors were examied immediately after delivery. Ay abormal physical fidigs were oted o the detailed physical examiatio stadardized with a code sheet, ad athropometric measuremets were doe by traied residets withi 24 h. Each ewbors weight ad legth were measured with the ifat i a supie positio, ad head circumferece was measured with a disposable tape at the largest diameter across the forehead. Chest circumferece was measured at the diameter across the ipple ad axilla. Ifats small for gestatioal age (SGA) at birth weighed below the 10th percetile for age, ad ifats large for gestatioal age (LGA) weighed above the 90th percetile accordig to Lubcheco ad colleagues (14,15). Relative obesity was assessed o the basis of the symmetry idex (16). Relative weight was measured as weight divided by the Lubcheco media weight for age. Relative height was measured as height divided by the Lubcheco media height for age. The relative weight divided by the relative height yields the symmetry idex. At delivery, cord-blood serum was sampled for later measuremets of C-peptide ad isuli ad stored froze at 70 C. Aalytical methods Plasma ad whole-blood glucose cocetratios were measured by a glucose oxidase method (YSI 2300 STAT, Yellow Sprigs Istrumets), ad capillary blood glucose cocetratios were measured by DIABETES CARE, VOLUME 20, NUMBER 10, OCTOBER

3 Pregacy outcome i Korea wome with GDM Table 1 Characteristics of the study subjects Materal age (years) Height (cm) Prepregacy weight (kg) Prepregacy BMI (kg/m 2 ) Obese subjects (>27.3 kg/m 2 ) (%) Weight gai durig gestatio (kg) Parity Gestatioal age at screeig test (weeks) GDM group 31.3 ± ± ± ± ± (58.5) 21 (32.3) 6 (9.3) 27.7 ±3.8 Normal cotrol group 30.3 ± ± ± ± ± (53.6) 63(41.2) 8 (5.2) 26.9 ±3.1 P <0.05 Data are meas ± SD or (%). The ormal cotrol group cosisted of 128 wome who had a egative scree ad 25 wome who had a positive scree but a ormal glucose tolerace test. glucose meter (Oe Touch II, Lifesca). Cocetratios of isuli ad C-peptide i cord serum were measured i duplicate at the Edocrie Laboratory of Samsug Cheil Hospital usig commercially available kits (isuli, Daiabot, Japa; C-peptide, Daichii, Japa). The itra- ad iterassay coefficiets of variatio for isuli were 4.5 ad 8.8%, ad the itraad iterassay coefficiets of variatio for C-peptide were 7.1 ad 9.7%, respectively Samsug Cheil Hospital). However, weight gai durig pregacy was sigificatly lower i the wome with GDM tha i the cotrol subjects. Gestatioal age at the time of the screeig test was similar i both groups. A diagostic OGTT was performed at 29.0 ± 2.7 weeks' gestatio i the wome with GDM. Amog the patiets with GDM, 42 were GDM class A 2 (FPG <5.8 mmol/1), 15 were GDM class A 2 (FPG >5.8, <7.2 mmol/1), ad 8 were GDM class Bj (FPG >7.2 mmol/1) at the time of diagostic OGTT. Of these patiets, 20 (30.8%) received isuli therapy for glycemic cotrol. Figure 1 shows mea values for fastig ad 2-h postpradial glucose cocetratios after the iitiatio of treatmet of GDM. Of the patiets with GDM, 45 were maaged by diet ad exercise (Fig. 1A) ad 20 required isuli treatmet (Fig. IB). Five wome with GDM were iitially treated with diet ad exercise, but required isuli therapy for glycemic cotrol. I the diet-treated patiets, fastig glucose decreased from 4.9 ± 0.4 to 4.6 ± 0.4 mmol/1 (P < 0.005) at the 2d week ad was maitaied at 4.5 mmol/1. Postpradial glucose decreased from 6.6±0.9to6.2± 0.8 mmol/1 (P < 0.005) at the 2d