Diabetic nephropathy: Pregnancy performance and fetomaternal outcome

Diabetic nephropathy: Pregnancy performance and fetomaternal outcome E. Albert Reece, MD,a Donald R. Coustan, MD: John P. Hayslett, MD," Theodore Holford, PhD,c Jeanne Coulehan, RN: Theresa Z. O'Connor, MPH,c and John C. Hobbins, MD" New Haven, Connecticut A study of 31 continuing pregnancies complicated by diabetic nephropathy was conducted to determine the effects of diabetes-associated renal disease on maternal health and fetal outcome. Throughout pregnancy there was a significant increase in maternal blood pressure (p < 0.001) and proteinuria (p < 0.0001), with nephrolic syndrome (>3.0 gm protein/day) developing in 71% of pregnancies. After birth, however, proteinuria reverted to levels not significantly different from values in early pregnancy. There was no apparent adverse effect of pregnancy on the natural course of the underlying renal disease. Stillbirths occurred in two patients (6%), and the remaining 29 pregnancies resulted in live-births at a mean gestational age of 36 weeks. Seventy percent of these infants were appropriate for gestational age, whereas 16% were small and 13% were large for gestational age. Birth weight was best correlated with gestational age and creatinine clearance (p < 0.0001 ). Neonatal complications included respiratory distress syndrome (19%), hyperbilirubinemia (26), and congenital malformations (10%). The uncorrected perinatal survival rate was 94%. These data suggest that with contemporary methods of maternal evaluation and treatment, fetal surveillance, and neonatal care, the risks to patients with diabetic nephropathy during pregnancy are not excessive. The likelihood of a successful fetal and neonatal outcome is comparable to that in other patients with insulin-dependent diabetes. (AM J OBSTET GYNECOL 1988;159:56-66.)

Key words: Diabetes and pregnancy, nephropathy and pregnancy, kidney or renal disease and pregnancy

Diabetic nephropathy is a complication of diabetes mellitus and occurs in 30% to 40% of patients with insulin-dependent (type I) and approximately 50% of subjects with noninsulin-dependent diabetes (type II). In type I disease, renal insufficiency eventually occurs in all patients who exhibit macroproteinuria,' whereas in type II disease a deterioration is found in only 5% to 10%.2 Mogensen" describes five stages in the course of type I diabetic nephropathy: (l) early hypertrophyhyperfunction, (2) glomerular lesions without clinical disease, (3) incipient nephropathy characterized by microproteinuria, (4) overt nephropathy characterized by macroproteinuria, and (5) end-stage diabetic renal disease. Pregnancies complicated by overt clinical nephropathy are considered to be at increased risk for fetomaternal morbidity and perinatal mortality. 2 · 1· 5 For From the Diabetes-in-Pregnancy Study Unit of the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology,' the Nephrology Section of the Department of Internal Medicine,' and the Biostatistics Section of the Department of Epidemiology and Public Health,' Yale University School of Medicine. Received for publication January 16, 1987; revised May 20, 1987; accepted January 7, 1988. Reprint requests: E. Albert Reece, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar St., P.O. Box 3333, New Haven, CT 06510.

56

example, Hare and White' reported a fetal survival rate of72% in patients with diabetic nephropathy compared with 94% in diabetic subjects without nephropathy between 1963 and 1975. Kitzmiller et al., 5 however, reported an 89% neonatal survival rate, without substantial maternal complications, in 26 women with diabetic nephropathy who attained 24 weeks' gestation. Uncertainties still remain among clinicians regarding pregnancy performance and outcome, and pregnancy termination is often advised for diabetic pregnancies associated with nephropathy. The purposes of this study were to examine the effects of diabetic nephropathy on maternal blood chemistry and renovascular function during pregnancy, to assess maternal and neonatal outcomes, and to evaluate maternal and infant status at long-term follow-up.

Material and methods

Patients. The medical records of all patients discharged from Yale-New Haven Hospital between 1975 and 1984 with the diagnosis at discharge of diabetes mellitus and pregnancy were reviewed and assigned to a specific diabetic classification according to the White criteria. We then determined which patients exhibited abnormal protein excretion or reduced glomerular

Diabetic nephropathy

Volume 159 Number I

filtration rate according to criteria established by Davidson• in normal pregnancies. He found that in normal pregnancies, urinary protein excretion rose from 103 ± 49. l mg/24 hr (mean ± SD) in the early first trimester to 151 ± 39.9 mg/24 hr in the second trimester and to 180 ± 50 mg/24 hr in the third trimester. He also observed that the 24-hour creatinine clearance increased from 117 ± 18.2 to 136 ± 11 ml/ min between early and midpregnancy, and the serum creatinine level in normal pregnant women averages 0.6 to 0.8 mg/di. In the current study patients were classified as having diabetic nephropathy if the urinary protein level was :;3300 mg/24 hr before the third trimester. Patients were classified as having renal insufficiency if the creatinine level was > 1.2 mg/di or creatinine clearance was <90 ml/min in the absence of urinary tract infection and other causes of primary or secoridary renal disease. The severity of the proteinuria was categorized as mild (300 to 499 mg/24 hr), moderate (500 to 3000 mg/24 hr), and severe or nephrotic syndrome (>3 gm/24 hr). Retrospective chart analysis also included documentation of the maternal status includin~ renal function, blood pressure, retinal examination, and information concerning delivery and fetal outcome. Categorization of infant birth weights was based on the scale of Usher and McLean;: small for gestational age (<10th percentile for gestational age), large for gestational age (>90th percentile for gestational age), and appropriate for gestational age (>I 0th and <90th percentiles for gestational age). Maternal and pediatric follow-up. Each patient and her private physician was contacted by telephone. Maternal information sought included current physical status and present level of activity, blood pressure, hematocrit, hemoglobin, blood urea nitrogen, serum creatinine level, creatinine clearance, and urinary protein excretion. Infant follow-up information included current age, height, weight, and the results of the most recent physical and neurologic examinations. Renovascular factors (serum creatinine, creatinine clearance, urine protein, hemoglobin, and blood pressure) were analyzed by linear and multiple regression analyses to determine what effect each factor had singly or in combination on birth weight. In addition, the change in renovascular function throughout the pregnancy was evaluated by repeated measures analysis of variance and compared with data from nondiabetic pregnant women with renal disease reported el sew here. 8 Fetomaternal. management. The management of pregnant patients with diabetes in our clinic has been previously described.9 A major goal in maternal management was normalization of blood glucose levels (average plasma values < 120 mg/ di). The diabetes in 24

