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Comparison of associated high-risk factors and perinatal outcome between symmetric and asymmetric fetal intrauterine growth retardation
Comparison of associated high-risk factors and perinatal outcome between symmetric and asymmetric fetal intrauterine growth retardation Chin-Chu Lin, MD, Shyr-Jou Su, MD, and L. Philip River, BA Chicago, Illinois This study compares associated high-risk factors and perinatal outcome between 273 symmetric and 445 asymmetric infants with intrauterine growth retardation. No differences were seen in 17 obstetric, medical, and environmental-behavioral high-risk factors between symmetric and asymmetric intrauterine growth retardation. In preeclampsia, the incidence of symmetric intrauterine growth retardation is higher than that of asymmetric intrauterine growth retardation. The timing of the interaction between the high-risk factor and the stage of gestation is more important than the specific high-risk factor in determining whether symmetric or asymmetric intrauterine growth retardation is produced. On comparison of perinatal outcome between the two groups, we concluded: (1) that the onset of symmetric intrauterine growth retardation occurs much earlier in the course of pregnancy than does asymmetric intrauterine growth retardation, (2) that more symmetric than asymmetric pregnancies with intrauterine growth retardation result in preterm delivery, (3) that the neonatal morbidity rate for symmetric intrauterine growth retardation is higher than that for asymmetric intrauterine growth retardation, and (4) that term symmetric infants with intrauterine growth retardation tend to have a lower mean birth weight and a higher incidence of small placentas than term infants with asymmetric intrauterine growth retardation. (AM J OBSTET GYNECOL 1991 ;164:1535-42.)
Key words: Symmetric IUGR, asymmetric IUGR, associated high-risk factors, perinatal outcome Intrauterine growth retardation (IUGR) is recognized as an important cause oflow birth weight, second only to the problem of preterm birth. I The IUGR infant is associated with multiple causative factors 2 ,3 and with high levels of perinatal mortality and morbidity!-7 Two types of IUGR infants have been identified clinically: symmetric and asymmetric." 6, 7 The purpose of this study was to compare associated high-risk factors and perinatal outcome between symmetric and asymmetric IUGR infants. Patients and methods Between July 1979 and December 1985, 718 IUGR infants among a total of 22,616 infants were delivered at the Chicago Lying-In Hospital, The University of Chicago. During the study period, all patients with high-risk factors were enrolled prenatally in either the From the DivislOn of Maternal-Fetal Medlczne, Department of Obstetrics and Gynecology, Pntzker School of Medicine, The Unzversity of Chicago. Supported in part by the Mother's AId Fund of the ChIcago LyingIn Hospital. Presented at the Fifty-eIghth Annual Meetzng of the Central AssoClatlOn ofObstetnclans and Gynecologzsts, LouisVIlle, Kentucky, October
II-13, 1990.
Reprint requests: Chin-Chu Lin, MD, Department of Obstetncs and Gynecology, The University of Chicago, 5841 South Maryland Ave., Box 446. ChIcago, IL 60637,
6/6/28942
Obstetric High-Risk Clinic or the Medical High-Risk Clinic. Historic high-risk factors were recorded during the initial visit, and high-risk factors that developed during gestation were identified in subsequent clinical visits. Clinical data for all high-risk patients during pregnancy were entered into the University of Chicago OB-File computer system whenever a high-risk factor was identified. High-risk patients then had close followup, with intervals of 1 to 2 weeks at our high-risk clinics. Clinical data of low-risk obstetric patients during pregnancy were not entered into the computer system. However, clinical data of labor and delivery and newborn data for both high- and low-risk patients who were delivered at our institution were entered into the computer system. During the study period, 3788 patients had prenatal care at our high-risk clinics. Clinically suspected IUGR cases, such as those with retarded uterine fundal height, were further evaluated by serial ultrasonographic measurements to establish the diagnosis of suspected IUGR. Multiple static axial and longitudinal images of the fetus and uterus were taken during each ultrasonographic examination. Each examination included fetal measurements such as biparietal diameter, head circumference, abdominal circumference, femur length, calculation of head circumference / abdominal circumference ratio, and estimated fetal weight. Each patient also was screened for gross fetal anomalies and quantitative amniotic fluid volume.