week ad 5.6 ± 0.8 mmol/1 (P < 0.05) at the 3rd week ad was maitaied at mmol/1. The overall averages of fastig ad 2-h postpradial veous glucose levels i the diet-treated group were 4.6 ± 0.4 ad 5.9 ± 0.8 mmol/1. I the isuli-treated group, fastig glucose decreased from 5.9 ± 0.8 to 5.0 ± 0.7 mmol/1 (P < 0.005) at the 2d week ad 4.7 ± 0.7 mmol/1 (P < 0.05) at the 3rd week ad was maitaied at mmol/1. The mea postpradial glucose decreased from 7.8 ± 0.7 to 7.2 ± Statistical aalysis Data are expressed as meas ± SD ad percetages uless otherwise stated. Compariso of obstetric ad eoatal outcome was computed by upaired t test, Ma-Whitey U test, x 2 test, or Fishers exact test where appropriate. The chages i materal glycemia were tested by paired t test. The relatioships amog the ifats' birth weight, athropometric measuremets, ad cord-blood C-peptide ad isuli cocetratios, ad the materal metabolic parameters were examied by Pearso correlatio, Spearma correlatio, partial correlatio, ad multiple liear regressio aalysis. Log trasformatio of isuli ad C-peptide cocetratio was applied to correct for oormal distributios. Statistical sigificace was defied as P < RESULTS The cotrol ad gestatioal diabetic groups were matched carefully, ad as expected, there were o sigificat differeces i age, prepregacy weight, height, BMI, ad parity (Table 1). The frequecy of obesity (BMI ^27.3 kg/m 2 ) was ot differet betwee the two groups (1.4% i the geeral obstetrical populatio at 7.5 i o <5 4.5 H E "3T 6.5 M Weeks Figure 1 Mea ± SE fastig (O) ad 2-h postpradial ( ) glucose cocetratios i wome with GDM after iitiatio of treatmet. A: veous blood glucose cocetratios i the diet-treated group. B: capillary blood glucose cocetratios i the isuli-treated group. The values caot be compared directly. There is ~15% differece betwee veous ad capillary blood glucose measuremet whe compared by the same aalytical method. The same may ot be the case whe laboratory measuremets of veous plasma glucose are compared with capillary whole-blood measuremets performed with reaget strips ad glucose meters DIABETES CARE, VOLUME 20, NUMBER 10, OCTOBER 1997

4 Jag ad Associates Table 2 Obstetric outcome i the study subjects Gestatioal age at delivery (weeks) Preterm delivery (<37 weeks) Preeclampsia Polyhydramios Total cesarea sectio Primary cesarea sectio Perieal laceratio (3 ad 4 ) Data are meas ± SD or GDM group 38.8 ±1.2 4 (6.2) 7 (10.8) 3 (4.6) 36 (55.4) 26 (40.0) 2(3.1) 0.6 mmol/l (P < 0.005) at the 2d week, 6.8 ± 0.4 mmol/l (P < 0.005) at the 3rd week, ad 6.5 ± 0.7 mmol/l (P < 0.05) at the 4th week ad was maitaied at mmol/l. The overall averages of capillary glucose levels were 4.7 ± 0.4 mmol/l (fastig) ad 6.9 ± 0.5 mmol/l (mea postpradial). The obstetric outcomes are summarized i Table 2. Although gestatioal age at delivery was sigificatly youger i patiets with GDM, the percetage of prematurity, deed as birth before 37 weeks' gestatio, was ot statistically differet betwee the gestatioal diabetic ad cotrol groups. The youger gestatioal age at delivery i the GDM group may be due, at least i part, to iductio of labor at 40 weeks' gestatio whe spotaeous labor had ot occurred. The frequecy of preeclampsia was sigificatly higher i the patiets with GDM, but the frequecy of polyhydramios was ot differet betwee the two groups. The overall rate of cesarea sectio was ot differet betwee the groups; however, the rate of primary cesarea sectio was sigificatly