57

patients (77%) was managed by multiple-dose insulin therapy of at least two doses of mixed insulin (short and intermediate acting) administered in the morning and afternoon, whereas seven patients (23%) used subcutaneous insulin infusion pumps. Blood glucose determinations were performed five to seven times each day in these patients to assess blood glucose levels and regulate insulin dosage. Blood glucose determinations were performed at home by the patient, and hospitalization was recommended only if control of blood glucose was not easily achieved on an outpatient basis. Patients were usually not treated with antihypertensive medications unless the diastolic blood pressure exceeded 105 rrim Hg, because fetal and maternal outcomes are reported to be satisfactory even in mild to moderate hypertension (diastolic pressure >90 and < 110 mm Hg). ' 0 Preferred medications to control hypertension included a-methyldopa or hydralazine. Patients taking diuretics for hypertension before pregnancy maintained the same therapy (hydrochlorothiazide or furosemide) throughout pregnancy. Because the diagnosis of preeclampsia is difficult to confirm in patients with 'nephropathy, our criteria for diagnosis included acute worsening of hypertension (> 15% increase in systolic or diastolic blood pressure) or deterioration of renal function associated with multisystemic involvement, resulting in abnormal liver function tests and coagulation studies, particularly elevation in the fibrin split products and thrombocytopenia. Unless there was evidence of fetal stress/ distress or a maternal indication for delivery (including worsening hypertension or severe preeclampsia), pregnancies were allowed to continue to term and were delivered vaginally if possible, after the establishment of fetal pulmonic maturity. Results Description of study population. During the study interval (1975 to 1984), 568 diabetic pregnancies were delivered by the perinatal service at Yale-New Haven Medical Center. Of these, 410 patients (72.2%) were diagnosed as having diabetes during pregnancy (White classes A and A/B), and 158 patients (27.81/i) had been insulin-requiring diabetics before pregnancy (White classes B through FR and H). There were 36 pregnancies (6.3%) in patients with type I diabetes who had diabetic nephropathy (class F or FR). Because firsttrimester termination of pregnancy occurred voluntarily in two pregnancies (6%) and spontaneously in three pregnancies (8%), the outcome data in this report will be based on 31 continuing pregnancies complicated by diabetic nephropathy. Table I lists the initial clinical status and gestational outcome of these 31 pregnancies. The women ranged in age from 14 to 37 years (mean 28 ± 5.7 years). Onset

58

Reece et al.

July 1988 Am J Obstet Gynecol

Table I. Description of study group at entry, mode and indications for delivery, and outcome of fetus

Patient No.

Year

I 2 3 4 5 6 7 8 9 IO II 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

1975 1977 1980 1979 1979 1983 1976 1976 1978 1978 1980 1979 1982 1977 1980 1978 1977 1980 1980 1979 1981 1982 1977 1976 1982 1982 1982 1982 1980 1982 1980

Nephropathy

DP PTP I yr PTP 3 yr PTP DP 4 yr PTP DP 3 yr PTP DP DP PTP DP DP DP DP DP PTP DP DP 2 yr PTP I yr PTP DP DP DP DP DP 2 yr PTP 2 yr PTP DP DP 2 yr PTP

Ser (mg/di)

Ccr (mllmjn)

Upr (gm/day)

BP (mm Hg)

Type of retinopathy

I. I I. I

58 82 75 100 102 102

1.4 6.8 4.6 0.3 2.6 2.6 0.3 0.3 2.0 2.8 4.2 0.3 0.3 0.3 I. I 5.2 1.5 2.4 1.5 4.0 0.3 0.9 5.5 0.3 2.3 2.7 4.6 0.8 0.3 1.8 4.7

150/85 130/90 143/94 146/82 130/90 140/90 140/85 116/86 I I0/70 131 /85 156/92 140/75 100170 120/86 120/80 142/85 120170 160/80 121/76 180/110 135/70 100/70 120/84 120/80 130/80 120176 128/100 160/80 110170 118/80 140/90

p p p p p p p p B p p p p B p B p B p p p B B B p B p B p B p

1.4 0.8 0.9 0.9 0.9 0.8 0.8 1.5 0.8 0.9 0.5 0.6 0.8 0.5 0.8 I. I 0.7 I. I 2.3 0.8 2.2 0.8 0.6 0.7 0.6 0.8 0.5 0.6 0.8

JOO

90 100 53 105 117 135 102 49 168 60 62 97 31 25 245 25 141 149 118 116 Ill 72 165 114

Weeks' gestation

12 12 20 8 8 20 28 IO IO 23 8 17 9 16 13 28 8 12 IO

8 12 16 26 20 14 9 7 8 IO 7 14

Ser, Serum creatining; Cer, creatinine clearance; Upr, urinary protein excretion; BP, blood pressure; LB, live-birth, SB, stillbirth; DP, during pregnancy; P, proliferative; CT, conventional therapy; 1°CS, first cesarean section; AFHRT, antepartum fetal heart rate testing; AGA, appropriate for gestational age; PTP, prior to pregnancy; 2°CS, second cesarean section; SCA, small for gestational age; Vag, vaginal; LGA, large for gestational age; B, background; CPD, cephalopelvic disproportion; PROM, premature rupture of the membranes; retin, retinopathy; mat comps, maternal complications.