1535
1536 Lin, Su, and River
June 1991 Am J Obstet Gynecol
Table I. Comparison of incidences of various high-risk factors between symmetric and asymmetric IUCR* High-risk factor
Symmetric
Asymmetric
Total cases Demographic-behavioral risk factor Primigravid Age <17 yr Age >35 yr Smoking Alcohol Drug abuse Obstetric risk factor Preeclampsia Twin gestation Poor obstetric history Poor weight gain Antepartum hemorrhage Medical risks in current pregnancy: Chronic hypertension Anemia (hemoglobin <10 gm/dl) Urinary tract infection (symptomatic) Asthma Hemoglobinopathy Cardiac disease Diabetes mellitus
273
445 100 26 12 136 37 33
(22.4%) (5.8%) (2.7%) (30.6%) (8.3%) (7.4%)
X2 Test
P= P= P= P= P= P=
64 24 8 77 24 28
(23.4%) (8.8%) (2.9%) (28.2%) (8.8%) (10.3%)
52 24 39 40 II
(19.0%) (8.8%) (14.3%) (14.7%) (4.0%)
55 (12.4%) 36(8.1%) 44 (9.9%) 70 (15.7%) 15 (3.4%)
P < 0.025 P = NS P = NS P = NS P = NS
25 (9.2%) 44 (16.1%) 14 (5.1 %) 11 8 5 1
28 (6.3%) 82 (18.4%) 36 (8.1%) 14 17 6 12
P= P= P=
NSt NS NS NS NS NS
NS NS NS
*Each case of rUCR may have one or more high-risk factors. tPower of statistics for 13 items with p = NS. We had a 7% chance of detecting a 20% difference in the groups.
A fetus with two abnormal results among the three parameters, such as abdominal circumference of < 10th percentile, with a head circumference/abdominal circumference ratio of >2 SD above the mean, (e.g., 1.21 at 34 weeks, 1.05 at 40 weeks) or an estimated fetal weight < 10th percentile was diagnosed as having suspected IUCR. Ultrasonographic evaluation, however, was not performed routinely for all of our obstetric patients, particularly during the first half of the study period, 1979 to 1982. Prenatally suspected IUCR cases were subjected to a weekly high-risk clinic visit and a nonstress test. A nonreactive nonstress test was followed by a contraction stress test,S a biophysical profile scoring evaluation,9 or both. Antenatally suspected IUCR pregnancies were terminated at 38 weeks of gestation after documentation of fetal lung maturity. Earlier termination was carried out either for fetal indications or because of maternal deterioration, consistent with our management protocol. 10 During labor and delivery, various signs of fetal distress, including abnormal fetal heart rate patterns, meconium-stained amniotic fluid, and fetal acidosis, were intensively monitored. At the time of delivery all IUCR infants were evaluated by two pediatricians. All of the preterm IUCR infants in the study series received neonatal care at The University of Chicago's intensive care nursery. After the infant was discharged from the intensive care nursery, the medical record of each preterm IUCR neonate was carefully reviewed and various neonatal morbidities such as respiratory distress syndrome, neonatal infection, neonatal acidosis, hypoglycemia, and hyperbilirubinemia were identified.
At the conclusion of data collection, all 718 IUCR infants were assigned to one of two groups, symmetric or asymmetric IUCR. The symmetric IUCR group was defined as < 10th percentile for both body weight and head circumference for the gestational age at birth. The asymmetric IUCR group was defined as a birth weight of < 10th percentile but head circumference of > 10th percentile for gestational age, on the basis of our own fetal growth curve, which has been in existence since 1983. 3 Preterm IUCR was defined as <10th percentile for birth weight with a gestational age of <37 weeks. For a comparison of associated high-risk factors, 18 factors (including seven medical complications, five obstetric factors, and six environmental-behavioral factors) were compared between the two groups. Fourteen factors were compared statistically by the X2 test for their incidence in each group. Four other factors were not analyzed because of the small number of cases in each category. Further analysis was performed for the 57 IUCR infants whose mothers developed preeclampsia; all of these cases had at least 4 weeks of prenatal care before delivery. Several parameters of perinatal outcome were compared between symmetric and asymmetric IUCR infants by means of either the t test or the X2 test for statistical analysis. Results
Associated high-risk factors. The overall incidence of IUCR during the study period was 3.2% (718 cases ofIUCR per 22,616 total births). Among the 718 IUCR infants, 273 (38%) were symmetric and 445 (62%) were asymmetric IUCR according to the criteria mentioned
Symmetric and asymmetric IUGR
Volume 164 Number 6, Part I
