- Email: [email protected]
Intrauterine growth retardation: A preliminary report of long-term morbidity
Intrauterine growth retardation: A preliminary report of long-term morbidity J. A.
LOW
R.
S. GALBRAITH
D.
MUIR
H.
KILLEN
J.
KARCHMAR
D.
CAMPBELL
Kingston,
Ontario, Canada
This is a preliminary report of a prospective follow-up study of 88 intrauterine growth-retarded (IUGR) babiis and a control group of 97 babiis with weights appropriate for gestational age. The characteristic clinical features of IUGR pregnancies were observed in the obstetric patients of the IUGR group. The babiis of the NJGR group have a phase of accelerated growth during the 3 months following delivery although they continue to be smaller than the babies of the controi group at 12 months of age. No major neurologic abnormalities have been noted in the IUGR babies atthough behavioral difterences were observed during the neonatal period and at 12 months of age. There were lower mental and physical development indices at 12 months of age which were due to the IUGR babies of lowest birth weight and those with a low maternal urinary estrogen index. (AM. J. OBSTET. GYNECOL.
130: X34,1978.)
FOLLOW-UP STUDIES of low-birth-weight infants born during the 1950’s and early 1960’s demonstrated a significant incidence of handicaps.lM4 However, the results of subsequent studies with improved perinatal care indicate few& neurologic sequelae and more normal mental development.5, 6 It is now recognized that a substantial number of these infants were of low birth weight because of growth retardation rather than prematurity.’ The present follow-up studies in surviving intrauterine growth-retarded (IUGR) children are directed toward the assessment of the long-term significance of this perinatal complication. The relevance of growth retardation to long-term disability in a pre-
THE
From the Departments of Obstetrics and Gynaecology Psychology, Queen’s University at Kingston.
and
Supported by research grants from the Ontario Mental Health Foundation and the Ontario Society for Crif@ed Children. Presented at the Thirty-third Annual Meeting of the Society of Obstetricians and Gynuecologists of Canada, Montreal, Quebec, Canada, June 14-18, 1977. Refnint requests: Dr. J. A. Low, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7.
534
liminary report by Drilliens indicated that 60 per cent of growth-retarded children weighing less than 1,500 grams at birth were abnormal, usually having mild degrees of mental retardation and minor neurologic abnormalities. Similarly, a retrospective survey of 1,345 mentally retarded individuals indicated that 14.4 per cent were growth retarded. Two thirds of these were retarded because of placental insufficiency, suggesting the importance of intrauterine growth retardation in the occurrence of mental retardation.g The present report represents the first phase of a prospective follow-up study of 86 IUGR newborn infants and 9? control newborn infants and will outline the characteristics of the obstetric patients and their pregnancies and the subsequent follow-up observations at 3, 6, and 12 months of age.
Material and methods The newborn infants in the present study were born of obstetric patients admitted to the obstetric service of the Queen’s and Kingston health sciences complex. The definitions of the control and IUGR groups were based upon the weightlgestational age scale of Gruenwald.‘O The control group included 97 newborn infants ooo2-9378/78/05130-0534$01.20/00
1978 The C.V.
Mosby Co.
Volume
130
Number
5
whose weights at delivery were greater than the 25th percentile for gestational age. The IUGR group included 86 newborn infants whose weights at delivery were less than the 10th percentile for gestational age (Fig. 1). Data in respect to the obstetric patients, their pregnancies, and the newborn infants were obtained from the medical records and, where necessary, by personal interview while the patients were hospitalized. The maternal characteristics included in this report are age at delivery, height, prepregnancy weight, weight gain during the pregnancy, and smoking habits. Maternal medical complications associated with the current pregnancy included hypertension, chronic renal disease, cardiac disease, anemia, diabetes, and endocrine disorders. Socioeconomic indices recorded include the number of years of education, Canadian or non-Canadian nationality, and race of each parent. The Blishen score was derived from the father’s occupation and socioeconomic status.” The family characteristics included annual income and the numbers of bedrooms and residents in the home. The features of the maternal obstetric history include maternal parity, the number of previous perinatal deaths, previous IUGR pregnancies, and previous congenital anomalies. Obstetric complications of the present pregnancy include antepartum hemorrhage in the first and second halves of pregnancy, the latter including abnormal bleeding due to placenta previa, premature placental separation, or an unknown cause. Toxemia was defined as a systolic blood pressure of greater than 140 mm. Hg or a rise of 30 mm. Hg and a diastolic pressure of greater than 90 mm. Hg or a rise of 20 mm. Hg, with or without significant proteinurea. Multiple pregnancies were recorded. The labor and delivery characteristics include the duration of labor, defined as the time in hours from the onset of continuous contractions to delivery, and the method of delivery. The fetal characteristics established at delivery include maturity and sex. Gestational age was derived from the first day of the last menstrual period and was classified to the nearest week (i.e., 39 weeks and 3 days = 39 weeks; 39 weeks and 4 days = 40 weeks) in order to be in keeping with the Gruenwald weight/gestational age scale. The maternal urinary estrogen index was calculated from three or more 24 hour urinary estrogen estimations, the last being estimated within two weeks of delivery. A per cent was calculated for each estimation in relation to the normal mean for the appropriate week of gestational age; the “estrogen index” is the averaged percentages. An acid-base assessment was carried out on
Intrauterine growth retardation
sook 26
3n
3s
34
GESTATIONAL
36
36 AGE
40
43
535
44
(WEEKS)
Fig. 1. Population distribution with respect to weight and gestational age. This study includes 97 control newborn infants whose birth weights were above the 45th percentile for gestational age and 86 newborn IUGR infants whose birth weights were less than the 10th percentile for gestational age.
the blood of the umbilical vein and artery at delivery. The umbilical artery buffer base provided a measure of the presence or absence of a metabolic acidosis due to an episode of intrapartum fetal asphyxia.12 The newborn characteristics include the following physical measures: birth weight and weight percentile according to the weight/gestational age scale of Gruenwald, the crown-heel birth length, head and chest circumference, and the corresponding percentiles according to Lubchenko and associates.13 A weight-length ratio was calculated and the maximum percentage of weight loss was derived from the lowest weight during the subsequent nursery course. Measures of neonatal morbidity include Apgar scores at one and five minutes, hypothermia defined as a body temperature of less than 36” C., hypoglycemia defined as a blood sugar level of less than 30 mg. per IO0 ml. in the mature infant and less than 20 mg. per 100 ml. in the preterm newborn infant, and hyperbilirubinemia defined as requiring phototherapy or an exchange transfusion. Respiratory complications include any significant indrawing, grunt, retraction, or tachypnea
Low et al.
536
Table
March 1, 1978 Am. J. Obstet. Gynecol.
I. The maternal
characteristics
and socioeconomic
indices of the parents
Controlgroup
Maternal Age
No. of observations
Mean
S.D.
97 91
26.7 163.6
5.6 6.3 13.5 5.8
of the control IUGR
No.
No. of obsetyations
%
Mean
and IUGR
groups
group
S.D.
No.
%
P value5
characteristics:
Height Weight Weight gain Smoking Education Canadian Caucasian Maternal
medical
27
89
92
97
91
94
97
15
16
85
94
62.1
87 84
11.8
94 97
13.1
2.8
27.1
5.5
161.7
6.9
56.8 9.9
12.7 5.1
11.9
co.01 CO.05 52
65
82 83
95 96
13
16
2.7
co.01 co.01
complications:
Hypertension-renal disease Diabetes-endocrinopathies Anemia Socioeconomic
22
86 84 85 72 81 84 86 86
characteristics:
89
Blishen score Family income Home-residents Home-bedrooms
2 71
47.3 J 5.0 3.8
16.5 6.3 1.1
2.9
0.9
74 44 65 64
45.6 12.5 4.1 2.7
18.1 5.6 1.5 0.9
CO.05
Table II. The characteristics of previous pregnancies, the obstetric complications, and the fetal and labor characteristics of the present pregnancy in the control and IUGR groups
No. of obstations Parity: 7l 21 Past obstetric complications:
Control
group
Mean
S.D.
97
L.&r
and delivery
%
53 44
55 45
6 3 1
14 7 2
17 9
No. of obser-uations
Mean
group
No.
%
36 50
42 58
S.D.
5 22 2
44 4
17 9
17 6
20 7
27 4
28 4
16
18
11
13
23 3 15
24 3 16
13 9 14
15 10 16
55 42
57 43
33 53
38 62
86
SigGjkant P value
50
97
complications:
Antepartum hemorrhage Antepartum hemorrhage Toxemia Multiple pregnancy
No.
44
Perinatal death ILJGR pregnancy Congenital anomaly Obstehic
IUGR
10 co.01
86
< 20 weeks > 20 weeks
characteristics:
Duration of labor Abdominal delivery-midforceps Abdominal delivery-breech Abdominal delivery-ceserean section
87
11.3
7.8
Q7
73
10.4
8.1
86
Fetal characteristics:
Gestational age at delivery Male Female Estrogen index Umbilical artery buffer base
96
40.3
1.5
97 71 69
95.0 39.9
requiring increased surveillance or oxygen therapy. Central nervous system (CNS) complications include any symptoms such as seizures or abnormalities of tone, consciousness, activity, or reflexes. Behavioral studies in the neonatal period include measures of activity, visual fixation or pursuit, and sleep patterns. General motor activity was measured by
30 2.0
86 86
39.1
65 59
60 36.9
1.8
26 3.6
CO.01 CO.05 co.01
a modified self-winding calendar watch, an actometer.14 Activity is expressed in arbitrary units per hour. Visual activity was recorded by a trained observer. Visual fixation in response to patterned stimuli was scored on a four-point scale and visual pursuit to the same stimuli on a three-point scale. The sleep pattern was similarly recorded by a trained observer and the
Volume Number
Intrauterine
130 5
Table III. The characteristics of the newborn in the control and IUGR groups
infants
and the subsequent
neonatal
Controlgroup No. of obsmatitiMz( Newborn
Height:
Gm. % cm.