of diabetes was at a mean age of 12.4 ± 5. 7 years (range of 2 to 30 years), while duration averaged 16.4 ± 4.5 years. Clinical evidence of nephropathy before pregnancy was found in 12 patients (39%) and was recognized in early pregnancy in 19 (61 %). At the initial visit there were 9 patients (29%) with mild, 14 (45%) with moderate, and 8 (26%) with severe proteinuria or nephrotic syndrome. Reduced renal function (serum creatinine level > 1.2 mg/ di or creatinine clearance <90 ml/min) associated with proteinuria was present in 12 (39%) of these gestations. Twenty-one patients (68%) had proliferative retinopathy, and background retinopathy was observed in the remainder. Overall, the incidence of renal insufficiency, heavy proteinuria, and proliferative retinopathy indicated that this group of patients had moderately severe vascular complications of diabetes at onset or during the course of pregnancy. Effect of pregnancy on diabetic nephropathy. Maternal renovascular performance during the 31 continuing pregnancies is outlined in Table II and Fig. I.

Changes in blood and urine determinations < 15% were considered to reflect normal variations. Serum creatinine levels increased in 35% of pregnancies and remained stable or decreased in 52%. Data were not available for calculations in three patients. Creatinine clearance decreased in 12 pregnancies (39%) and increased in 11 (35%), with a mean decrease in clearance of 46% and a mean increase of26%, respectively. Most patients had significant increases in proteinuria, and nephrotic syndrome occurred during the pregnancy in 22 (71 %). An increase in blood pressure occurred in 19 pregnancies (mean of 15% systolic or diastolic) and ameliorated in 5 pregnancies (mean of 8.8% systolic or diastolic). By repeated measures analysis of variance we found no significant difference in serum creatinine values (F[2,71] = 0.46, p < 0.63) throughout the pregnancy. Urinary protein excretion ( F[2,64] = 11.52, p = 0.0001) and diastolic blood pressure (F(2,69) = 9.06, p = 0.0003), however, increased significantly as pregnancy progressed but reverted in the puerperium.

Volume 159 Number I

Diabetic nephropathy 59

Feta! outcome White's class FR FR FR FR FR FR FR FR F FR FR FR FR F FR F FR F FR FR FR F F F FR F FR F FR

F FR

Insulin

Weeks at delivery•

Deliver1 mode I indic~tiom

LB/SB

CT Pump Pump CT Pump CT CT CT Pump CT CT CT CT CT CT CT CT CT CT Pump CT CT CT CT CT CT Pump CT CT Pump CT

34.0 32.0 38.0 38.0 36.0 31.0 36.0 38.0 39.0 38.0 36.0 35.0 39.0 40.0 37.0 35.0 33.0 37.0 39.0 31.0 37.0 40.0 38.5 28.0 34.0 34.0 36.5 37.5 29.5 36.0 24.0

l°CS/ + AFHRT 2°CS I Repeat 2°CS I Repeat 2°CS/ Repeat Vag/bradycardia J°CS/ + AFHRT l°CS/breech 2°CS/ repeat 2°CS/ repeat l°CS/CPD I °CS/breech 2°cs I repeat 2°CS/ repeat Vag/term Vag/term l°CS/ + AFHRT Vag/PROM; retin l°CS/ + AFHRT l°CS/CPD J°CS/ + AFHRT l°CS/ + AFHRT 1°CS/CPD l°CS/mat comps Vag/SB l°CS/ + AFHRT 1°CS/mat comps Vag/term Vag/term l°CS/mat comps Vag/PROM Vag/SB

LB LB LB LB LB LB LB LB LB LB LB LB LB LB LB LB LB LB LB LB LB LB LB SB LB LB LB LB LB LB SB

Creatinine clearance increased transiently in the second trimester, but levels in the third trimester were similar to those measured in the first trimester ( F( 1,56) = 2.48, p = 0.12). No patient experienced worsening retinopathy that was not responsive to photocoagulation therapy during pregnancy or post partum. Effect of pregnancy on maternal outcome. Fig. 2 summarizes glycemic control during each trimester. There was significant improvement in control during consecutive trimesters. There were no occurrences of diabetic ketoacidosis in this series, and although episodes of hypoglycemia were not uncommon, precise records of these were unavailable. Other complications encountered in these pregnancies included anemia (hemoglobin
I

Apgar score (I min I 5 min)

3/8 2/8 9/8 8/9 8/9 217

515 415 919 919 919 8/9 5/8

919 919 114 3/5 7/8

919 4/8

919 8/9 8/8

010 2/5 5/8

719 9110 7/8 8/8 0/0

I

Weight (gm) 1540/AGA 1029/SGA 2800/ AGA 2070/SGA 3120/AGA 1280/AGA 3272/LGA 2915/AGA 3100/AGA 2600/AGA 2400/AGA 2280/AGA 3055/AGA 2470/AGA 2580/AGA 2850/AGA 2320/AGA 1420/SGA 4100/LGA 1350/AGA 1620/AGA 4200/LGA 2100/SGA 3100/AGA 1928/AGA 1887/AGA 3410/LGA 2640/AGA 1060/AGA 2590/AGA 700/AGA

age of 36 ± 2.7 weeks. Stillbirths occurred at 28 and 24 weeks in two patients with poor blood glucose control. The stillborn fetus at 28 weeks was large for gestational age and was severely anomalous, while the other fetus at 24 weeks was appropriate for gestational age and had no gross malformations. Two neonates had birth defects (ventricular septa) defect and a large patent ductus arteriosus), and in both of these pregnancies the maternal first trimester glucose control had been unsatisfactory. Antepartum fetal heart rate testing results were abnormal in seven pregnancies (23%) and were the most common indication for a primary cesarean section. Other indications included malposition in two (6%), worsening maternal disease in three ( 10%), and cephalopelvic disproportion in three ( 10% ). Among the seven pregnancies delivered because of abnormal antepartum fetal heart rate testing, respiratory distress syndrome occured in five (84%). The mean birth weight was 2808.6 ± 807 gm at a mean gestational age of 36 weeks. Examination of the correlations between renovascular factors and birth weight revealed that both appropriate- and smallfor-gestational age infants were delivered of women with similar degrees of renovascular compromise. Re-

60

July 1988 Am J Obstet Gynccol

Reece et al.