previously. Approximately 80% of symmetric IUGR (217/273) and 70% of asymmetric lUGR (312/445) had one or more identifiable high-risk factors. A comparative analysis of the 18 associated risk factors is shown in Table 1. The incidence of each of the following risk factors was not statistically different between symmetric and asymmetric IUGR: chronic hypertension, anemia, symptomatic urinary tract infection, twin gestation, poor obstetric history, poor weight gain, antepartum hemorrhage, maternal age < 17 years, smoking, use of alcohol, and drug abuse. For those risk factors with a small number of cases in each category, such as asthma, hemoglobinopathy, cardiac disease, diabetes mellitus, and maternal age >35 years, there was no difference in the incidence of symmetric and asymmetric IUGR. Preeclampsia was the only high-risk factor that exhibited a higher incidence of symmetric than asymmetric IUGR (19% vs 12%, P < 0.025). Table II compares symmetric and asymmetric IUGR infants whose mothers had preeclampsia before delivery. The mean gastational age at the diagnosis of IUGR, the mean gestational age at delivery, and the mean birth weight all were significantly lower in the symmetric IUGR group when compared with the asymmetric IUGR group. Most symmetric IUGR infants were delivered of women with either early onset of moderate to severe preeclampsia or chronic hypertension with superimposed preeclampsia. One symmetric and 12 asymmetric IUGR infants were born to diabetic mothers. Seven of the 12 asymmetric IUGR infants were the products of mothers with juvenile diabetes (three with class C, three with class D, and one with class F diabetes). Antenatal diagnosis of IUGR. Approximately one third of the IUGR cases in the study were identified clinically and confirmed by ultrasonography during pregnancy in both groups (93 cases or 34.0% in the symmetric group and 134 cases or 30.1 % in the asymmetric group, p = NS). Among IUGR fetuses diagnosed antenatally, the difference in the timing of clinical detection between symmetric and asymmetric IUGR was quite striking: before 32 weeks, 23% (21 cases) symmetric versus 2% (3 cases) asymmetric (p < 0.001, X' test); at 34 weeks, 46% (43 cases) symmetric versus 14% (19 cases) asymmetric (p < 0.001, X' test); and at 36 weeks, 82% (76 cases) symmetric versus 64% (86 cases) asymmetric (p < 0.01, X' test). Fig. 1 illustrates cumulative curves of the incidences of clinical detection of the two types of IUGR according to gestational age. Preterm delivery, birth weight, and placental weight. As shown in Table III, the incidence of preterm delivery was higher for symmetric than for asymmetric lUGR (32.6% vs 12.4%, P < 0.001). Fig. 2 shows the mean birth weight according to gestational week for both symmetric and asymmetric pre-
1537
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GESTATIONAL AGE
Fig. 1. Cumulative curves of incidences at time of clinical detection for symmetric and asymmetric IUGR according to weeks of gestation (see text for details).
Table II. Comparison between symmetric and asymmetric IUGR associated with maternal preeclampsia* _ _ _ _ _ _ _ I-s-y-m-~-ne-tnc-·-,..--A-sy-m-71-!e-t-nc- t Test Total No. of cases Gestational week IUGR Diagnosed Gestational week at delivery Interval between diagnosts and delivery (wk) Birth weight (gm)
31
26
29.5 ± 2.0
34.1 ± 1.5
p < 0.001
32.7 ± 3.1
36.7 ± 2.2
p < 0.001
3.2 ± 2.8
2.6 ± 2.2
1300 ± 418
2050 ± 338
p
=
NS
p < 0.001
*All patients had at least 4 weeks of prenatal care before delivery. All data expressed as mean ± SO. term IUGR infants. For the purpose of comparison, a control curve of the mean birth weight by gestational week on the basis of a total of 3216 preterm non-IUGR infants delivered prematurely at out institution during the study period, ranging from 28 to 36 weeks, also is illustrated. As expected, the mean weight curves for both symmetric and asymmetric IUGR infants are far below the control curve. It is of interest to note that the mean weight curve for symmetric IUGR runs below that of asymmetric IUGR at each gestational week before 37 weeks. Of those IUGR infants who were delivered at term (:::37 weeks' gestation), the mean birth weight of symmetric IUGR infants was significantly lower than that of asymmetric IUGR infants (2167 ± 260 vs 2385 ± 105 gm, p < 0.001 by t test). The incidence of small placenta at term gestation (defined as a placental weight of <400 gm) was significantly higher in symmetric than
1538 Lin, Su, and River
June 1991 Am J Obstet Gyneco1
3000
iil :E
lI: C)
2000
I:I: C)
iii
3:
:I: lll:
1000
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iii
_ _ ASYMMETRICAL _ _ SYMMETRICAL
O+-..--......-,,-.---r..,...............,---r-......-,,-.---r..,..............., 26
30
28
32
36
34
38
Comment
GESTATIONAL AGE (WEEKS)
Fig. 2. Mean body weight by weeks of gestation for preterm symmetric and asymmetric IUCR. Control curve is obtained from mean birth weight data for our 3216 preterm appropriate-for-gestational-age population during the study period. Mean birth weight data were calculated week by week according to gestational age between 28 and 36 weeks.