97 97
70
Head circumference:
cm.
97
%
Chest circumference: (cm.) Weight-length
3485 62 52.5
452 23 2.9
complications
IUGR
No.
%
537
group
No. of obsmatiom
Mean
S.D.
86
2302
354 2.1 3.2 27 1.9 18 2.6
No.
%z
Sign$cant P value
96 97 89 97
79 35.1
19 1.3
72 33.6
23 1.8
83 85
15 6 6.3
81 83 84 85
15 7
2.6
5.5 47.8 42 32.1 23 29.1
a.00 1
4.1
77 52
2.6
1 1
complicatkms:
Apgar score 1 min. Apgar score 5 min. Hypothermia Hypoglycemia Hyperbilirubinemia Respiratory complications CNS complications
Table
S.D.
retardation
characteristics:
Weight:
Neonatal
Mean
growth
97
8.1
1.7
35
9.3
0.7
95 14 95 97 97
4
2
4 7 2 2
1
1
:
IV. The assessment of neonatal
behavior
of the newborn
86 39 86 61 86 86 86
infants
c&01 group
7.2 8.7
2.4 1.5 24 9 3 ;
of the control IUGR
and IUGR
28 IJ -1 6 0
groups
group P
No.
Activity score Visual fixation Visual pursuit Sleep: Rapid eye movements Quiet Transitional
44 43 43 44
Mean
0.69 4.8 8.1
S.D.
i
0.35
1.9
No.
Mean
40
0.48 4.0 6.7
31
3.5
31
S.D.
values
0.25
1.8 3.0
co.07 CO.08
39 27.7
9.0
30.8
8.9
13.4
6.5 6.4
12.9
5.9
15.4
6.9
17.5
sleep states described included active or rapid eye movement (REM) sleep, transitional sleep, and quiet sleep. Follow-up observations were done at 3, 6, and 12 months of age. The numbers of observations at 3 and 6 months were less than the number at 12 months because this part of the protocol was added when the study had been in progress for one year. The measures of physical growth, weight, height, and head and chest circumference were obtained at each visit, and a detailed physical examination was done at 3 and 12 months of age. The Drillien test of tone was carried out at 3 months of age with a detailed neurologic examination at 12 months. Tone was assessed by passive movement of the limbs. Active movement was assessed by symmetry and amount of movement, complex movement by the precision with which small objects were manipulated, and involuntary movement by the presence of tremors or
choreiform movements. The deep tendon reflexes and superficial abdominal reflexes were tested. The cranial nerves tested were the second by vision: third, fourth, and sixth by eye movements; seventh by facial symmetry and movement; eighth by hearing; and ninth and tenth by the gag reflex. The Bayley15 test of mental and physical development and behavioral characteristics was carried out in the home at 6 months of age and in the clinic at 12 months. Results The maternal characteristics and socioeconomic indices of the parents of the control and IUGR groups are outlined in Table I. As compared to the control group the mothers of the IUGR group had a lower prepregnancy weight, 56.8 kilograms in relation to 62.1 kilograms, with a trend fo less weight gain during pregnancy, and a greater incidence of smoking, 65 per
538
Low
et al.
March 1, 1978 Am. J. Obstet. Gynecol.
WEIGHT
GAIN
S-6 NON
HEAD
HEIGHT
6-12 MON.
CIRCUMFERENCE GROWTH
O-3 NON. IO
CHEST
1
3-6
GROWTH
MON.
6-12YON.
CIRCUMFERENCE GROWTH
Cm S-
g@tj OJ
3-6 MON Control
Groups
6-12 MON.
1-3 MON.
3-6
MON.
6-12 NON
I U G R G~JP~
Fig. 2. The rate of growth for each physical measure in the babies of the control and IUGR groups before 3 months, between 3 and 6 months, and between 6 and 12 months of age. Table V. The measures 6, 12 months of age
of physical
growth
of the babies of the control
3 MO.
weighi
group
at 3, 12 MO.
6 MO.
No.
Mean
S.D.
P value
No.
Mean
S.D.
P value
No.
Mean
S.D.
P value
43 40
6.3 5.2
0.7 0.6
47 41
8.0 69
1.0 0.8
77 69
9.8 8.8
1.0 1.1
43 40
61.5 58.4
3.1 2.5
50 42
66.0 63.1
2.9 2.7
76.1 73.3
2.8 3.1
co.00
50 41
44.2 42.2
4.3 1.4
co.01
77 7.
46.6 45.3
1.5 1.6
50 42
44.1 42.5
2.0 2.1
76
47.8 46.6
2.1 2.3
(Cm.):
Control IUGR Height
and IUGR
(cm.)
Control IUGR
Head circumference Control
(cm.):
IUGR Chest circumfenmce
Control IUGR
1
43
41.2
1.1
41
39.6
1.2
43
41.6 39.2
2.0 2.2
(cm. j:
41
cent in relation to 27 per cent. Major maternal medical complications were observed in both groups but with no difference in the incidence between groups. The vast majority of the parents were Caucasian and Canadian. The mothers of the IUGR group had fewer years of education, 11.9 years, than the mothers of the control group, 13.1 years. However, no difference was observed between the fathers of the two groups in this regard. There was a trend to a lower family income in the IUGR group in relation to the control group. The characteristics of previous pregnancies, the ob stetric complications, and the fetal and labor characteristics of the present pregnancies of the control and IUGR groups are outlined in Table II. In the history of
6g
past pregnancies there was an increased incidence of IUGR pregnancies in the mothers of the IUGR group, 44 per cent, in relation to the mothers of the control group, 7 per cent. There were no differences in regard to obstetric complications and labor and delivery characteristics between the two groups with the exception that the gestational age at delivery was slightly less in the IUGR group, 39.1 weeks, in relation to the control group, 40.3 weeks. The maternal urinary estrogen index was characteristically lower in the IUGR group, 60 per cent, in relation to the control group, 95 per cent. There was a trend to an increased incidence of female fetuses in the IUGR group. The lower umbilical artery buffer base in
Volume Number
intrauterine growth retardation
130 5
the IUGR group, 36.9 mEq. per liter, in relation to the control group, 39.9 mEq. per liter, is due to an increased incidence of metabolic acidosis resulting from an episode of intrapartum fetal asphyxia. The characteristics of the newborn infants and the subsequent neonatal complications in the control and IUGR groups are outlined in Table III. As compared to the control infants the newborn infants of the IUGR group were smaller in weight and length, with an increased incidence of weight-length ratio of less than 10 per cent, and had a smaller head and chest circumference. The newborn infants of the IUGR group had lower Apgar scores at one minute and an increased incidence of hypothermia during the initial 24 hours of the neonatal period. There were otherwise no differences in the occurrence of neonatal complications between the two groups. The assessment of neonatal behavior of the newborn infants of the control and IUGR groups is summarized in Table IV. As compared to the control group the newborn infants of the IUGR group had a lower activity score, with a trend to less visual activity as expressed by measures of visual fixation and visual pursuit. There were no differences observed in respect to the sleep patterns between the two groups. The measures of physical growth at 3, 6, and 12 months of age of the babies in the control and IUGR groups are outlined in Table V. The measures of weight, height, and head and chest circumference in the babies of the IUGR group are lower than those in the control group at each stage until 12 months of age. Although all the physical measures of the infants of the IUGR group at 12 months of age are smaller, the relative differences decreased with age, indicating some measure of “catch-up” in the IUGR babies. The rates of growth for each physical measure during the initial 3 months, between 3 and 6 months of age, and between 6 and 12 months are illustrated in Fig. 2. The rates of growth during the initial 3 months in the IUGR and control groups in respect to weight were not different, but the IUGR group had greater gains in respect to height, 10.6 cm. in relation to 9.6 cm. (p < 0.01); head circumference, 7.6 cm. in relation .,” Y”L “6”’ L.....‘. ss 39:9 Umbilical artery buffer base 2.0
requiring increased surveillance or oxygen therapy. Central nervous system (CNS) complications include any symptoms such as seizures or abnormalities of tone, consciousness, activity, or reflexes. Behavioral studies in the neonatal period include measures of activity, visual fixation or pursuit, and sleep patterns. General motor activity was measured by
539
60-’ so40-
% 3o
PATtENTSzO-
toi
-2
control
Group
----
IUGR
Gmup
-
3
4
Fig. 3. The distribution of the scores in respect to activity and level of energy during the Bayley test in the babies of the control and IUGR groups at 12 months of age. Table VI. The results of neurologic examination of the babies of the control and IUGR groups at 12 months of age
Tone
Moummnt: Active Complex Involuntary
Rejlexes: Deep Superficial Cranial nerves
70
0
70 70 70
L
64 48 69
75 1.5
0
76
0
0
76 76
10 0
0 0 2
70 65 74
0 0 3
11
3
13
The Bayley scores at 6 and 12 months of age in the control and IUGR groups are “I “Y _” outlined in Table .“.“I VII.