Table II. Effect of pregnancy on maternal renovascular disease Mean urinary protein excretion (mg/day)

Mean serum creatinine (mgldl)

Trimester

Tn.mester

I

Patient No.

I

I 2 3 4 5 6 7 8 9 JO JI 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

I. I I. I 1.4 0.8 0.9 LR LR 0.8 0.8 LR 0.8 LR 0.5 LR 0.8 LR 0.8 I. I 0.7 I. I 2.3 LR LR LR LR 0.7 0.6 0.8 0.5 0.6 LR

2 1.3 1.3 1.4 0.7 1.0 0.9 LR 0.7 0.7 1.5 0.7 0.9 0.5 0.6 1.0 0.5 1.2 1.3 0.6 1.9 2.9 0.8 2.2 0.8 0.6 0.7 0.6 0.8 0.7 0.6 0.8

I

3

Follow-up (mo)

1.2 2.0 1.9 1.3 1.0 3.0 0.9 0.6 0.8 1.4 0.8 0.8 0.5 0.6 1.3 0.8 1.5 1.5 0.7 3.3 3.0 0.5

1.4 (86) 5.5 (13) 14.3 (48) 1.6 (3) 1.7 (34) 3.5 (I) 0.8 (63) 0.7 (46) 1.4 (42) 6.5 (67) 0.9 (I) I. I (42) 0.6 (I)

0.9 I. I

0.9 0.6 1.3 0.7 0.6

2.0 (37) 6.6 (75) 1.5 (9) 7.0(19) 1.5 (18) 0.6 (I) 3.0 (38) 0.5 (23) 0.7 (2) 1.3 (2) 0.8 (4) 1.4 (2) 0.8 (3)

'7c Change* 9 82 36 63 11 333 -25 0 0 0 -II 0 0 63 60 88 36

0 200 30 -38 13 8 29 0 63 40 0

1.5 ( I)

I

I

1.4 6.8 4.6 0.3 2.6 LR LR 0.3 2.0 LR 4.2 LR 0.3 LR LR LR 1.5 2.4 1.5 4.0 0.3 0.9 LR LR LR 2.7 4.6 0.8 0.3 1.8 LR

2

I

4.3 I 1.6 9.2 0.3 3.6 2.6 LR 0.5 2.8 2.8 4.5 0.3 0.3 0.3 I. I 5.2 1.8 4.4 I. I

6.0 0.3 0.8

3

Follow-up (mo)

6.1 16.4 12.1 5.6 4.2 5.0 0.3 0.2 3.6 6.2

8.2 (13) 12.0 (48) 0.3 (3) 0.3 (34) 8.8 (I) 6.1 (87) 6.1 (46) 2.9 (46) 0.3 (67)

2.3 5.0 6.6 3.6 1.0 4.1 4.7

336 141 163 1767 62 92 -33 80 121 24 0 0 0 27 96 380 96 20 45 0 400

• 9

:J.~

0.3 0.3 0.3 1.4 10.2 7.2 4.7 1.8 5.8 0.3 4.5

3.0 (I) ).() (37) 8.0 (75) 6.6 (9) 0.3 0.4 7.1 2.2

5.5

(U

% Change*

(19) (18) (I)

(38) 666 61 85 78 400 1700 83

2.3 3.7 2.7 (2) 4.4 (5) 6.3 (2)

8.2 4.0 5.4 3.3

- Vnavailable; LR, late registration. *From presentation to delivery.

Table III. Delivery and perinatal outcome of 31 continuing pregnancies complicated by diabetic nephropathy

Proteinuria at entry A-lild

Cesarean section Primary Repeat Vaginal Birthweight Small for gestational age Appropriate for gestational age Large for gestational age Stillbirths Perinatal Complications Respiratory distress syndrome* Hypoglycemia (blood glucose <40 mg/di) Hyperbilirubinem ia (> 12 mg/di) Birth defectst Perinatal survival Uncorrected Corrected

7 (22.0%) 3 (9.6%) 4 (12.9%) 2 (6.5%)

9 (29.0%) 8 (26.0%) I (3.2%) 5 (16.0o/c)

2 (6.5o/c) 6(19.0%) I (3.2%) I (3.2o/c)

I (3.2%) 11 (35.0%) 2 (6.5%) 0 (0.0%)

Total

Severe

Moderate

Mode of delivery

6(19.0%) 4 (12.9%) 2 (6.5%) 2 (6.5o/c) 2 5 I I

(6.5%) (16.0%) (3.2%) (3.2o/c)

22 15 7 9

(70.0%) (48.5%) (22.6%) (29.0%)

5 (16.0%) 22 (70.0%) 4 (12.9%) 2 (6.5%) 6 2 8 3

(19.2%) (6.5%) (25.8%) (9.6%)

29 (93.6%) (96.6%)

*Grunting, tachypnea, retractions, need for supplemental oxygen for more than 24 hours, x-ray picture of bilateral reticulogranular pattern with air bronchograms, and negative blood cultures. tLarge patent ductus arteriosis, ventricular septa! defect, and multiple anomalies.