Table III. Perinatal events and fetal outcome Symmetric
Total No. of cases Preterm birth Total intrapartum fetal distress* Abnormal FHR with MSAF Abnormal FHR with pH <7.20 Cesarean section Apgar score $6 1 min 5 min Neonatal death Fetal anomaliest
I Asymmetric
I
X2 Test
445 273 89 (32.6%) 55 (12.4%) P < 0.001 117 (42.9%) 153 (34.4%) P = NS 54 (19.8%)
69 (15.5%) P = NS
36 (13.1%)
23 (5.2%)
55 (20.1%)
71 (16.0%) P = NS
87 43 24 16
91 (20.4%) 35 (7.9%) 8 (1.8%) 13 (2.9%)
(31.9%) (15.8%) (8.8%) (5.9%)
tum fetal distress, cesarean delivery, and gross fetal anomalies were not significantly different between the two groups. Neonatal morbidity among preterm IUGR infants. Neonatal morbidity among the 89 preterm symmetric IUGR and the 55 preterm asymmetric IUGR infants is compared in Table IV. The incidences of low 5-minute Apgar score, respiratory distress syndrome, neonatal infection, and neonatal acidosis were higher for symmetric than for asymmetric preterm IUGR infants. There were no significant differences between the two groups in the incidence of hyperbilirubinemia, hypoglycemia, or low I-minute Apgar score.
P < 0.05
P < 0.01 P < 0.05 P < 0.001 P = NS
FHR, Fetal heart rate; MSAF, meconium-stained amniotic fluid. *Intrapartum fetal distress. All cases had abnormal fetal heart rate patterns, some of them combined with meconiumstained amniotic fluid and fetal acidosis. tTwo cases of chromosomal abnormalities and one case of cytomegalovirus in the symmetric group and three cases of chromosomal abnormalities in the asymmetric group.
in asymmetric lUGR (37.5% vs 12.6%, P< 0.001 by X2 test). Perinatal events and fetal outcome. As shown in Table III, fetal outcome for symmetric IUGR was much worse than for asymmetric IUGR infants. There was a higher incidence of preterm delivery, depressed Apgar scores at both 1 and 5 minutes, fetal acidosis, and neonatal death. However, the incidences of total intrapar-
An IUGR infant is commonly defined as one weighing < 10th percentile in birth weight for gestational age. ll However, because there is no standard population from which to derive these percentiles, the birth weights that serve as the cutoff point by various published studies may differ as much as several hundred grams at any gestational week during the third trimester. [2 This variability may result from population differences in sex, or race and from different geographic areas studied, as well as differences in study methods. In this study we used a fetal growth curve (constructed by Lowensohn and based on total live births between 1978 and 1982 at our institution) to define IUGR if the birth weight fell below the 10th percentile line for each gestational week (Fig. 3).3 A comparison of the 10th percentile line of two different fetal growth curves shows a close similarity between the Chicago and the Colorado curve. l l The 10th percentile growth curve from the state of California,[3 however, suggests that their newborns at the cutoff point for IUGR between 26 and 36 weeks of gestation are heavier than ours. When we used the Chicago curve to study a total of 7177 deliveries at our institution between January 1979 and May 1981, there were 426 IUGR newborn infants, an incidence of 5.9%.3 In this study the incidence of IUGR was 3.2% according to the same study method in the same institution but during a different study period. The reason for this difference in the incidence of IUGR during two time periods is not well understood. Among 718 IUGR infants in this study series, 189 (26.3%) were not associated with any high-risk factors. We believe that many of them, particularly those with symmetric IUGR, may belong to the group of so-called "constitutionally small" babies. On the basis of a four times increased risk of stillbirth, Myers and Ferguson" studied a population in the state of Illinois and argued that the 3rd percentile should be used to define IUGR in preterm gestations before 31 weeks, whereas the 15th to 17th percentile should be used to define IUGR
Symmetric and asymmetric IUGR
Volume 164 Number 6, Part 1
1539
WEIGHT - GESTATION GROWTH CURVES
---- University of Chicago Live Births: 1978-1982 0-0-0 California Total Single Live Births: 1966-1970 Colorado General Hospital Live Births: 1948-1960
5.0 4. 5 4.0 ~
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Weeks of Gestation Completed
Fig. 3. Weight-gestational age fetal growth curves of the University of Chicago, state of California, and Colorado General Hospital. Both 10th and 90th percentile lines are shown. Note Chicago and Colorado 10th percentile lines are in close agreement. (Courtesy of R.I. Lowensohn. From Lin C-C, Evans MI, eds. Intrauterine Growth Retardation: Pathophysiology and Clinical Management. New York: McGraw-Hill, 1984:40. Reproduced with permission from McGraw-Hill, Inc.)