59
36.9
3.6
a modified self-winding calendar watch, an actometer.14 Activity is expressed in arbitrary units per hour. Visual activity was recorded by a trained observer. Visual fixation in response to patterned stimuli was scored on a four-point scale and visual pursuit to the same stimuli on a three-point scale. The sleep pattern was similarly recorded by a trained observer and the
540
Low
Table
VII.
et al.
March 1, 1978 Am. J. Ohsta. Gynecol.
The Bayley scores of the babies of the control
and IUGR
groups
clmtr01group
IUGR
of age
group
Mean
S.D.
No.
Mean
S.D.
51
113.3
18.6
18.3
107.6
18.9
41 42
108.4
50
107.9
18.9
74 75.
109.8
12.5
102.1
18.1
67 68
102.9 93.5
15.2 18.9
NO.
6 mo.: Mental development index Physical development index
at 6 and 12 months
P values
12 mo.
Mental development index Physical development index
Km
SIX MONTHS
MENTAL Control 0
Twm.vE MONTHS
DEVELOPMENT
INDEX
I.U.Q.R. Birch Wt>23OOOm~
SIX MONTHS
PHYSICAL
TWELVE MONTHS
DEVELOPMENT
I.U.G.R. Birth Wt<2300Gm
INDEX m
Fig. 5. The Bayley scores at 6 and 12 months of age of the control and IUGR babies of birth weight categories ~2,300 grams and <2,300 grams.
Co,,tro!Gmup ----
lu,GR,8WhWl>2300Gl;l
,UGR Bir,hW,,<2300
6m -
Fig. 4. The measures of physical growth at 3, 6, and 12 months of age in the control and IUGR babies of birth weight categories ~2,300 grams and <2,300 grams. mean score for activity in the IUGR group, 4.1, was lower than that in the control group, 5.0 (p < O.OOl), and similarly the mean score for level of energy in the babies of the IUGR group, 2.8, was lower than that for the babies of the control group, 3.3 (p < 0.001). Significance of birth weight in the IUGR group. The mean birth weight in the IUGR group was 2,300 grams. Two categories of the IUGR group, that is, those with a birth weight of less than 2,300 grams and those with a birth weight of more than 2,300 grams, have been compared. The newborn IUGR infants weighing less than 2,300 grams were shorter, 45.2 cm. in relation to 49.6 cm. (p < 0.001); had a smaller head circumference, 30.9 cm. in relation to 33.0 cm.
(p < 0.001); and had a smaller chest circumference, 27.3 cm. in relation to 30.4 cm. (p < 0.001). There were no significant differences in the maternal characteristics, socioeconomic indices, or antenatal obstetric complications between the two categories. The gestational age at delivery of the IUGR infants weighing less than 2,300 grams, 38 weeks, was earlier than that of the infants weighing more than 2,300 grams, 40 weeks (p < 0.001). Similarly, the maternal urinary estrogen index of the IUGR infants weighing less than 2,300 grams, 45 per cent, was lower than that of the infants weighing 2,300 grams or more, 71 per cent (p < 0.001). The measures of physical growth at 3, 6, and 12 months of age in the IUGR babies of both weight categories follow the pattern of the control group (Fig. 4). As compared to the IUGR 22,300 gram babies, the measures at 12 months of age show the IUGR <2,300 gram babies to be smaller in weight, 8.4 kilograms in relation to 9.1 kilograms (p < 0.01); in height, 72.2 cm. in relation to 74.2 cm. (p < 0.01); and in chest circum-
Volume Number
Intrauterine growth retardation
130 5
TW
MENTAL con,ro,
SIX
DEVELOPMENT 0
I “G
R
Estrogen
INDEX Index,60Xe7ld
I UGR
TWELVE
MONTHS
PHYSICAL
541
MONTHS
DEVELOPMENT
Estrogen
hdex
CM)%
tNDEX a
Fig. 7. The Bayley scores at 6 and 12 months of age of the control and IUGR per cent and ~60
Fig. 6. The measures of physical growth at 3, 6, and 12 months of age of the control and ILJGR babies of estrogen index categories ~60 per cent and <60 per cent.
ference, 45.6 cm. in relation to 47.3 cm. (p < 0.01). The difference in respect to head circumference was not statistically significant. The Bayley stokes of the IUGR babies in both birth weight categories in relation to the score for the control group are illustrated in Fig. 5. As compared to the IUGR ~2,300 gram infants, the mental development index in the IUGR <2,300 gram infants was lower at 6 months of age, 97.8 in relation to 115.2 (p < O.Ol), and at 12 months of age, 96.0 in relation to 108.6 (p < 0.00 1‘). Similarly, the physical development index in the IUGR <2,300 gram category is lower at 6 months of age, 96.7 in relation to 114 (p < O.Ol), and at 12 months of age, 86.3 in relation to 99.2 (p < 0.01). SlgnScance of estrogen index in the IUGR @up. The mean estrogen index in the IUGR group was 60 per cent. Two categories of the IUGR group, that is, an estrogen index ~60 per cent and an estrogen index ~60 per cent have been compared. There were no differences in the maternal characteristics, socioeconomic indices, or antenatal obstetric complications between the two categories. There was no difference in respect to the gestational age at delivery between the IUGR
babies of estrogen per cent.
index
rategories
260
infants of the two estrogen index categories and the control group. A comparison of the two groups shows the IUGR newborn infants with an estrogen index ~60 per cent to weigh less at birth, 2.15 kilograms in relation to 2.48 kilograms (p < 0.01); to be shorter, 46.5 cm. in relation to 48.9 cm. (p C 0.01); to have a smaller head circumference, 31.4 cm. in relation to 32.7 cm. (p < 0.01); and to have a smaller chest circumference, 27.9 cm. in relation to 30.5 cm. (p < 0.01). The measures of physical growth at 3. 6, and 12 months of age in the IUGR babies with estrogen indices of 2 60 per cent and <60 per cent follow the pattern of the control group (Fig. 6). The differences in respect to weight, height, and head and chest circumference at 12 months of age between the IUGR babies of the two estrogen index categories are not statistically significant. The Bayley scores of the IUGR babies of the two estrogen index categories in relation to those of the control group are illustrated in Fig. 7. The mental development index in the IUGR babies with an estrogen index of ~60 per cent in relation to that in the ~60 per cent estrogen index category is lower at 6 months, 100.1 in relation to 120.8 (p < O.Ol), and at 12 months, 99.6 in relation to 112.3 (p < 0.01). Similarly, the physical development index in the IUGR infants of the (60 per cent estrogen index category is lower at 6 months, 99.7 in relation to 119.5 (p c O.Ol), with a trend to be lower at 12 months of age. 88.2 in relation to 99.5 (p < 0.05).
542
Low et al.
March 1, 1978 Am. J. Otstet. Gynecol.
MENTAL
Cm
DEVELDPMEW INDEX
CONTRDL GROUP 0
PMYSICAL
DEVELOPMENT INDEX
I.U.G.R. GROUP
69
Fig. 9. The mental and physical development indices at 12 months of age in the babies of the control and IUGR groups. Controt Group l”GRGrwp
----
Fig. 8. The measures of physical growth of the babies of the control and IUGR groups at 3, 6, and 12 months .of age. Signific~e of fetal sex and intrapartum fetal asphyxia in the IUGR group. In the IUGR group there was a greater proportion of female babies, 53, in comparison to male fetuses, 33. Similarly, there were a number of episodes of intrapartum fetal asphyxia with metabolic acidosis at delivery in the IUGR group. The fetuses of 37 patients exhibited no evidence of a metabolic acidosis at delivery, while the fetuses of 22 patients had evidence of a significant metabolic acidosis at delivery, that is an umbilical artery buffer base of less than 36.1 mEq. per liter. The IUGR infants were categorized by sex and by evidence of (with and without) intrapartum fetal asphyxia and were compared to assess the significance of these variables in respect to the relevant observations in the IUGR group. No significant differences were observed between these categories in respect to the newborn measures at delivery; measures of physical growth at 3,6, and 12 months of age; or Bayley scores at 6 and 12 months.
The characteristic clinical features of IUGR pregnancies were observed in the obstetric patients of the IUGR group. The mothers had lower prepregnancy weight, less weight gain during pregnancy, and an in-
creased incidence of smoking. The pattern of maternal urinary estrogen excretion was low and there was a significant incidence of intrapartum fetal asphxyia. In comparison to the control group, growth retardation affected all physical measures, that is, lower birth weight, shorter length, and smaIler head and chest circumference. The measures of physical growth at 3, 6, and 12 months of age in the control and IUGR groups are illustrated in Fig. 8. In comparison to the control babies the initial acceleration of growth in IUGR babies as reported by Fitzhardinge and SteverP during the first 6 months, was observed in the present study during the first 3 months of life; this growth was found in height and head and chest circumference. The importance of this acceleration of growth, particularly in respect to head circumference, is emphasized by the evidence of a relationship among head circumference, brain growth, and subsequent intelligence.17-2’ The growth pattern between 3 and 12 months of age in the IUGR babies is similar to that of the control babies. Thus at 12 months of age the IUGR babies are still smaller than the control babies in respect to weight, height, and head and chest circumference, although the relative difference is less than that at birth. The continuing difference of these physical measures at 12 months of age is in keeping with observations in long-term follow-up studies that growth-retarded children continue to be smaller in later years.t6* 22-24
Volume Number
Intrauterine growth retardation
130 5
543
2800 1
MENTAL
DEVELOPMENT
Fig. 10. Scattergram demonstrating the relationship index at 12 months of age in the IUGR group.