higher i those with GDM. The higher rate of primary cesarea sectio i those with GDM was related to higher frequecies of fetal distress (30.8% [8 of 26] vs. 8.6% [3 of 35], P < 0.05) ad of fetal weight estimated to be >4,000 g (15.4% [4 of 26] vs. 0% [0 of 35], P < 0.05). The fetal weight estimated by ultrasoud performed withi 7 days of delivery ad the actual birth weight were 4,187 ± 245 ad 4,115 ± 361 g i four patiets who delivered by cesarea sectio because of macrosomia. The frequecies of other idicatios for primary cesarea sectio did ot differ i the two groups: cephalopelvic disproportio (19.2% [5 of 26] vs. 34.3% [12 of 35], P = 0.16), elderly primigravida (19.2% [5 of 26] vs. 37.1% Normal cotrol group 39.6 ±1.2 4 (2.6) 2(1.3) 2(1.3) 69(45.1) 35 (22.9) 7 (4.6) P <0.001 <0.01 <0.05 [13 of 35], P = 0.11), abormal presetatio (7.7% [2 of 26] vs. 11.4% [4 of 35], P = 0.49), ad failure to progress (7.7% [2 of 26] vs. 8.6% [3 of 35], P = 0.64). The frequecy of perieal laceratios (3 ad 4 ) at delivery was also similar i the gestatioal diabetic ad cotrol groups. The eoatal outcomes ad athropometric measuremets of the offsprig at birth are summarized i Table 3. Mea birth weight was 138 g heavier i the ifats of mothers with GDM tha that i the ifats of cotrol mothers, eve though delivery was almost 1 week earlier. The frequecy of a LGA ifat was three times higher i the mothers with GDM. Macrosomia (birth weight >4,000 g) was four times more frequet i the pregacies complicated by GDM, eve though delivery was 1 week earlier. Although legths ad head circumfereces of ifats were ot differet betwee the two groups, chest circumfereces ad symmetry idexes were sigificatly higher i the ifats of mothers with GDM. The proportio of ifats with symmetry idexes >1.2 (a value ofte equated with fetal obesity) i mothers with GDM (23.1%) was much higher tha that i cotrol mothers (1.3%; P < 0.001). The diet-treated ad isulitreated subgroups with GDM did ot differ i gestatioal age at delivery (38.9 ± 1.1 vs ± 1.3 weeks, P = 0.14), birth weight (3,559 ± 468 vs. 3,406 ± 628 g, P = 0.28), frequecy of a LGA (42.2 vs. 35.0%, P = 0.39) or macrosomic (11.1 vs. 20.0%, P = 0.28) ifat, or i offsprig's chest circumferece (33.3 ± 1.7 vs ± 1.9 cm, P = 0.22) ad symmetry idex (1.11 ± 0.12 vs ± 0.15, P = 0.67). Ifats of mothers with GDM were at four times higher risk of requirig phototherapy (ifats with a serum bilirubi cocetratio ^205 umol/1 were referred for phototherapy), eve after cotrollig for gestatioal age at delivery. I ifats of mothers with GDM, the frequecy of eoatal hypoglycemia (plasma glucose 2 h after birth <1.7 mmol/l) was 7.7%, hypocalcemia (serum calcium <2.0 mmol/l) 9.2%, ad polycythemia (hematocrit >%) 12.3%. We were ot able to compare these eoatal complicatios betwee the two groups because ifats of cotrol mothers were ot routiely checked for hypoglycemia, hypocalcemia, ad polycythemia. We examied the relatioships betwee eoatal athropometric measuremets ad some materal characteristics that may ifluece fetal growth (Table 4). I the cotrol group, gestatioal age at delivery correlated with birth weight ad parity correlated with both birth weight ad symmetry idex. I uivariate aalyses, oly materal age was correlated with birth weight or symmetry idex i the GDM group. A sigificat relatioship betwee gestatioal age ad birth weight was ot see i the GDM group i uivariate aalyses; however, as expected, a sigificat correlatio