in those pregnancies approaching term gestation. In view of the heterogeneity of the various causes of IUGR, there are some inevitable limitations to using the 10th percentile of birth weight as the sole criterion for diagnosing IUGR. Among six infants with chromosomal abnormalities and congenital viral infection, three cases were in the symmetric IUGR group and the other three cases were in the asymmetric IUGR group. In all three cases in the asymmetric group, the head circumference measurements were between the 10th and 25th percentiles. Using a definition of less than the 25th instead of the 10th percentile for head circumference to define symmetric IUGR would place all of these cases in the symmetric group. This idea is consistent with the findings of Sabbagha,15 who reported an incidence of IUGR infants of >50% in cases associated with a small biparietal diameter «25th percentile) in early pregnancy. However, if adopting a definition of <25th percentile for head circumference to differentiate symmetric from asymmetric IUGR would lead to an unrealistically high incidence of symmetric IUGR in our study population. If a criterion of < 10th percentile for head circumference is used to define symmetric IUGR, the 38% incidence of symmetric IUGR in this study series is already somewhat higher than the 20% to 25% incidence of symmetric IUGR cited in the literature!' 3.16 Obviously, this dilemma of whether to use the 10th or
Table IV. Neonatal morbidity among preterm IUGR infants _ _ _ _ _ _ _-J._S;,.ym_m_et_rl_c
Total No. of preterm births Apgar score ::;:6 1 min 5 min RDS Neonatal infection Neonatal acidosis Hyperbilirubinemia Hypoglycemia
89
57 39 44 22 20 29 39
(64%) (43.8%) (49.4%) (24.7%) (22.5%) (32.6%) (3.4%)
Asymmetric
I
X2 Test
55
27 (49.1%) 11(20.0%) II (20.0%) 8 (14.5%) 4 (7.3%) 13 (23.6%) 5 (9.1%)
p = NS
P<
0.025
P < 0.025
P < 0.05 P < 0.025 P = NS P = NS
RDS, Respiratory distress syndrome. Neonatal acidosis, pH <7.20. Hyperbilirubinemia, serum bilirubin level> 10.0 mg/dl. Hypoglycemia, plasma glucose level <30.0 mg/dl.