Diabetic nephropathy 61

Volume 159 Number I

Mean creatinine clearance (mg/min)

Mean blood pressure (mm Hg) Trimester

Trimester

I

1

58 82 75 100 102 LR LR 90 100 LR 105 LR 135 LR LR LR 60 62 97 31 25 245 LR LR LR 118 116 Ill 72 LR

2 71 75 150 110 72 102 LR 119 85 53 110 117 114 102 49 168 90 61 140 28 38 268 25 141 149 80 113 117 128 165 114

I

3 62 42 42 64 73 68 100 147 Ill 58 113 97 102 124 40 94 43 35 129 40 28 290

Follow-up (mo) 11 (13) 68 (24) 27 (I) 119 (63) 140 (49) 50 (46) 62 (I)

28 (50) 50.4 (9) 17 48 261 27

(2) (18) (I)

100 55

1

7 -49 -20 -36 -29 -33

150/85 130/90 143/94 146/82

59 (2) 67 (5) 50 (2)

132

-15 -61 -32 14 -50 77 -20

I

150190 172/90 143/90 140/85 LR 120/80 I I I iii 131/85

LR LR 116/86 110170 LR 156/92 LR 100170 LR 120/80 LR 120170 160/80 121176 1801110 135/iO 100170 LR LR LR 120176

-63 II 10 8 -17 -24 22 -18 -44 -28 -44 33 29 12 18

2 140/84 145/102

140190

(38)

120 58

I

% Change*

156188 140/75 107/67 120/86 122/86 142/85 143/82 148/80 140/82 130/95 130/80 118/80 120/84

120180 130/80 128/76 130/89 160/86

128110 160/80 110/70 118/80 LR

110160

3

Follow-up (mo)

143/90 140/90 154/92 165/100 150/98 174/102 140/90 113177 121185 140/90 170/94 133171 114/70 137/84 154/100 152/101 152/85 160/90 140/83 140/112 150/100 130/80 130/80 124/86 180/100 160/94 120/80 160/90 140/85

150170 180/95

160190

122/88 140/90

190190 188/106 150/94 160/98 138/86 130/90 130/90 170/110 160/100 130170 120/80 130/86 132172 138/90 160/100 118/80 114/86

120180 146/86 164/82 146/86

Table IV. Infant birth weight and renovascular function Infant birth weight

No. of patients* Mild proteinuria Moderate proteinuria Severe proteinuria Renovascular factors High blood pressure(> 140/90 mm/Hg) Toxemiat Nephrotic syndrome (>3.0 gm protein/day) Renal insufficiency

SCA

LCA

ACA

Total

2 (40.0%) I (20.0%) 2 (40.0%)

I (25.0%) 2 (50.0%) I (25.0%)

6 (27.2%) 11 (50.0%) 5 (22.7%)

9 (29.0%) 14 (45.0%) 8 (26.0'lc)

3 (60.0%) 2 (40.0%) 2 (40.0%) 3 (60.0%)

I (25.0%) I (25.0%)

15 8 5 IO

19 (61.37c) 11 (35.57c)

I (25.0%) I (25.0%)

(68.2%) (36.4%) (22.7%) (45.5%)

8 (25.8%)

14 (45.2%:)

SCA, small for gestational age; LGA, large for gestational age; ACA, appropriate for gestational age.

*Proteinuria based on entry values. tDiagnosis of toxemia was made on the basis of worsening hypertension and multisystemic involvement usually resulting in coagulopathy and abnormal liver function.

nal insufficiency, however, was more frequent in the mothers who eventually delivered infants small forgestational age (Table IV). Similarly, an inverse correlation was found between birth weight and other renovascular

complications, namely hypertension, preeclampsia, and nephrotic syndrome. For the entire population, linear regression was used to analyze further the relationship between renovas-

62

Reece et al.

July 1988 Am .J Obstet Gynecol

URINE PROTEIN

10

10

6

6

SERUM CREATININE

(gm/day)

(mg)

(•)

(a)

2

2

180

180

SYSTOLIC ( •) 140 AND DIASTOLIC ( o) 100 BLOOD PRESSURE

140 CREATININE CLEARANCE

100

(ml/min) (a)

(mm Hg)

60

60

20

20

3

2

1

Postpartum

TRIMESTER Delivery

Fig. 1. Reno\'ascular function during pregnancy and post partum. Differences between trimesters were compared by repeated measures analysis of \'ariance.

240

12

200

10 HbA 1 (%)

MBG (mg/di) (.)

160

8

120

6

80

4

40

2

3

(a)

2

TRIMESTER Fig. 2. Glycemic control throughout pregnancy, with mean blood glucose (MBG) and glycosylated hemoglobin (HhA 1) as indicators.

cular factors and birth weight. In addition, intervariable correlation was also determined. A significant association was found between birth weight and gestational age (r = 0.62, p = 0.02), systolic blood pressure (r = 0.39, p = 0.03 I), creatinine clearance (r = 0.0009), serum creatinine level (r = - 0.4 7, p = 0.009), and mean blood glucose (r = 0.45, p = 0.012). The associations were not significant between birth weight and urinary protein excretion (r = 0.30, p = 0.107) or diastolic blood pressure (r = - 0.26, p = 0.161; Fig. 3 ). Multiple regression analysis was used to determine the combined effect of more than one variable. All possible models, which included the factors

urine protein, creatinine clearance, serum creatinine, diastolic and systolic blood pressures, mean blood glucose, and gestational age, were considered by the SAS program PROC RSQUARE. 11 The best combination of factors, based on the use of C,, statistics, included gestational age and creatinine clearance. The resulting equation was: Birth weight = - 3045 + 9.33 (creatinine clearance) + 127 (gestational age) (F[2,27] = 23.15, p = 0.0001; R2 = 0.63; root mean square error = 545 gm)

Volume 159 Number I

Diabetic nephropathy

..

4500

r•0.619 4000 BIRTH

p•0.0002

r•0.574

p•OD009

.. . .

3500

WEIGHT (91")

3000

..

2500 2000

63

1500 IOOO 24

26

28

30

32

34

GESTATIONAL AGE

36

38

40

0

BIRTH

3500

WEIGHT (91")

r•·0.461 p•Q.0090

.'

80

120

..