50
60
70
6.0
MENTAL
INDEX
between birth weight and mental development
90
loo
DEVELOPMENT
110
120
no
INDEX
Fig. 11. Scattergram demonstrating the relationship between the maternal urinary estrogen index and the mental development index at 12 months of age in the IUGR group.
Major neurologic disabilities have not been observed in follow-up studies of IUGR infants and were not evident in the babies of this IUGR group at 12 months of age. Evidence has been presented of differences in motor behavior of IUGR infants at birth,2s and in subsequent follow-up studies minimal cerebral dysfunction has been identified by hyperactivity, poor fine motor coordination, and hyperreflexia.z6 In neonatal behavioral studies it was shown that, as compared to the control group, the babies of the IUGR group exhibited a pattern of decreased motor and visual activity with, at 12 months of age, decreased activity and level of energy during the Bayley tests.
Although the IUGR children have normal physical development, there is evidence of an increased incidence of mental handicap and subsequent learning difficulties. In a study of 22 mature IUGR babies and 25 normal mature babies with comparable nerve conduction velocities at birth, Parmalee and Schultes’ reported similar results in the two groups with the Gesell development tests at 40 weeks of age. In a study of 96 mature IUGR children, Fitzhardinge and Stevenze reported an average IQ. of 95 in the boys and 101 in the girls. However, 50 per cent of the boys and 36 per cent of the girls performed poorly in school, in&ding one third of the children with I.Q.‘s of more than 100. In a
544
Low
ef al,
study of 33 IUGR newborn infants and 72 newborn infants whose weights were appropriate for dates, all of whom weighed less than 1,500 grams at birth, Francis-Williams and Davies28 reported a lower mean full-scale IQ. in the children of the IUGR group with subsequent learning difficulties in one fifth of the children. In this study the lower mental and physical development indices at 12 months of age in the babies of the IUGR group in relation to the control group are illustrated in Fig. 9. The significance of the severity of the growth retardation in the babies of the IUGR group in respect to the mental development index is illustrated in Fig. 10; there is a coefficient of correlation of 0.49 between birth weight and the mental development index at 12 months of age. This is in keeping with observations reported by Fancourt and colleagueszg that the children in whom the growth retardation began before 26 weeks’ gestation, as demonstrated by serial ultrasound examination of biparietal diameters, had a lower developmental quotient at 4 years of age.
March 1, 1978 Am. J. O&et. Gynecol.
There is a close but not absolute relationship between the maternal urinary estrogen index and severity of growth retardation as expressed by weight in relation to gestational age. The significance of a low estrogen index in respect to mental development index in the IUGR babies is illustrated in Fig. 11; there is a coefficient of correlation of 0.49 between the estrogen index and the mental development index at 12 months of age. Although normal development has been reported in children of mothers with low urinary excretion patterns, 3o later neurologic and psychological abnormalities were observed in 14 children of such mothers. The occurence of an episode of intrapartum asphyxia in the IUGR fetuses was not a factor in the low Bayley scores observed at 12 months of age. Follow-up studies of the children of the control and IUGR groups are under way and will include observations and
of physical neurologic
sures of vision,
growth
and
assessment hearing,
intellectual in
and
conjunction
development with
mea-
speech.
REFERENCES G.: Psychologic correlates of premature birth, J. 1. Weiner, Nerv. Ment. Dis. 134: 129, 1962. 2. Lubchenko, L. O., Horner, F. A., Reed, L. H., Hix, L. E., Metcalf, D., Coleig, R., Elliott, H. C., and Bourg, M.: Sequeiae of premature birth. Evaluation of premature infants of low birth weight at ten years of age, Am. J. Dis. Child. 106: 101, 1963. 3. Drillien, C. M.: The Growth and Development of the Prematurely Born Infant, Edinburgh, 1964, E. & S. Livingstone, Ltd. 4. McDonald, A.: Children of Very Low Birth Weight, M.E.I.U. Research Monograph, No. 1, London, 1967, S.I.M.P. with Heinemann Medical. 5. Davies, P. A., and Russell, H.: Later progress of 100 infants weight 1000 to 2000 gm at b&h f;d immediately with breast milk. Dev. Med. Child Neuroi. 10: 725. 1968. 6. Rawjings, G., Reynolds, E. 0. R., Stewart, A., and &rang, L. B.: Changing prognosis for infants of very low birth weight, Lancet 1: 516, 1971. 7. Yerushaimy, J., van den Berg, B. J., Erhardt, C. L., and Jacobziner, H.: Birth weight and gestation as indices of “immaturity,” Am. J. Dis. Child. 109: 43, 1965. 8. Driiiien, C. M.: Prognisis of infants of very low birth weight, Lancet 1: 697, 1971. E., and Turner, G.: The importance of the 9. Collins, small-for-dates baby to the problem of-mental retardation. Med. I. Aust. 2: 313. 1971. 10. Gruenwald: P.: Growth of the human fetus. I. Normal growth and its variation, AM. J. OBSTET. GYNECOL. 94: 1112, 1966. 11. Biishen, B. R., and McRoberts, H. A.: A revised socioeconomic index for occupations in Canada, Can. Rev. Social. Anthropol. 13: 71, 1976. 12. Low, J. A., Pancham, S. R., Worthington, D., and Boston, R. W.: The acid-base and biochemical characteristics of intrapartum asphxyia, AM. J. OBSTET. GYNECOL. 121: 446, 1975.
13. Lubchenko, L. O., Hansman, C., and Dressier, M.: Intrauterine growth as estimated from live born birth weight data at 24 to 42 weeks of gestation, Pediatrics 32: 793, 1963. 14. Campbell, D., Kuyek, J., Lang, E., and Partington, M. W.: Motor activity in early life. II. Daily motor activity output in the Neonatal period, Biol. Neonate 18: 108, 1971. N.: Bayley Scales of Infant Development, New 15. Bayley, York, 1969, Psychological Corp. 16. Fitzhardinge, P. M., and Steven, E. M.: The small-fordate infant. 1. Late growth patterns, Pediatrics 49: 671, 1972. 17. O’Connell, E. J., Feidt, R. H., and Stickler, G. B.: Head circumference, mental retardation and growth failure, Pediatrics 36: 62, 1965. 18. Prior, H. B., and Thelander, H.: Abnormally small head size and intellect in children, J. Pediatr. 73: 593, 1968. 19. Nelson, K. B., and Deutschberger, J.: Head size at one year as a predictor of four year I.Q., Dev. Med. Child Neural. 12: 487, 1970. and celiu20. Winick, M., and Rosso, P.: Head circumference lar growth of the brain, J. Pediatr. 74: 774, 1969. 21. Babson, S. G., and Henderson, N. B.: Fetal undergrowth: Relation of head growth to later intellectual performance, Pediatrics 53: 890, 1974. 22. Cruise, M. 0.: A longitudinal study of the growth of low birth weight infants. I. Velocity and distance growth birth to 3 years, Pediatrics 51: 620, 1973. 23. Ounsted, M.: Post-natal growth of children who were S.F.D. and L.F.D., Dev. Med. Child Neuroi. 13: 121, 1971. 24. Bjerre, I.: Physical growth of 5-year-old children with a low birth weight. Acta Paediatr. Stand. &L: 33. 1975. 25. Michaelis, R.,-Schuitze, F. J., and Noite, R.: Motor behavior of small for gestational age newborn infants, J. Pediatr. 76: 208, 1970. 26. Fitzhardinge, P. M., and Steven, E. M.: The small for date
Volume Number
130 5
Intrauterine
infant. I. Neurological and intellectual sequelae, Pediatrics 50: 50, 1972. 27. Parmalee, A. H., and Schulte, F. J.: Developmental testing of preterm and small for dates infants, Pediatrics 45: 21, 1970. 28. Francis-Williams, J., and Davies, P. A.: Very low birthweight and later intelligence, Dev. Med. Child Neurol. 16: 709, 1974. 29. Fancourt. R.. Campbell, S., Harvey, D., and Norman, A.
Inf~on
growth
retardation
545
P.: Follow-up study of small-for-dates bab1t.s. hr. Med. J. 1: 1435, 1976. 30. Greene, J. W., Beargie, R. A., Clark, B. K.. And Smith, K.: Correlation of & excretion patterns of pregnant female with subsequent development of their children, A%, J. OBSTET. GYNECOL. 105: 730. 1969. 31. Wallace, S. J.. and Mitchie, E. (2.: A follow-up study of infants born to mothers with low Es ~‘YS retion during pregnancy, Lancet 2: 560, 1966.
for authors
Most of the provisions of the Copyright Act of 1976 became effective on January I, 1978. Therefore, all manuscripts must be accompanied by the following statement, signed by each author: “The undersigned author(s) transfers ah copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published.” Authors will be consulted, when possible, regarding republication of their material.