the 25th percentile for head circumference to define symmetric IUGR is difficult to resolve. Eighteen high-risk factors that my be attributed to the development of fetal growth retardation were found in 80% of symmetric and 70% of asymmetric IUGR in our study population. Our data are consistent with Galbraith et al.,e who found that two thirds of IUGR infants come from the population with risk factors. It is interesting to find that an almost equal incidence of symmetric and asymmetric IUGR infants were produced by pregnancies associated with such high-risk
1540 Lin, Su, and River
factors as chronic hypertension, anemia, antepartum hemorrhage, and twin gestation. These factors were previously thought to be related only to the production of asymmetric IUGR!·S,17 In addition, more symmetric than asymmetric IUGR infants were associated with preeclampsia. The majority of the preeclampsia cases in this study series, however, was cases involving either an early onset of preeclampsia (before 32 weeks of gestation) or chronic hypertension with superimposed preeclampsia. The extremely poor fetal outcome seen in severe cases of preeclampsia during midpregnancy and in chronic hypertension with superimposed severe preeclampsia has been well documented. lB. 19 The preterm growth-retarded fetus so produced resembles symmetric rather than asymmetric IUGR in its appearance. On the basis of the results of the present study, medical, obstetric, and environmental-behavioral high-risk factors do not produce predominantly symmetric or asymmetric IUGR infants. We speculate that the timing of the interaction between high-risk factors and the stage of gestation, rather than the nature of each highrisk factor, plays the more important role in determining whether symmetric or asymmetric IUGR will occur in human pregnancies. Intrauterine fetal growth can be viewed as series of incremental changes in the size of the fetus, as well as in the function of various fetal organ systems, throughout the entire period of pregnancy. These changes are influenced by both genetic and environmental factors, which interact with cell proliferation, organ differentiation, and metabolic development in the process of fetal growth. On the basis of animal experiments and human observations, Rosso and Winick l7 ,20 have described three phases of fetal cellular growth. The first phase is cellular hyperplasia, which includes an increase in cell number occurring during the first 16 weeks of embryonic and fetal life. Fetal insult during this phase leads to the development of symmetric IUGR with the primary effect being a reduced cell number. These infants are usually small in size with a reduction in all external measurements, e.g., weight, length, and head circumference, thus producing a normal ponderal index. This type of growth retardation is frequently associated with congenital malformations. The second phase of fetal growth is concomitant hyperplasia and hypertrophic cellular growth. This phase encompasses the period from 16 to 32 weeks' gestation, during which time there is progressive decrease in the rate of cell hyperplasia and a progressive increase in hypertrophic cell growth. Fetal insult during this phase usually produces a mixed or intermediate type of IUGR with features resembling symmetric IUGR if the insult occurs earlier and asymmetric IUGR if the insult occurs in the latter half of this phase. The third phase of fetal growth extends from 32 weeks to term. During this time period, cell size rapidly increases, along with the rate of glycogen and fat deposition. An insult during this phase
Am J
June 1991 Obstet Gynecol
leads to the development of asymmetric IUGR with its relative brain-sparing phenomenon. This well-known hypothesis serves as a basis to support our speculation that the timing of the interaction between high-risk factors and the stage of gestation is far more important than the nature of each high-risk factor. Thus a symmetric IUGR fetus can be produced by the pregnant woman with an early onset of severe preeclampsia. Approximately one third of both the symmetric and asymmetric IUGR cases in our study series were identified by prenatal examination and subsequent ultrasonographic examination during pregnancy. Using serial ultrasonography for prenatal detection of IUGR in a large study population in London, Warsof et aJ.21 were able to detect IUGR with an accuracy of 48%. Hughey22 was able to detect only 23% of IUGR fetuses by means of clinical methods and selective screening, but he was able to increase his IUGR detection rate to 57% by using routine ultrasonographic screening. The relatively low prenatal IUGR detection rate in this study series is mainly due to the fact that routine ultrasonographic screening is not performed on our entire obstetric population. The major findings in the comparison of perinatal outcome between symmetric and asymmetric IUGR in this study series include: (1) that the onset of symmetric IUGR occurs much earlier in the course of pregnancy than that of asymmetric IUGR, (2) that more symmetric than asymmetric IUGR results in preterm delivery, (3) that the morbidity rate for symmetric IUGR is higher than that for asymmetric preterm IUGR neonates, and (4) that term symmetric IUGR infants tend to have a lower body weight and a smaller placenta than do term asymmetric IUGR infants. Recently, investigators 2s. 2' have paid special attention to the preterm growth-retarded infant because, in general, infants in this category have the worst prognosis. In addition to the knowledge of a worse prognosis for preterm IUGR than for preterm appropriate-forgestational-age infants, this study has further documented that the neonatal morbidity rate among preterm symmetric IUGR infants is significantly higher than that of preterm asymmetric IUGR infants. However, some of these differences in neonatal morbidity rates may be attributed in part to the difference in preterm birth rate observed between the two groups. REFERENCES I. Goldenberg RL, Nelson KG, Koski JF, Cutter GR. Low birth weight, intrauterine growth retardation, and preterm delivery. AM J OBSTET GYNECOL 1985; 152:980-4. 2. Galbraith RS, Karchmar EJ, Piercy WN, Low jA. The clinical prediction of intrauterine growth retardation. AM J OBSTET GYNECOL 1979;133:281-6. 3. Lin C-C, Evans Ml, eds. Intrauterine growth retardation: pathophysiology and clinical management. New York: McGraw-Hill, 1984:385. 4. Lin C-C, Moawad AH, Rosenow Pj, River LP. Acid-base characteristics of fetuses with intrauterine growth retar-
Volume 164 Number 6, Part I
5. 6. 7. 8. 9. 10.