4500

4000

40

160

200

240

CAEATININE CLEARANCE (ml/min)

(wb)

r•O.Z94

p•0.1079

3000

2500 2000

.

1500 1000 Qll

09

1.3

1.7

2.1

2.5

4 6 8 URINE PROTEIN (om/cloy)

0

2.9

~ ~ATININE ("'I)

10

12

Fig. 3. Scatter plots showing the relationship of birth weight with gestational age, creatinine clearance, serum creatinine level, and urinary protein excretion.

Table V. Perinatal outcome of patients with nonsystemic renal disease and patients with diabetes-associated renal disease

Pregnant nondiabetic patients with renal disease*

No. of patients Fetal death Preterm deliveries Small for gestational age Large for gestational age Appropriate for gestational age Major congenital anomalies Neonatal Respiratory distress syndrome Hypoglycemia Hyperbilirubinemia phototherapy Death Perinatal survival

121 7 (5.7%) 24 (20.0%) (<36 wk) 27 (24.3%) 6 (5.4%) 78 (70.2%)

6 (4.9%) 90.0%

Pregnant diabetic patients with renal diseasef (White class For FR) 26 2 (7.7%) 8 (30.8%) IO (32.0%) (<34 wk) 5 (20.8%) 3 (12.5%) 18 (69.2%) 3 (11.1%)

Proteinuria at entry (White class For FR; curr~nt stud_v) Mild

I

Moderate

I

Severe

9 (29.0%) I (11.1%) 2 (22.2%)

14 (45.0%) 0 (0.0%) 5 (35.7%)

2 (22.2%) 1(11.1%) 6 (6.6%)

(< 34 wk) I (7.2%) 2 (25.0'lc) 2 (14.3'7c) I (12.5'7c) 11 (78.6%) 5 (62.5%)

8 (26.0%) I (12.5%) 3 (35.7'7c)

I

Total 31 (100%) 2 (6.4%) 3 (37.5%)

5 (16.0%) 4 (12.9%) 22 (72.0%) 3 (9.6%)

6 (23.0%)

6 (19.3'7c)

II (44.0%) II (44.0%)

2 (6.5%) 8 (25.8%)

I

(4.0%) 88.9%

0 (0.0%) 93.6%

*Katz et al.' tKitzmiller et al. 9

lntervariable correlation was also present among several of the factors studied. A significant association was found between urinary protein excretion and diastolic blood pressure (r = 0.53, p = 0.0026), between serum creatinine level and diastolic blood pressure (r = 0.37, p = 0.043), and between serum creatinine level and systolic blood pressure (r = 0.43, p = 0.49). Long-term follow-up. Twenty-seven patients and their physicians were successfully contacted at a mean

follow-up of 3 years (range 0.5 to 9 years). The majority (74%) of patients enjoyed active, productive lives and remained capable of caring for their children. Four patients (13%) were receiving dialysis therapy and two patients (6%) had received renal transplants, while the remaining 21 patients (68%) were reported to have adequate renal function and full· physical activity. With one exception of mild learning disability, all infants were reported to have normal developmental exami-

64

Reece et al.

nations and had achieved developmental milestones appropriately.

Comment In the pregnant diabetic population as a whole, there has been a progressive improvement in maternal survival and morbidity and in fetal survival over the past four decades. By the late 1970s maternal survival was 100% and fetal survival had reached levels comparable with nondiabetic patients. 1 Individuals with major vascular complications, including diabetic nephropathy, have been recognized as a special group with major maternal complications during gestation and with persistently reduced perinatal survival. 1 At odds with this ominous outlook for patients with diabetic nephropathy, Kitzmiller et al." recently described a fetal survival rate of 89% in 26 pregnancies that had completed at least 24 weeks of gestation. The present study analyzed the maternal course and pregnancy outcome in a series of 31 pregnancies complicated by diabetic nephropathy that were managed in the Division of Maternal-Fetal Medicine at the Yale University School of Medicine from 1975 to 1984. This group of patients reflected the spectrum of renal and ocular complications found in long-standing type I diabetes mellitus. At the initial antepartum visit 39% had renal insufficiency, 26% exhibited heavy proteinuria (>3.0 gm/24 hr), and 26% had a diastolic blood pressure ;;?;90 mm Hg. During the course of pregnancy the incidence of renal insufficiency increased to 45% and included four subjects with a serum creatinine value ;;?;2.0 mg/di and an increase in heavy proteinuria to 71 %. Diastolic hypertension (;;?;90 mm Hg) was observed at some time during pregnancy in 18 patients (58%). Proliferative retinopathy was present in 68% of cases. This spectrum of vascular complications of diabetes, comprising worsening of renal functional parameters and increasing hypertension, compares favorably with the series of 26 pregnancies reported by Kitzmiller et al.' In that series, for example, the incidence of renal insufficiency in the third trimester, with the same criteria as we used (serum creatinine ;;?; 1.2 mg/ di or creatinine clearance <90 ml/min) was 77%; three subjects had a serum creatinine level 32 mg/di, while heavy proteinuria was observed in 85%. Diastolic hypertension in the third trimester was present in 73o/c of patients. The cause for the decline in glomerular filtration rate and increase in proteinuria during pregnancy in these patients remains unknown. It is possible that in the present series the concurrent development of preeclampsia (diagnosed by clinical criteria in 36%), worsening of preexisting hypertension, or the occurrence of hypertension may have played a role. An increase in the rate of protein excretion as pregnancy progresses