LOW
R.
S. GALBRAITH
D.
MUIR
H.
KILLEN
J.
KARCHMAR
D.
CAMPBELL
Kingston,
Ontario, Canada
This is a preliminary report of a prospective follow-up study of 88 intrauterine growth-retarded (IUGR) babiis and a control group of 97 babiis with weights appropriate for gestational age. The characteristic clinical features of IUGR pregnancies were observed in the obstetric patients of the IUGR group. The babiis of the NJGR group have a phase of accelerated growth during the 3 months following delivery although they continue to be smaller than the babies of the controi group at 12 months of age. No major neurologic abnormalities have been noted in the IUGR babies atthough behavioral difterences were observed during the neonatal period and at 12 months of age. There were lower mental and physical development indices at 12 months of age which were due to the IUGR babies of lowest birth weight and those with a low maternal urinary estrogen index. (AM. J. OBSTET. GYNECOL.
130: X34,1978.)
FOLLOW-UP STUDIES of low-birth-weight infants born during the 1950’s and early 1960’s demonstrated a significant incidence of handicaps.lM4 However, the results of subsequent studies with improved perinatal care indicate few& neurologic sequelae and more normal mental development.5, 6 It is now recognized that a substantial number of these infants were of low birth weight because of growth retardation rather than prematurity.’ The present follow-up studies in surviving intrauterine growth-retarded (IUGR) children are directed toward the assessment of the long-term significance of this perinatal complication. The relevance of growth retardation to long-term disability in a pre-
THE
From the Departments of Obstetrics and Gynaecology Psychology, Queen’s University at Kingston.
and
Supported by research grants from the Ontario Mental Health Foundation and the Ontario Society for Crif@ed Children. Presented at the Thirty-third Annual Meeting of the Society of Obstetricians and Gynuecologists of Canada, Montreal, Quebec, Canada, June 14-18, 1977. Refnint requests: Dr. J. A. Low, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7.
534
liminary report by Drilliens indicated that 60 per cent of growth-retarded children weighing less than 1,500 grams at birth were abnormal, usually having mild degrees of mental retardation and minor neurologic abnormalities. Similarly, a retrospective survey of 1,345 mentally retarded individuals indicated that 14.4 per cent were growth retarded. Two thirds of these were retarded because of placental insufficiency, suggesting the importance of intrauterine growth retardation in the occurrence of mental retardation.g The present report represents the first phase of a prospective follow-up study of 86 IUGR newborn infants and 9? control newborn infants and will outline the characteristics of the obstetric patients and their pregnancies and the subsequent follow-up observations at 3, 6, and 12 months of age.
Material and methods The newborn infants in the present study were born of obstetric patients admitted to the obstetric service of the Queen’s and Kingston health sciences complex. The definitions of the control and IUGR groups were based upon the weightlgestational age scale of Gruenwald.‘O The control group included 97 newborn infants ooo2-9378/78/05130-0534$01.20/00
1978 The C.V.
Mosby Co.
Volume
130
Number
5
whose weights at delivery were greater than the 25th percentile for gestational age. The IUGR group included 86 newborn infants whose weights at delivery were less than the 10th percentile for gestational age (Fig. 1). Data in respect to the obstetric patients, their pregnancies, and the newborn infants were obtained from the medical records and, where necessary, by personal interview while the patients were hospitalized. The maternal characteristics included in this report are age at delivery, height, prepregnancy weight, weight gain during the pregnancy, and smoking habits. Maternal medical complications associated with the current pregnancy included hypertension, chronic renal disease, cardiac disease, anemia, diabetes, and endocrine disorders. Socioeconomic indices recorded include the number of years of education, Canadian or non-Canadian nationality, and race of each parent. The Blishen score was derived from the father’s occupation and socioeconomic status.” The family characteristics included annual income and the numbers of bedrooms and residents in the home. The features of the maternal obstetric history include maternal parity, the number of previous perinatal deaths, previous IUGR pregnancies, and previous congenital anomalies. Obstetric complications of the present pregnancy include antepartum hemorrhage in the first and second halves of pregnancy, the latter including abnormal bleeding due to placenta previa, premature placental separation, or an unknown cause. Toxemia was defined as a systolic blood pressure of greater than 140 mm. Hg or a rise of 30 mm. Hg and a diastolic pressure of greater than 90 mm. Hg or a rise of 20 mm. Hg, with or without significant proteinurea. Multiple pregnancies were recorded. The labor and delivery characteristics include the duration of labor, defined as the time in hours from the onset of continuous contractions to delivery, and the method of delivery. The fetal characteristics established at delivery include maturity and sex. Gestational age was derived from the first day of the last menstrual period and was classified to the nearest week (i.e., 39 weeks and 3 days = 39 weeks; 39 weeks and 4 days = 40 weeks) in order to be in keeping with the Gruenwald weight/gestational age scale. The maternal urinary estrogen index was calculated from three or more 24 hour urinary estrogen estimations, the last being estimated within two weeks of delivery. A per cent was calculated for each estimation in relation to the normal mean for the appropriate week of gestational age; the “estrogen index” is the averaged percentages. An acid-base assessment was carried out on
Intrauterine growth retardation
sook 26
3n
3s
34
GESTATIONAL
36
36 AGE
40
43
535
44
(WEEKS)
Fig. 1. Population distribution with respect to weight and gestational age. This study includes 97 control newborn infants whose birth weights were above the 45th percentile for gestational age and 86 newborn IUGR infants whose birth weights were less than the 10th percentile for gestational age.
the blood of the umbilical vein and artery at delivery. The umbilical artery buffer base provided a measure of the presence or absence of a metabolic acidosis due to an episode of intrapartum fetal asphyxia.12 The newborn characteristics include the following physical measures: birth weight and weight percentile according to the weight/gestational age scale of Gruenwald, the crown-heel birth length, head and chest circumference, and the corresponding percentiles according to Lubchenko and associates.13 A weight-length ratio was calculated and the maximum percentage of weight loss was derived from the lowest weight during the subsequent nursery course. Measures of neonatal morbidity include Apgar scores at one and five minutes, hypothermia defined as a body temperature of less than 36” C., hypoglycemia defined as a blood sugar level of less than 30 mg. per IO0 ml. in the mature infant and less than 20 mg. per 100 ml. in the preterm newborn infant, and hyperbilirubinemia defined as requiring phototherapy or an exchange transfusion. Respiratory complications include any significant indrawing, grunt, retraction, or tachypnea
Low et al.
536
Table
March 1, 1978 Am. J. Obstet. Gynecol.
I. The maternal
characteristics
and socioeconomic
indices of the parents
Controlgroup
Maternal Age
No. of observations
Mean
S.D.
97 91
26.7 163.6
5.6 6.3 13.5 5.8
of the control IUGR
No.
No. of obsetyations
%
Mean
and IUGR
groups
group
S.D.
No.
%
P value5
characteristics:
Height Weight Weight gain Smoking Education Canadian Caucasian Maternal
medical
27
89
92
97
91
94
97
15
16
85
94
62.1
87 84
11.8
94 97
13.1
2.8
27.1
5.5
161.7
6.9
56.8 9.9
12.7 5.1
11.9
co.01 CO.05 52
65
82 83
95 96
13
16
2.7
co.01 co.01
complications:
Hypertension-renal disease Diabetes-endocrinopathies Anemia Socioeconomic
22
86 84 85 72 81 84 86 86
characteristics:
89
Blishen score Family income Home-residents Home-bedrooms
2 71
47.3 J 5.0 3.8
16.5 6.3 1.1
2.9
0.9
74 44 65 64
45.6 12.5 4.1 2.7
18.1 5.6 1.5 0.9
CO.05
Table II. The characteristics of previous pregnancies, the obstetric complications, and the fetal and labor characteristics of the present pregnancy in the control and IUGR groups
No. of obstations Parity: 7l 21 Past obstetric complications:
Control
group
Mean
S.D.
97
L.&r
and delivery
%
53 44
55 45
6 3 1
14 7 2
17 9
No. of obser-uations
Mean
group
No.
%
36 50
42 58
S.D.
5 22 2
44 4
17 9
17 6
20 7
27 4
28 4
16
18
11
13
23 3 15
24 3 16
13 9 14
15 10 16
55 42
57 43
33 53
38 62
86
SigGjkant P value
50
97
complications:
Antepartum hemorrhage Antepartum hemorrhage Toxemia Multiple pregnancy
No.
44
Perinatal death ILJGR pregnancy Congenital anomaly Obstehic
IUGR
10 co.01
86
< 20 weeks > 20 weeks
characteristics:
Duration of labor Abdominal delivery-midforceps Abdominal delivery-breech Abdominal delivery-ceserean section
87
11.3
7.8
Q7
73
10.4
8.1
86
Fetal characteristics:
Gestational age at delivery Male Female Estrogen index Umbilical artery buffer base
96
40.3
1.5
97 71 69
95.0 39.9
requiring increased surveillance or oxygen therapy. Central nervous system (CNS) complications include any symptoms such as seizures or abnormalities of tone, consciousness, activity, or reflexes. Behavioral studies in the neonatal period include measures of activity, visual fixation or pursuit, and sleep patterns. General motor activity was measured by
30 2.0
86 86
39.1
65 59
60 36.9
1.8
26 3.6
CO.01 CO.05 co.01
a modified self-winding calendar watch, an actometer.14 Activity is expressed in arbitrary units per hour. Visual activity was recorded by a trained observer. Visual fixation in response to patterned stimuli was scored on a four-point scale and visual pursuit to the same stimuli on a three-point scale. The sleep pattern was similarly recorded by a trained observer and the
Volume Number
Intrauterine
130 5
Table III. The characteristics of the newborn in the control and IUGR groups
infants
and the subsequent
neonatal
Controlgroup No. of obsmatitiMz( Newborn
Height:
Gm. % cm.