Table 3 Neoatal outcomes ad athropometric measuremets i offsprig of the study subjects Birth weight (g) LGA ifat Birth weight >4,000 g Phototherapy Legth (cm) Head circumferece (cm) Chest circumferece (cm) Symmetry idex GDM group 3,514 ± (40.4) 9(13.8) 15(23.1) 50.1 ± ± ± ±0.13 Normal cotrol group 3,376 ±358 20(13.1) 5 (3.3) 6 (3.9) 50.1 ± ± ± ±0.06 Data are meas ± SD or (%). *Ajusted for effect of gestatioal weeks at delivery. P <0.05 <0.001 <0.01 <0.001 <0.01 <0.001 DIABETES CARE, VOLUME 20, NUMBER 10, OCTOBER

5 Pregacy outcome i Korea wome with GDM Table 4 Coefficiets of correlatio betwee birth weight ad symmetry idex of ifats ad characteristics of mothers Materal Age Prepregacy weight Prepregacy BMI Height Gestatioal age at delivery Parity GDM group Birth weight Normal cotrol group (-0.31*) = 0.17* (0.23t) Neoatal symmetry idex GDM group Normal cotrol group -0.26* (-0.31.*) (0.26T) Data are correlatio coefficiets (coefficiet after adjustig for gestatioal age at delivery). *P < 0.05,?P < 0.01, *P< betwee gestatioal age ad birth weight existed i the GDM group i multivariate aalyses. There was o sigificat correlatio betwee materal prepregacy weight, prepregacy BMI, or height ad ewbor birth weight or symmetry idex i the cotrol or GDM group. We compared 3-cell fuctio i the ifats of mothers with GDM ad ormal cotrol subjects by measurig cocetratios of C-peptide ad isuli i cordblood serum (Fig. 2). The level of cord-blood C-peptide was sigificatly higher i ifats of mothers with GDM. The mea cocetratio of isuli i the ifats of mothers with GDM was more tha twice that i the ifats of ormal cotrol mothers. p$-cell fuctio i the offsprig of mothers with GDM was also correlated with their athropometric developmet. Birth weight ad cocetratio of cord-blood C-peptide or isuli correlated strogly i the offsprig of mothers with GDM (r = 0.51, P < 0.001; r = 0.38, P < 0.01, respectively) but weakly i the offsprig of ormal cotrol subjects (r = 0.21, P < 0.01; r = 0.14, P < 0.05, respectively). However, the correlatio betwee birth weight ad cocetratio of cord C-peptide or isuli i the offsprig of ormal cotrol subjects was o loger sigificat after cotrollig for gestatioal age at delivery (r = 0.11, P > 0.05; r= 0.07, P > 0.05, respectively). Furthermore the slope of regressio betwee birth weight ad C-peptide or isuli i offsprig of mothers with GDM was greater tha that i offsprig of ormal cotrol mothers (Cpeptide, P < 0.001; isuli, P < 0.01). The relatioship betwee idexes of fetal (3-cell fuctio ad athropometric idexes of fetal adiposity was examied. Figure 3 illustrates a sigificat positive correlatio betwee cord-blood C-peptide cocetratio ad ifat chest circumferece ad symmetry idex i the offsprig of mothers with GDM. Similar correlatios were obtaied betwee cord isuli cocetratio ad both athropometric measures (chest circumferece, r = 0.29, P < 0.05; symmetry idex, r = 0.40, P < 0.01). I cotrast, we foud o sigificat correlatio betwee C-peptide or isuli i cord-blood serum ad these athropometric measures i the offsprig of cotrol mothers. We examied the relatioships betwee metabolic cotrol ad fetal (3-cell fuctio ad birth weight. I the diettreated group with GDM, ifat birth weight was correlated with materal 2-h postpradial glucose i the 2d week (31 weeks' gestatio; r = 0.45, P < 0.05) ad i the 1st week (30 weeks' gestatio; r = 0.29) mol/l 0.8 -, OGDM ONM C-peptide after iitiatio of treatmet with borderlie sigificace (P = 0.07), but ot with glycemia i subsequet weeks. Similar relatioships were foud betwee materal postpradial glucose early after the start of dietary treatmet ad ifat symmetry idex ad cord isuli i the 2d week (r = 0.51, P < 0.01; r = 0.44, P < 0.05) ad i the 1st week (r = 0.27, P = 0.08; r = 0.34, P = 0.06, respectively). We did ot fid correlatios betwee materal glycemia ad birth weight, symmetry idex, or cord isuli i the isuli-treated subjects. There were o sigificat correlatios betwee fastig glucose levels durig the 3rd trimester or plasma glucose cocetratios durig the diagostic OGTT (fastig, 1 h, 2 h, ad 3 h) ad birth weight, symmetry idex, or cord C-peptide or isuli i either group with GDM. Materal characteristics (age, prepregacy weight, BMI, height, gestatioal age at delivery, ad parity) ad idexes of fetal 3-cell fuctio (cord C-peptide ad isuli) were examied by stepwise multiple liear regressio aalysis to idetify those variables idepedetly associated with ifat birth weight i the GDM group. Cord C-peptide (P < 0.001) ad gestatioal age at delivery (P < 0.005) were sigificat ad idepedet predictors of birth weight. Cord isuli was ot sigificat; however, C-peptide ad isuli were strogly correlated, with a correlatio coefficiet of 0.79 (P < 0.001). CONCLUSIO From a obstetric view, the potetial sigificace of GDM is related to the magitude of risk for adverse outcomes of pregacy, rather tha the risk for subsequet overt diabetes i wome. I pmol/l P<0.05, ** P<0.01 B OGDM ONM Isuli Figure 2 (3-cell fuctio i offsprig of mothers with GDM (OGDM, ) ad ormal cotrol mothers (ONM, ). A: mea ± SE cocetratios of cord serum C-peptide. B: mea ± SE cocetratios of cord serum isuli DIABETES CARE, VOLUME 20, NUMBER 10, OCTOBER 1997

6 Jag ad Associates cm 38 -i 00. () A.' B '." (mol/l) ' / y ^ r =0.39 p<0.01 r =0.61 p< C-peptide cocetratio i cord blood (mol/l) Figure 3 Relatioship betwee C-peptide cocetratio i cord blood ad athropometric measuremets i 56 offsprig of mothers with GDM. A: correlatio betwee ifat's chest circumferece ad cord serum C-peptide cocetratio. B: correlatio betwee ifat's symmetry idex ad cord serum C-peptide cocetratio. two early studies i which there was o itervetio to correct hyperglycemia, O'Sulliva et al. (17) foud a periatal mortality rate of 6.4% amog 187 pregacies i wome with GDM compared with 1.5% amog 259 cocurret radomly selected pregacies i wome without GDM, ad Pettitt et al. (18) demostrated that the periatal mortality rate i Pima Idias icreased with a icrease i 3rd trimester 2-h plasma glucose cocetratio durig 75-g OGTT. I additio, the periatal morbidity rate ad the frequecy of obstetric complicatios icreased with icreasig 2- h glucose levels (18). Icreased periatal morbidities have subsequetly bee reported i pregacy complicated by GDM. Excess periatal mortality has ot bee observed. However, there has bee cotroversy regardig the specificity of adverse outcomes associated with GDM. Some have attributed the observed risk to cofoudig characteristics such as materal obesity ad advaced age of subjects with GDM rather tha to glucose itolerace. Lucas et al. (7) reported that there were o sigificat differeces i periatal morbidities ad obstetric outcomes betwee GDM class A x patiets ad cotrol subjects with ormal glucose tolerace tests, ad that materal obesity was a idepedet ad more potet risk factor for large ifats tha was glucose itolerace. However, materal obesity was defied as