July 1988 Am J Obstet Gynecol

was seen in both this study and that of Kitzmiller et al.,5 and has also been observed in patients with primary renal disease with proteinuria before conception. 8 In all these series the severity of proteinuria regressed post partum to levels comparable to first trimester or preconception values. This pregnancy-related, transient increase in protein excretion in patients with preexisting proteinuria parallels in an amplified manner the changes in protein excretion observed in normal pregnancy,'' and could represent an increase in the amount of filtered protein, a decrease in tubular reabsorption of filtered protein, or both. Because tubular reabsorption of j3 2 -microglobulin 12 as well as glucose" and amino acids" has been demonstrated in normal pregnancy, it seems likely that a decrease in proximal tubular transport processes, including reabsorption of filtered protein, plays an important role in amplifying protein excretion during pregnancy in patients with preexisting alterations in filtered protein because of glomerular injury. Nevertheless, despite the changes in renal functional parameters during gestation, the natural course of diabetic nephropathy in this series of patients did not appear to be adversely affected by pregnancy. Recent studies have shown that in patients with type I diabetes, renal function declines inexorably to end-stage renal disease in all patients after the onset of macrop~otein­ uria.' The mean interval of time between onset of proteinuria to end-stage renal disease has been reported as 4.8 years," 5.3 years, 16 5 years, 17 5 to 10 years, 18 and 10 years.' In this study serum creatinine and creatinine clearance values were not statistically different at follow-up compared with third trimester values, despite a follow-up interval of 3 years (range 0.5 to 9 years). The onset of end-stage renal disease in six patients at follow-up, therefore, appears to be consistent with the expected course of diabetic nephropathy. A similar conclusion was reached in the report by Kitzmiller et al.' and in patients with primary renal disease who had normal or near-normal renal function at the time of pregnancy." In the present series complications related to growth and development of the fetus were considerable and included stillbirths (6.5%), primary cesarean section (48.5%), and major congenital abnormalities (nearly 10%). Preterm deliveries occurred in 32% of pregnancies and 16% of infants were small for gestational age. In addition, neonatal complications of respiratory disease, hypoglycemia, and hyperbilirubinemia were high. These rates occurred despite reasonably good control of blood glucose levels in second and third trimesters, as shown in Fig. 1. These higher rates of pregnancy complications and alterations in fetal development in patients with diabetic nephropathy contrast with reports in subjects with diabetes who did not have ne-

Volume 159 Number I

phropathy. In one report on the outcome in 232 pregnancies in patients with White's classes B, C, D and R diabetes, preterm delivery occurred in 4.3%, fetal death occurred in 0.4%, and growth retardation was found in 2%.' The incidence of major congenital abnormalities of 8.6% and neonatal complications, however, were similar to rates observed in our patients with nephropathy. Jovanovic and Jovanovic 1" reported that the achievement of euglycemia before conception and its maintenance during pregnancy in patients with diabetic vasculopathy virtually eliminated perinatal complications. These authors concluded that normoglycemia does not affect the course of diabetic vasculopathy and vice versa. Despite the complications of pregnancy encountered in the present study, the infant survival rate was 94%; when corrected for major congenital anomalies it was 97%. In the study by Kitzmiller et al.'' of patients with diabetic nephropathy, infant survival was 89%. In addition, our long-term follow-up suggests that all surviving infants enjoy normal subsequent development. It seems probable that many of the complications of fetal growth and development are related to elevated maternal blood glucose levels, and that the incidence of fetal and neonatal complications including congenital anomalies will be reduced in future pregnancies when normalization of maternal blood glucose levels are achieved throughout the first trimester as well as during later stages of pregnancy. It also seems likely, however, that some complications are linked directly to renal insufficiency and possibly related hypertension. As shown in Table V, when the present series is compared with that of Kitzmiller et al.' in patients with diabetic nephropathy and with that of Katz et al." in patients with primary renal disease, the incidences of fetal death, preterm deliveries, and small-forgestational age infants were similar. Not surprisingly, the low infant birth rate in the present series most strongly correlated with gestational age and serum creatinine level. It is also of interest that the incidence of fetal survival was approximately the same (89% to 94%) among the three series. Regarding the high primary cesarean section rate in this study (48%), an abnormal antepartum fetal heart rate test accounted for approximately 50% of the indications for this procedure. Infants delivered under this condition accounted for 83% of neonates with respiratory distress syndrome. This high rate of fetal compromise and respiratory distress syndrome in patients with diabetic nephropathy contrasts with our previous experience in patients with diabetes mellitus in which nephropathy was absent.'' In that population the cesarean section rate was 26% and an abnormal fetal heart rate test result was associated with only a low incidence of respiratory distress syndrome. It seems

Diabetic nephropathy

65

possible, therefore, that fetal compromise occurs in a substantial number of diabetic women with nephropathy and was responsible for the high fetal death rate in previously reported studies. Detection of fetal compromise by current methods of fetal monitoring prevented wastage by early delivery, but respiratory distress syndrome, treatable with appropriate measures, may therefore be a trade-off for a higher fetal survival rate. In summary, these data indicate that, with the use of contemporary methods of maternal evaluation and management and appropriate fetal surveillance and neonatal care, a successful outcome of pregnancy can be achieved even in patients with diabetic nephropathy. Results can approach the overall success in other insulin-dependent diabetics and normal populations of pregnant individuals. In this light, recommendation against conception or the continuation of pregnancies in patients with diabetic nephropathy is unwarranted. We thank Ms. Peggy Leahy, RN, Ms. Barbara Coster, and Ms. Kathryn Toensmeier for their assistance in the preparation of this manuscript. REFERENCES I. Krolewski AS. Warram JH. Cristleib R. Busick E, Kahn