97 97
70
Head circumference:
cm.
97
%
Chest circumference: (cm.) Weight-length
3485 62 52.5
452 23 2.9
complications
IUGR
No.
%
537
group
No. of obsmatiom
Mean
S.D.
86
2302
354 2.1 3.2 27 1.9 18 2.6
No.
%z
Sign$cant P value
96 97 89 97
79 35.1
19 1.3
72 33.6
23 1.8
83 85
15 6 6.3
81 83 84 85
15 7
2.6
5.5 47.8 42 32.1 23 29.1
a.00 1
4.1
77 52
2.6
1 1
complicatkms:
Apgar score 1 min. Apgar score 5 min. Hypothermia Hypoglycemia Hyperbilirubinemia Respiratory complications CNS complications
Table
S.D.
retardation
characteristics:
Weight:
Neonatal
Mean
growth
97
8.1
1.7
35
9.3
0.7
95 14 95 97 97
4
2
4 7 2 2
1
1
:
IV. The assessment of neonatal
behavior
of the newborn
86 39 86 61 86 86 86
infants
c&01 group
7.2 8.7
2.4 1.5 24 9 3 ;
of the control IUGR
and IUGR
28 IJ -1 6 0
groups
group P
No.
Activity score Visual fixation Visual pursuit Sleep: Rapid eye movements Quiet Transitional
44 43 43 44
Mean
0.69 4.8 8.1
S.D.
i
0.35
1.9
No.
Mean
40
0.48 4.0 6.7
31
3.5
31
S.D.
values
0.25
1.8 3.0
co.07 CO.08
39 27.7
9.0
30.8
8.9
13.4
6.5 6.4
12.9
5.9
15.4
6.9
17.5
sleep states described included active or rapid eye movement (REM) sleep, transitional sleep, and quiet sleep. Follow-up observations were done at 3, 6, and 12 months of age. The numbers of observations at 3 and 6 months were less than the number at 12 months because this part of the protocol was added when the study had been in progress for one year. The measures of physical growth, weight, height, and head and chest circumference were obtained at each visit, and a detailed physical examination was done at 3 and 12 months of age. The Drillien test of tone was carried out at 3 months of age with a detailed neurologic examination at 12 months. Tone was assessed by passive movement of the limbs. Active movement was assessed by symmetry and amount of movement, complex movement by the precision with which small objects were manipulated, and involuntary movement by the presence of tremors or
choreiform movements. The deep tendon reflexes and superficial abdominal reflexes were tested. The cranial nerves tested were the second by vision: third, fourth, and sixth by eye movements; seventh by facial symmetry and movement; eighth by hearing; and ninth and tenth by the gag reflex. The Bayley15 test of mental and physical development and behavioral characteristics was carried out in the home at 6 months of age and in the clinic at 12 months. Results The maternal characteristics and socioeconomic indices of the parents of the control and IUGR groups are outlined in Table I. As compared to the control group the mothers of the IUGR group had a lower prepregnancy weight, 56.8 kilograms in relation to 62.1 kilograms, with a trend fo less weight gain during pregnancy, and a greater incidence of smoking, 65 per
538
Low
et al.
March 1, 1978 Am. J. Obstet. Gynecol.
WEIGHT
GAIN
S-6 NON
HEAD
HEIGHT
6-12 MON.
CIRCUMFERENCE GROWTH
O-3 NON. IO
CHEST
1
3-6
GROWTH
MON.
6-12YON.
CIRCUMFERENCE GROWTH
Cm S-
g@tj OJ
3-6 MON Control
Groups
6-12 MON.
1-3 MON.
3-6
MON.
6-12 NON
I U G R G~JP~
Fig. 2. The rate of growth for each physical measure in the babies of the control and IUGR groups before 3 months, between 3 and 6 months, and between 6 and 12 months of age. Table V. The measures 6, 12 months of age
of physical
growth
of the babies of the control
3 MO.
weighi
group
at 3, 12 MO.
6 MO.
No.
Mean
S.D.
P value
No.
Mean
S.D.
P value
No.
Mean
S.D.
P value
43 40
6.3 5.2
0.7 0.6
47 41
8.0 69
1.0 0.8
77 69
9.8 8.8
1.0 1.1
43 40
61.5 58.4
3.1 2.5
50 42
66.0 63.1
2.9 2.7
76.1 73.3
2.8 3.1
co.00
50 41
44.2 42.2
4.3 1.4
co.01
77 7.
46.6 45.3
1.5 1.6
50 42
44.1 42.5
2.0 2.1
76
47.8 46.6
2.1 2.3
(Cm.):
Control IUGR Height
and IUGR
(cm.)
Control IUGR
Head circumference Control
(cm.):
IUGR Chest circumfenmce
Control IUGR
1
43
41.2
1.1
41
39.6
1.2
43
41.6 39.2
2.0 2.2
(cm. j:
41
cent in relation to 27 per cent. Major maternal medical complications were observed in both groups but with no difference in the incidence between groups. The vast majority of the parents were Caucasian and Canadian. The mothers of the IUGR group had fewer years of education, 11.9 years, than the mothers of the control group, 13.1 years. However, no difference was observed between the fathers of the two groups in this regard. There was a trend to a lower family income in the IUGR group in relation to the control group. The characteristics of previous pregnancies, the ob stetric complications, and the fetal and labor characteristics of the present pregnancies of the control and IUGR groups are outlined in Table II. In the history of
6g
past pregnancies there was an increased incidence of IUGR pregnancies in the mothers of the IUGR group, 44 per cent, in relation to the mothers of the control group, 7 per cent. There were no differences in regard to obstetric complications and labor and delivery characteristics between the two groups with the exception that the gestational age at delivery was slightly less in the IUGR group, 39.1 weeks, in relation to the control group, 40.3 weeks. The maternal urinary estrogen index was characteristically lower in the IUGR group, 60 per cent, in relation to the control group, 95 per cent. There was a trend to an increased incidence of female fetuses in the IUGR group. The lower umbilical artery buffer base in
Volume Number
intrauterine growth retardation
130 5
the IUGR group, 36.9 mEq. per liter, in relation to the control group, 39.9 mEq. per liter, is due to an increased incidence of metabolic acidosis resulting from an episode of intrapartum fetal asphyxia. The characteristics of the newborn infants and the subsequent neonatal complications in the control and IUGR groups are outlined in Table III. As compared to the control infants the newborn infants of the IUGR group were smaller in weight and length, with an increased incidence of weight-length ratio of less than 10 per cent, and had a smaller head and chest circumference. The newborn infants of the IUGR group had lower Apgar scores at one minute and an increased incidence of hypothermia during the initial 24 hours of the neonatal period. There were otherwise no differences in the occurrence of neonatal complications between the two groups. The assessment of neonatal behavior of the newborn infants of the control and IUGR groups is summarized in Table IV. As compared to the control group the newborn infants of the IUGR group had a lower activity score, with a trend to less visual activity as expressed by measures of visual fixation and visual pursuit. There were no differences observed in respect to the sleep patterns between the two groups. The measures of physical growth at 3, 6, and 12 months of age of the babies in the control and IUGR groups are outlined in Table V. The measures of weight, height, and head and chest circumference in the babies of the IUGR group are lower than those in the control group at each stage until 12 months of age. Although all the physical measures of the infants of the IUGR group at 12 months of age are smaller, the relative differences decreased with age, indicating some measure of “catch-up” in the IUGR babies. The rates of growth for each physical measure during the initial 3 months, between 3 and 6 months of age, and between 6 and 12 months are illustrated in Fig. 2. The rates of growth during the initial 3 months in the IUGR and control groups in respect to weight were not different, but the IUGR group had greater gains in respect to height, 10.6 cm. in relation to 9.6 cm. (p < 0.01); head circumference, 7.6 cm. in relation .,” Y”L “6”’ L.....‘. ss 39:9 Umbilical artery buffer base 2.0
requiring increased surveillance or oxygen therapy. Central nervous system (CNS) complications include any symptoms such as seizures or abnormalities of tone, consciousness, activity, or reflexes. Behavioral studies in the neonatal period include measures of activity, visual fixation or pursuit, and sleep patterns. General motor activity was measured by
539
60-’ so40-
% 3o
PATtENTSzO-
toi
-2
control
Group
----
IUGR
Gmup
-
3
4
Fig. 3. The distribution of the scores in respect to activity and level of energy during the Bayley test in the babies of the control and IUGR groups at 12 months of age. Table VI. The results of neurologic examination of the babies of the control and IUGR groups at 12 months of age
Tone
Moummnt: Active Complex Involuntary
Rejlexes: Deep Superficial Cranial nerves
70
0
70 70 70
L
64 48 69
75 1.5
0
76
0
0
76 76
10 0
0 0 2
70 65 74
0 0 3
11
3
13
The Bayley scores at 6 and 12 months of age in the control and IUGR groups are “I “Y _” outlined in Table .“.“I VII.