last atepartum weight >90 kg istead of usig prepregacy BMI or relative weight. Jacobso ad Cousis (19) reported that patiets with GDM had a higher rate of LGA ifats tha did ormal subjects, eve though acceptable glucose cotrol was achieved, ad that oly materal weight at delivery was a sigificat predictor of LGA ifats, but prepregacy BMI ad weight were ot associated with ifat birth weight percetile i their report. Leiki et al. (20) reported that severely obese (> 150% IBW) patiets with GDM with fastig hyperglycemia had a four times higher frequecy of macrosomia tha did ormal subjects, but oobese patiets with fastig hyperglycemia had a frequecy of macrosomia similar to that i ormal subjects. However, the frequecy of macrosomia i the fastig euglycemic obese patiets with GDM was ot differet from that i fastig euglycemic oobese patiets with GDM or ormal subjects. I our study, prepregacy weight ad BMI, ad weight at delivery i the patiets with GDM were quite differet from those i the above reports from North America. Obesity is relatively ucommo i Korea wome. Furthermore, our cotrol subjects were of similar age ad weight as those with GDM to miimize the iflueces of materal age ad obesity. We also excluded patiets with other medical coditios that might affect pregacy outcome. I our subjects, who were matched for age, prepregacy weight, ad height, we foud that the frequecies of preeclampsia ad primary cesarea sectio were higher i pregacies complicated by GDM. The higher frequecy of primary cesarea sectio was attributed to higher frequecies of fetal distress ad estimated macrosomia i wome with GDM. However, wome with GDM were treated by a high-risk obstetrical service. I wome with GDM, frequet fetal surveillace by ultrasoud ad ostress tests ad the kowledge of GDM might cotribute to a icreased frequecy of primary cesarea sectio. As poited out by Naylor et al. (21), the diagosis of GDM may ifluece obstetrical practice ad icrease the probability of cesarea delivery The rates of cesarea sectio foud i this study caot be compared directly to may other reports because curret idicatios for cesarea sectio i Korea are somewhat differet from those i North America ad Europe. Birth weight, frequecy of macrosomia, ad idexes of fetal adiposity (symmetry idex ad chest circumferece) were greater ad ifats requirig phototherapy were also more commo i offsprig of mothers with GDM. We foud o correlatios betwee birth weight ad materal height, prepregacy weight, or BMI i wome with GDM or i cotrol subjects. Materal age i wome with GDM was egatively correlated with birth weight, but it was cofouded by the relatioship betwee materal age ad cord C-peptide or isuli cocetratio. Fetal hyperisuliemia has bee reported i wome with GDM (22,23). I this study we also foud that cord C-peptide ad isuli cocetratios i ifats of Korea mothers with GDM were higher tha those i ifats of cotrol mothers, despite close supervisio of diet ad exercise ad additio of isuli whe treatmet goals were ot met. There were o differeces i birth weight, frequecies of LGA ad macrosomic ifats, ad ifat adiposity betwee the diet-treated ad isulitreated subgroups with GDM. These results suggested that isuli therapy was effective i achievig the treatmet goal. Ifat birth weight was sigificatly ad idepedetly correlated with cord C-peptide or isuli cocetratio i the wome with GDM, but ot i the cotrol subjects. We also foud sigificat positive correlatios betwee cord-blood