RC. The changing natural history of nephropathy in type I diabetes. Am J Med 1985;78:785-94. 2. Fabre J, Balant LP, Dayer PG, Fox HM, Vernet AT. The kidnev in maturitv onset diabetes mellitus: A clinical studv of 510 patients. Kidney Int 1987;21:730-8. . 3. \fogensen CE. Renal function changes in diabetes. Diabetes l 976;25:872-9. 4. I !are JW, White P. Pregnancy in diabetes complicated by vascular disease. Diabetes l 977;26:953-5. 5. Kitzmiller JL, Brown ER, Phillippe \1, et al. Diabetic nephropathy and perinatal outcome. A~tJ 0BSTET (;y:--;r:c:oL 1981 ; 141: 741-51. 6. Davison J \I. The effect of pregnancy on kidney function in renal allograft recipients. Kidney Int l 985;27:74-9. 7. Usher R, \!clean F. Intrauterine growth oflive-born caucasian infants at sea level: Standards obtained from measurements in i dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 1969;74:901-IO. 8. Katz AI, Davison JM, Davison JM, Hayslett JP, Singson E, Lindheimer \1D. Pregnancy in women with kidney disease. Kidnev Int 1980;18:192-206. 9. Coustan DR, Berkowitz RL, Hobbins JC. Tight control of overt diabetes mellitus in pregnancy. Am J Med 1980; 68:845-8. I 0. Redman CWG. Controlled trials of treatment of hypertension during pregnancy. Obstet Gynecol Surv 1982; 37:523. 11. SAS Institute Inc. SAS user's guide: Statistics. Cary, :\'C: SAS Institute Inc, 1982. 12. Pedersen EB, Rasmussen AB, Johannesen P, et al. Vrinary excretion of albumin, beta-2-microglobulin and light chains in pre-eclampsia, essential hypertension in pregnancy and normotensive pregnant and non-pregnant control subjects. Scand.J Clin Lab Invest 1981;41:777-84. 13. Davison JM, Hytten FE. The effect of pregnancy on the renal handling of glucose. Br J Obstet Gynecol I 97:i; 82:374-81. 14. H ytten FE, Cheyne GA. The aminoaciduria of pregnancy. .J Obstet Gynecol Br Commonweal I 982;79:424-32.

Reece et al.

15. Kussman MJ, Goldstein HH, Gleason RE. The clinical course of diabetic nephropathy. JAMA 1976;36: 1861-3. 16. Andersen AR, Andersen J K, Christiansen JS, Deckert T. Prognosis for ju\'enile diabetics with nephropathy and failing renal function. Acta Med Scand 1978;20'.~:131-4. 17. Andersen AR, Christiansen JS, Kreiner S, Deckert T. Diabetic nephropathy in type I (insulin-dependent) diabetes: An epidemiological study. Diabetologia 1983:25:496501.

July 1988 Am .J Obstet Gynecol

18. Knowles HC. Magnitude of the renal failure problem in diabetic patients. Kidney Int 1974;6:2-7. 19. Jo\'anm·ic R, Jo\'anovic L. Obstetric management when normoglycemia is maintained in diabetic pregnant women with vascular compromise. A~I J O!ISTET GY:\ECOL 1984; 149:617-2:~.

Fructosamine in the management of gestational diabetes Alistair B. Roberts, MD; John R. Baker, MB, ChB,' Andrew G. James, MB, ChB," and Patrick Henley, MB, ChB• Auckland, New Zealand The role of maternal serum fructosamine estimation in the management of gestational diabetes was assessed in 78 consecutive patients over a 3-year period. Fructosamine results correlated significantly with mean plasma glucose levels over a 1- to 3-week interval, with the closest association being in the preceding week. Eighty-five percent of women with gestational diabetes had peak serum fructosamine levels above the normal range. If maternal levels exceeded 3.2 mmol/L, there was an 88% chance of abnormal glucose tolerance post partum. Our aim of management was a serum fructosamine level <2.5 mmol/L; patients who achieved this goal by 35 to 37 weeks' gestation had fewer obese babies with lower cord insulin and C-peptide levels as compared with neonates of mothers with elevated fructosamine concentrations. (AM J OBSTET GYNECOL 1988;159:66-71.)

Key words: Fructosamine, monitoring gestational diabetes, glucose tolerance We have been investigating serum fructosamine measurement as a screening method for diabetes in pregnancy since 1982.1. 2 Useful properties of the test include its relative stability at different times of the day and from I day to the next,' providing a reliable index of blood glucose control over the pre,·ious I to 3 weeks from random nonfasted blood specimens. Fructosamine results are more responsive than glycosylated hemoglobin to alterations in management. In this study we examined fructosamine measurement as a means of monitoring women with gestational diabetes. We compared results with plasma glucose concentrations and assessed the usefulness of the test in predicting macrosomic babies and in identifying mothers with abnormal glucose tolerance post partum. Patients and methods Patients. We studied 78 consecutive patients diagnosed as having gestational diabetes between 1982 and From the Department of Obstetrics, Gynecology, and Neonatology, National Womens Hospital,' and the Department of Clinical Biochemistry, Green Lane Hospital.' Received for publication May 18, 1987; revised November 13, 1987; accepted January 28, 1988. Reprint requests: Dr. Alistair Roberts, Department of Obstetrics, Gynecology, and Neonatology, National Womens Hospital, Claude Road, Auckland 3, New Zealand.

66

1985 at National Women's Hospital. Five patients had gestational diabetes in previous pregnancies but reverted to normal glucose tolerance post partum. Diagnosis of gestational diabetes was based on a 3-hour I 00 gm glucose tolerance test interpreted according to O'Sullivan's criteria.'' Details of these patients are compared with a normal population' in Table I. Every I to 2 weeks patients attended a gestational diabetes clinic staffed by a specialist dietitian, physician, and obstetrician. Serum fructosamine and random glucose levels were measured at each clinic visit; once a week patients attended the local laboratory for preprandial and I-hour postprandial plasma glucose estimations in the middle of the day. Hospital admission was arranged if glucose control was poor and required insulin treatment or if patients developed obstetric complications. During hospitalization plasma glucose levels were measured at 0630, 1130, 1430, and 2030 hours. Thirty-four patients were treated with insulin administered according to a standard twice-a-day mixed rapid and intermediate-acting insulin regimen, whereas 44 women were treated with diet alone. For the purposes of the study, a mean plasma glucose concentration was calculated for each week for each patient with the use of all glucose measurements. Cnfortunately, there were not enough data to permit cal-