59
36.9
3.6
a modified self-winding calendar watch, an actometer.14 Activity is expressed in arbitrary units per hour. Visual activity was recorded by a trained observer. Visual fixation in response to patterned stimuli was scored on a four-point scale and visual pursuit to the same stimuli on a three-point scale. The sleep pattern was similarly recorded by a trained observer and the
540
Low
Table
VII.
et al.
March 1, 1978 Am. J. Ohsta. Gynecol.
The Bayley scores of the babies of the control
and IUGR
groups
clmtr01group
IUGR
of age
group
Mean
S.D.
No.
Mean
S.D.
51
113.3
18.6
18.3
107.6
18.9
41 42
108.4
50
107.9
18.9
74 75.
109.8
12.5
102.1
18.1
67 68
102.9 93.5
15.2 18.9
NO.
6 mo.: Mental development index Physical development index
at 6 and 12 months
P values
12 mo.
Mental development index Physical development index
Km
SIX MONTHS
MENTAL Control 0
Twm.vE MONTHS
DEVELOPMENT
INDEX
I.U.Q.R. Birch Wt>23OOOm~
SIX MONTHS
PHYSICAL
TWELVE MONTHS
DEVELOPMENT
I.U.G.R. Birth Wt<2300Gm
INDEX m
Fig. 5. The Bayley scores at 6 and 12 months of age of the control and IUGR babies of birth weight categories ~2,300 grams and <2,300 grams.
Co,,tro!Gmup ----
lu,GR,8WhWl>2300Gl;l
,UGR Bir,hW,,<2300
6m -
Fig. 4. The measures of physical growth at 3, 6, and 12 months of age in the control and IUGR babies of birth weight categories ~2,300 grams and <2,300 grams. mean score for activity in the IUGR group, 4.1, was lower than that in the control group, 5.0 (p < O.OOl), and similarly the mean score for level of energy in the babies of the IUGR group, 2.8, was lower than that for the babies of the control group, 3.3 (p < 0.001). Significance of birth weight in the IUGR group. The mean birth weight in the IUGR group was 2,300 grams. Two categories of the IUGR group, that is, those with a birth weight of less than 2,300 grams and those with a birth weight of more than 2,300 grams, have been compared. The newborn IUGR infants weighing less than 2,300 grams were shorter, 45.2 cm. in relation to 49.6 cm. (p < 0.001); had a smaller head circumference, 30.9 cm. in relation to 33.0 cm.
(p < 0.001); and had a smaller chest circumference, 27.3 cm. in relation to 30.4 cm. (p < 0.001). There were no significant differences in the maternal characteristics, socioeconomic indices, or antenatal obstetric complications between the two categories. The gestational age at delivery of the IUGR infants weighing less than 2,300 grams, 38 weeks, was earlier than that of the infants weighing more than 2,300 grams, 40 weeks (p < 0.001). Similarly, the maternal urinary estrogen index of the IUGR infants weighing less than 2,300 grams, 45 per cent, was lower than that of the infants weighing 2,300 grams or more, 71 per cent (p < 0.001). The measures of physical growth at 3, 6, and 12 months of age in the IUGR babies of both weight categories follow the pattern of the control group (Fig. 4). As compared to the IUGR 22,300 gram babies, the measures at 12 months of age show the IUGR <2,300 gram babies to be smaller in weight, 8.4 kilograms in relation to 9.1 kilograms (p < 0.01); in height, 72.2 cm. in relation to 74.2 cm. (p < 0.01); and in chest circum-
Volume Number
Intrauterine growth retardation
130 5
TW
MENTAL con,ro,
SIX
DEVELOPMENT 0
I “G
R
Estrogen
INDEX Index,60Xe7ld
I UGR
TWELVE
MONTHS
PHYSICAL
541
MONTHS
DEVELOPMENT
Estrogen
hdex
CM)%
tNDEX a
Fig. 7. The Bayley scores at 6 and 12 months of age of the control and IUGR per cent and ~60
Fig. 6. The measures of physical growth at 3, 6, and 12 months of age of the control and ILJGR babies of estrogen index categories ~60 per cent and <60 per cent.
ference, 45.6 cm. in relation to 47.3 cm. (p < 0.01). The difference in respect to head circumference was not statistically significant. The Bayley stokes of the IUGR babies in both birth weight categories in relation to the score for the control group are illustrated in Fig. 5. As compared to the IUGR ~2,300 gram infants, the mental development index in the IUGR <2,300 gram infants was lower at 6 months of age, 97.8 in relation to 115.2 (p < O.Ol), and at 12 months of age, 96.0 in relation to 108.6 (p < 0.00 1‘). Similarly, the physical development index in the IUGR <2,300 gram category is lower at 6 months of age, 96.7 in relation to 114 (p < O.Ol), and at 12 months of age, 86.3 in relation to 99.2 (p < 0.01). SlgnScance of estrogen index in the IUGR @up. The mean estrogen index in the IUGR group was 60 per cent. Two categories of the IUGR group, that is, an estrogen index ~60 per cent and an estrogen index ~60 per cent have been compared. There were no differences in the maternal characteristics, socioeconomic indices, or antenatal obstetric complications between the two categories. There was no difference in respect to the gestational age at delivery between the IUGR
babies of estrogen per cent.
index
rategories
260
infants of the two estrogen index categories and the control group. A comparison of the two groups shows the IUGR newborn infants with an estrogen index ~60 per cent to weigh less at birth, 2.15 kilograms in relation to 2.48 kilograms (p < 0.01); to be shorter, 46.5 cm. in relation to 48.9 cm. (p C 0.01); to have a smaller head circumference, 31.4 cm. in relation to 32.7 cm. (p < 0.01); and to have a smaller chest circumference, 27.9 cm. in relation to 30.5 cm. (p < 0.01). The measures of physical growth at 3. 6, and 12 months of age in the IUGR babies with estrogen indices of 2 60 per cent and <60 per cent follow the pattern of the control group (Fig. 6). The differences in respect to weight, height, and head and chest circumference at 12 months of age between the IUGR babies of the two estrogen index categories are not statistically significant. The Bayley scores of the IUGR babies of the two estrogen index categories in relation to those of the control group are illustrated in Fig. 7. The mental development index in the IUGR babies with an estrogen index of ~60 per cent in relation to that in the ~60 per cent estrogen index category is lower at 6 months, 100.1 in relation to 120.8 (p < O.Ol), and at 12 months, 99.6 in relation to 112.3 (p < 0.01). Similarly, the physical development index in the IUGR infants of the (60 per cent estrogen index category is lower at 6 months, 99.7 in relation to 119.5 (p c O.Ol), with a trend to be lower at 12 months of age. 88.2 in relation to 99.5 (p < 0.05).
542
Low et al.
March 1, 1978 Am. J. Otstet. Gynecol.
MENTAL
Cm
DEVELDPMEW INDEX
CONTRDL GROUP 0
PMYSICAL
DEVELOPMENT INDEX
I.U.G.R. GROUP
69
Fig. 9. The mental and physical development indices at 12 months of age in the babies of the control and IUGR groups. Controt Group l”GRGrwp
----
Fig. 8. The measures of physical growth of the babies of the control and IUGR groups at 3, 6, and 12 months .of age. Signific~e of fetal sex and intrapartum fetal asphyxia in the IUGR group. In the IUGR group there was a greater proportion of female babies, 53, in comparison to male fetuses, 33. Similarly, there were a number of episodes of intrapartum fetal asphyxia with metabolic acidosis at delivery in the IUGR group. The fetuses of 37 patients exhibited no evidence of a metabolic acidosis at delivery, while the fetuses of 22 patients had evidence of a significant metabolic acidosis at delivery, that is an umbilical artery buffer base of less than 36.1 mEq. per liter. The IUGR infants were categorized by sex and by evidence of (with and without) intrapartum fetal asphyxia and were compared to assess the significance of these variables in respect to the relevant observations in the IUGR group. No significant differences were observed between these categories in respect to the newborn measures at delivery; measures of physical growth at 3,6, and 12 months of age; or Bayley scores at 6 and 12 months.
The characteristic clinical features of IUGR pregnancies were observed in the obstetric patients of the IUGR group. The mothers had lower prepregnancy weight, less weight gain during pregnancy, and an in-
creased incidence of smoking. The pattern of maternal urinary estrogen excretion was low and there was a significant incidence of intrapartum fetal asphxyia. In comparison to the control group, growth retardation affected all physical measures, that is, lower birth weight, shorter length, and smaIler head and chest circumference. The measures of physical growth at 3, 6, and 12 months of age in the control and IUGR groups are illustrated in Fig. 8. In comparison to the control babies the initial acceleration of growth in IUGR babies as reported by Fitzhardinge and SteverP during the first 6 months, was observed in the present study during the first 3 months of life; this growth was found in height and head and chest circumference. The importance of this acceleration of growth, particularly in respect to head circumference, is emphasized by the evidence of a relationship among head circumference, brain growth, and subsequent intelligence.17-2’ The growth pattern between 3 and 12 months of age in the IUGR babies is similar to that of the control babies. Thus at 12 months of age the IUGR babies are still smaller than the control babies in respect to weight, height, and head and chest circumference, although the relative difference is less than that at birth. The continuing difference of these physical measures at 12 months of age is in keeping with observations in long-term follow-up studies that growth-retarded children continue to be smaller in later years.t6* 22-24
Volume Number
Intrauterine growth retardation
130 5
543
2800 1
MENTAL
DEVELOPMENT
Fig. 10. Scattergram demonstrating the relationship index at 12 months of age in the IUGR group.