C-peptide ad two idexes of relative adiposity (symmetry idex ad chest circumferece) i the offsprig of mothers with GDM. Chest circumferece icreases as subcutaeous soft tissues ad isuli-sesitive orgas (e.g., liver, heart) grow (24), ad symmetry idex relates to relative weight i a maer somewhat like BMI (16). Thus, a large chest circumferece ad a high symmetry idex reflect disproportioate growth of the fetus. Materal 2-h postpradial glucose level, but ot fastig plasma glucose, was positively correlated with birth weight, symmetry idex, ad cord isuli i the diet-treated wome with GDM. Jovaovic-Peterso et al. (25) previously demostrated a stroger positive correlatio betwee 1-h postpradial glucose level ad birth weight tha betwee fastig level ad birth weight i wome with type 1 diabetes. Fetal islet fuctio was ot measured (25). The associatios we foud were sigificat oly i the first 2 weeks. These fidigs support the hypothesis that there is a critical period for DIABETES CARE, VOLUME 20, NUMBER 10, OCTOBER

7 Pregacy outcome i Korea wome with GDM materal glucose stimulatio of fetal isuli secretio that may occur eve before the diagosis ad treatmet of GDM (26). It is also likely that alteratios of other isulisesitive materal utriets (lipids ad amio acids) cotribute to the developmet of fetal hyperisuliemia ad macrosomia i the offsprig of mothers with GDM (26). The loss of correlatio betwee metabolic cotrol later i gestatio ad outcome measures of fetal growth ad (3-cell fuctio may also reflect the fact that these parameters did ot fully retur to ormal eve though metabolic cotrol improved for the remaiig weeks of gestatio. I summary, i Korea wome, we observed more adverse outcomes of pregacies i patiets with GDM tha i cotrol subjects. Obesity is ifrequet, ad measures were take to elimiate the cofoudig effects of materal age ad weight. Icreased periatal morbidities ad macrosomia, ad the ifats' athropometric measuremets were related to the magitude of perturbatio of the materal metabolic eviromet. These fidigs support a direct role for metabolic factors i adverse outcomes i pregacies complicated by GDM. Ackowledgmets This study was supported i part by a research grat from Cheil Medical Foudatio ad by Natioal Istitutes of Health Grats HD ad DK We thak Drs. H.Y. Chug ad S.K. Lee i the Departmet of Iteral Medicie; Drs. Y.B. Lee, E.S. Kim, ad M.Y. Kim i the Departmet of Obstetrics; ad Dr. H.K. Ha i the Departmet of Pediatrics for their cotributios. We also thak M.S. Kim, M.H. Park, ad other staff of the Edocrie Laboratory, Samsug Cheil Hospital, ad A. Raji, Radioimmuoassay Laboratory, Divisio of Edocriology, Northwester Uiversity Medical School. We are particularly grateful to Dr. S. Dooley for may helpful suggestios durig the preparatio of this mauscript. Preseted at the 54th Aual Meetig ad Scietific Sessios of the America Diabetes Associatio, New Orleas, LA, 9-13 Jue Refereces 1. Pederso J, Moller B, Poulso A: Blood sugar i ewbor ifats of diabetic mothers. Acta Edocriol 15:33-36, Hod M, Merlob P, Friedma S, Schoefeld A, Ovadia J: Gestatioal diabetes mellitus: a survey of periatal complicatios i the 1980s. Diabetes 40 (Suppl. 2):74-78, Pettitt DJ, Beett PH, Saad MF, Charles MA, Nelso RG, Kowler WC: Abormal glucose tolerace durig pregacy i Pima Idia wome: log-term effects o offsprig. Diabetes 40 (Suppl. 2): , Silverma BL, Rizzo T, Gree OC, Cho NH, Witer RJ, Ogata ES, Richards GE, Metzger BE: Log-term prospective evaluatio of offsprig of diabetic mothers. Diabetes 40 (Suppl. 2): , Silverma BL, Cho NH, Metzger BE, Loeb CA: Impaired glucose tolerace i adolescet offsprig of diabetic mothers: relatioship to fetal hyperisuliism. Diabetes Care 18: , Rizzo T, Metzger BE, Burs WJ, Burs K: Correlatios betwee atepartum materal metabolism ad itelligece of offsprig. NEglJMed 325: , Lucas MJ, Lowe TW, Bowe L, Mcltire DD: Class Al gestatioal diabetes: a meaigful diagosis? Obstet Gyecol 82:260-2, GreeJR, Schumacher LB, Pawso IG, Partridge JC, Kretchmer N: Ifluece of materal body habitus ad glucose tolerace o birth weight. Obstet Gyecol 78: , Willma SP, Leveo KJ, Guzick DS, Williams ML, Whalley PJ: Glucose threshold for macrosomia i pregacy complicated by diabetes. Am J Obstet Gyecol 154: , Cudy T, Gamble G, Mauel A, Towed K, Roberts A: Determiats of birth-weight i wome with established ad gestatioal diabetes. Aust NZJ Obstet Gyaecol 33: , Jag HC, Cho NH, Jug KB, Oh KS, Dooley SL, Metzger BE: Screeig for gestatioal diabetes mellitus i Korea. It J Gyecol Obstet 51: , Metzger BE: Summary ad recommedatios of the Third Iteratioal Workshop- Coferece o Gestatioal Diabetes Mellitus. Diabetes 40 (Suppl. 2): , Natioal Diabetes Data Group: Classificatio ad diagosis of diabetes ad other categories of glucose itolerace. Diabetes 28: , Lubcheco LO, Hasma C, Dressier M, Boyd E: Itrauterie growth as estimated from livebor birthweight data at weeks of gestatio. Pediatrics 32: , Lubcheco LO, Hasma C, Boyd E: Itrauterie growth i legth ad head circumferece as estimated from live births at gestatioal ages from weeks. Pediatrics 37: , Farquhar JW: Progosis for babies bom to diabetic mothers i Ediburgh. Arch Dis Child 44:36-47, O'Sulliva JB, Charles D, Maha CM, Dadrow RV: Gestatioal diabetes ad periatal mortality rate. Am J Obstet Gyecol 116: , Pettitt DJ, Kowler WC, Baird RH, Beett PH: Gestatioal diabetes; ifat ad materal complicatios of pregacy i relatio to third-trimester glucose tolerace i the Pima Idias. Diabetes Care 3: , Jacobso JD, Cousis L: A populatiobased study of materal ad periatal outcome i patiets with gestatioal diabetes. Am J Obstet Gyecol 161: , Leiki E, Jekis JH, Graves WL: Prophylactic isuli i gestatioal diabetes. Obstet Gyecol 70: , Naylor CD, Sermer M, Che E, Sykora K, the Toroto Trihospital Gestatioal Diabetes Ivestigators: Cesarea delivery i relatio to birth weight ad gestatioal glucose tolerace: pathophysiology or practice style? JAMA 275: , Ogata ES, Freikel N, Metzger BE, Phelps RL, Depp R, Boehm JJ, Dooley SL: Periatal islet fuctio i gestatioal diabetes: assessmet by cord plasma C-peptide ad amiotic fluid isuli. Diabetes Care 3: , Weiss PAM, Hofma HM, Witer RR Lichteegger W, Piirster P, Haas J: Diagosis ad treatmet of gestatioal diabetes accordig to amiotic fluid isuli levels. Arch Gyecol 239:81-91, Susa JB, Neave C, Sehgal P, Siger DB, Zeller WP, Schwartz R: Chroic hyperisuliemia i the fetal rhesus mokey: effects of physiologic hyperisuliemia o fetal growth ad compositio. Diabetes 33:6-660, Jovaovic-Peterso L, Peterso CM, Reed GF, Metzger BE, Mills JL, Kopp RH, Aaros JH, the NICHD-DIEP: Materal postpradial glucose levels ad ifat birth weight: the Diabetes i Early Pregacy Study. Am J Obstet Gyecol 164: , Metzger BE: Biphasic effects of materal metabolism o fetal growth: quitessetial expressio of fuel-mediated teratogeesis. Diabetes 40 (Suppl. 2):99-105, DIABETES CARE, VOLUME 20, NUMBER 10, OCTOBER 1997