50
60
70
6.0
MENTAL
INDEX
between birth weight and mental development
90
loo
DEVELOPMENT
110
120
no
INDEX
Fig. 11. Scattergram demonstrating the relationship between the maternal urinary estrogen index and the mental development index at 12 months of age in the IUGR group.
Major neurologic disabilities have not been observed in follow-up studies of IUGR infants and were not evident in the babies of this IUGR group at 12 months of age. Evidence has been presented of differences in motor behavior of IUGR infants at birth,2s and in subsequent follow-up studies minimal cerebral dysfunction has been identified by hyperactivity, poor fine motor coordination, and hyperreflexia.z6 In neonatal behavioral studies it was shown that, as compared to the control group, the babies of the IUGR group exhibited a pattern of decreased motor and visual activity with, at 12 months of age, decreased activity and level of energy during the Bayley tests.
Although the IUGR children have normal physical development, there is evidence of an increased incidence of mental handicap and subsequent learning difficulties. In a study of 22 mature IUGR babies and 25 normal mature babies with comparable nerve conduction velocities at birth, Parmalee and Schultes’ reported similar results in the two groups with the Gesell development tests at 40 weeks of age. In a study of 96 mature IUGR children, Fitzhardinge and Stevenze reported an average IQ. of 95 in the boys and 101 in the girls. However, 50 per cent of the boys and 36 per cent of the girls performed poorly in school, in&ding one third of the children with I.Q.‘s of more than 100. In a
544
Low
ef al,
study of 33 IUGR newborn infants and 72 newborn infants whose weights were appropriate for dates, all of whom weighed less than 1,500 grams at birth, Francis-Williams and Davies28 reported a lower mean full-scale IQ. in the children of the IUGR group with subsequent learning difficulties in one fifth of the children. In this study the lower mental and physical development indices at 12 months of age in the babies of the IUGR group in relation to the control group are illustrated in Fig. 9. The significance of the severity of the growth retardation in the babies of the IUGR group in respect to the mental development index is illustrated in Fig. 10; there is a coefficient of correlation of 0.49 between birth weight and the mental development index at 12 months of age. This is in keeping with observations reported by Fancourt and colleagueszg that the children in whom the growth retardation began before 26 weeks’ gestation, as demonstrated by serial ultrasound examination of biparietal diameters, had a lower developmental quotient at 4 years of age.
March 1, 1978 Am. J. O&et. Gynecol.
There is a close but not absolute relationship between the maternal urinary estrogen index and severity of growth retardation as expressed by weight in relation to gestational age. The significance of a low estrogen index in respect to mental development index in the IUGR babies is illustrated in Fig. 11; there is a coefficient of correlation of 0.49 between the estrogen index and the mental development index at 12 months of age. Although normal development has been reported in children of mothers with low urinary excretion patterns, 3o later neurologic and psychological abnormalities were observed in 14 children of such mothers. The occurence of an episode of intrapartum asphyxia in the IUGR fetuses was not a factor in the low Bayley scores observed at 12 months of age. Follow-up studies of the children of the control and IUGR groups are under way and will include observations and
of physical neurologic
sures of vision,
growth
and
assessment hearing,
intellectual in
and
conjunction
development with
mea-
speech.
REFERENCES G.: Psychologic correlates of premature birth, J. 1. Weiner, Nerv. Ment. Dis. 134: 129, 1962. 2. Lubchenko, L. O., Horner, F. A., Reed, L. H., Hix, L. E., Metcalf, D., Coleig, R., Elliott, H. C., and Bourg, M.: Sequeiae of premature birth. Evaluation of premature infants of low birth weight at ten years of age, Am. J. Dis. Child. 106: 101, 1963. 3. Drillien, C. M.: The Growth and Development of the Prematurely Born Infant, Edinburgh, 1964, E. & S. Livingstone, Ltd. 4. McDonald, A.: Children of Very Low Birth Weight, M.E.I.U. Research Monograph, No. 1, London, 1967, S.I.M.P. with Heinemann Medical. 5. Davies, P. A., and Russell, H.: Later progress of 100 infants weight 1000 to 2000 gm at b&h f;d immediately with breast milk. Dev. Med. Child Neuroi. 10: 725. 1968. 6. Rawjings, G., Reynolds, E. 0. R., Stewart, A., and &rang, L. B.: Changing prognosis for infants of very low birth weight, Lancet 1: 516, 1971. 7. Yerushaimy, J., van den Berg, B. J., Erhardt, C. L., and Jacobziner, H.: Birth weight and gestation as indices of “immaturity,” Am. J. Dis. Child. 109: 43, 1965. 8. Driiiien, C. M.: Prognisis of infants of very low birth weight, Lancet 1: 697, 1971. E., and Turner, G.: The importance of the 9. Collins, small-for-dates baby to the problem of-mental retardation. Med. I. Aust. 2: 313. 1971. 10. Gruenwald: P.: Growth of the human fetus. I. Normal growth and its variation, AM. J. OBSTET. GYNECOL. 94: 1112, 1966. 11. Biishen, B. R., and McRoberts, H. A.: A revised socioeconomic index for occupations in Canada, Can. Rev. Social. Anthropol. 13: 71, 1976. 12. Low, J. A., Pancham, S. R., Worthington, D., and Boston, R. W.: The acid-base and biochemical characteristics of intrapartum asphxyia, AM. J. OBSTET. GYNECOL. 121: 446, 1975.
13. Lubchenko, L. O., Hansman, C., and Dressier, M.: Intrauterine growth as estimated from live born birth weight data at 24 to 42 weeks of gestation, Pediatrics 32: 793, 1963. 14. Campbell, D., Kuyek, J., Lang, E., and Partington, M. W.: Motor activity in early life. II. Daily motor activity output in the Neonatal period, Biol. Neonate 18: 108, 1971. N.: Bayley Scales of Infant Development, New 15. Bayley, York, 1969, Psychological Corp. 16. Fitzhardinge, P. M., and Steven, E. M.: The small-fordate infant. 1. Late growth patterns, Pediatrics 49: 671, 1972. 17. O’Connell, E. J., Feidt, R. H., and Stickler, G. B.: Head circumference, mental retardation and growth failure, Pediatrics 36: 62, 1965. 18. Prior, H. B., and Thelander, H.: Abnormally small head size and intellect in children, J. Pediatr. 73: 593, 1968. 19. Nelson, K. B., and Deutschberger, J.: Head size at one year as a predictor of four year I.Q., Dev. Med. Child Neural. 12: 487, 1970. and celiu20. Winick, M., and Rosso, P.: Head circumference lar growth of the brain, J. Pediatr. 74: 774, 1969. 21. Babson, S. G., and Henderson, N. B.: Fetal undergrowth: Relation of head growth to later intellectual performance, Pediatrics 53: 890, 1974. 22. Cruise, M. 0.: A longitudinal study of the growth of low birth weight infants. I. Velocity and distance growth birth to 3 years, Pediatrics 51: 620, 1973. 23. Ounsted, M.: Post-natal growth of children who were S.F.D. and L.F.D., Dev. Med. Child Neuroi. 13: 121, 1971. 24. Bjerre, I.: Physical growth of 5-year-old children with a low birth weight. Acta Paediatr. Stand. &L: 33. 1975. 25. Michaelis, R.,-Schuitze, F. J., and Noite, R.: Motor behavior of small for gestational age newborn infants, J. Pediatr. 76: 208, 1970. 26. Fitzhardinge, P. M., and Steven, E. M.: The small for date
Volume Number
130 5
Intrauterine
infant. I. Neurological and intellectual sequelae, Pediatrics 50: 50, 1972. 27. Parmalee, A. H., and Schulte, F. J.: Developmental testing of preterm and small for dates infants, Pediatrics 45: 21, 1970. 28. Francis-Williams, J., and Davies, P. A.: Very low birthweight and later intelligence, Dev. Med. Child Neurol. 16: 709, 1974. 29. Fancourt. R.. Campbell, S., Harvey, D., and Norman, A.
Inf~on
growth
retardation
545
P.: Follow-up study of small-for-dates bab1t.s. hr. Med. J. 1: 1435, 1976. 30. Greene, J. W., Beargie, R. A., Clark, B. K.. And Smith, K.: Correlation of & excretion patterns of pregnant female with subsequent development of their children, A%, J. OBSTET. GYNECOL. 105: 730. 1969. 31. Wallace, S. J.. and Mitchie, E. (2.: A follow-up study of infants born to mothers with low Es ~‘YS retion during pregnancy, Lancet 2: 560, 1966.
for authors
Most of the provisions of the Copyright Act of 1976 became effective on January I, 1978. Therefore, all manuscripts must be accompanied by the following statement, signed by each author: “The undersigned author(s) transfers ah copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published.” Authors will be consulted, when possible, regarding republication of their material.