II.
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13. 14. 15. 16. 17.
18. 19.
20. 21. 22. 23. 24.
dation during labor and delivery. AM J OBSTET GYNECOL 1980;137:553-9. Cefalo RC. The hazards of labor and delivery for the intrauterine growth retarded fetus. J Reprod Med 1978; 21 :300-4. Daikoku NH, Johnson JWC, Graf C, Kearney K, Tyson JE, King TM. Patterns of intrauterine growth retardation. Obstet Gynecol 1979;54:211-9. Kurjak A, Latin V, Polak J. Ultrasound recognition of two types of growth retardation by measurement of four fetal dimensions. J Perinat Med 1978;6:102-8. Lin C-C, Devoe LD, River LP, Moawad AH. Oxytocin challenge test and intrauterine growth retardation. AM J OBSTET GYNECOL 1981;140:282-8. Manning FA, Baskett TF, Morrison L, Lange 1. Fetal biophysical profile scoring: a prospective study in 1,184 highrisk patients. AM J OBSTET GYNECOL 1981; 140:289-94. Lin COCo Intrauterine growth retardation: In: Wynn RM, ed. Obstetrics and gynecology annual. New York, Connecticut: Appleton-Century-Crofts, 1985 vol 4:127-221. Lubchenco LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics 1963; 32:793-800. Goldenberg RL, Cutter GR, Hoffman HJ, FosterJM, Nelson KG, HauthJC. Intrauterine growth retardation: standards for diagnosis. AM J OBSTET GYNECOL 1989;161: 271-7. William RL. Intrauterine growth curve: intra- and international comparisons with different ethnic groups in California. Prev Med 1975;4: 163-8. Myers SA, Ferguson R. A population study of the relationship between fetal death and altered fetal growth. Obstet Gynecol 1989;74:325-31. Sabbagha RE. Intrauterine growth retardation: antenatal diagnosis by ultrasound. Obstet Gynecol 1978;52:252-6. Brar HS, Rutherford SE. Classification of intrauterine growth retardation. Semin Perinatol 1988;12:2-10. Rosso P, Winick M. Intrauterine growth retardation: a new systematic approach based on the clinical and biochemical characteristics of this condition. J Perinat Med 1974;2:147-60. Lin C-C, Lindheimer MD, River LP, Moawad AH. Fetal outcome in hypertensive disorders of pregnancy. AM J OBSTET GYNECOL 1982; 142:255-60. Anderson GD, Sibai BM. Hypertension in pregnancy. In: Gabbe SG, NiebylJR, SimpsonJL, eds. Obstetrics: normal and problem pregnancies. New York: Churchill Livingstone, 1986:819-63. Winick M. Cellular changes during placental and fetal growth. AM J OBSTET GYNECOL 1971; 109: 166-76. Warsof SL, Cooper DJ, Little 0, Campbell S. Routine ultrasound screening for antenatal detection of intrauterine growth retardation. Obstet Gynecol 1986;67:33-9. Hughey MJ. Routine ultrasound for detection and management of the small-for-gestational-age fetus. Obstet Gynecol 1984;64:101-7. Koops BL, Morgan LJ, Battaglia FC. Neonatal mortality risk in relation to birthweight and gestational age: update. J Pediatr 1982;101:969-77. Nishida H. Is intrauterine growth retardation worse than prematurity? In: Maeda K, Okyyama K, Takeda Y, eds. Recent advances in perinatology. Amsterdam: Excerpta Medica, 1986:63-7; international congress series 712.
Editors' note: This manuscript was revised after these discussions were presented. Discussion DR. ALFRED B. KNIGHT, Temple, Texas. This article is a review of IUGR newborns in a data base of 22,616 patients delivered between 1979 and 1985. I have presumed in this discussion that information was collected on all patients in the data base.
Symmetric and asymmetric IUGR 1541
There many complex issues regarding abnormal fetal growth yet to be answered, not the least of which is the definition.' The further classification of IUGR as symmetric or asymmetric was an attempt to associate cause and prognosis after the child was born with a gestational pathophysiologic condition. This concept could then be extended to in utero diagnosis. Lin and colleagues were unable to confirm the classic clinical association of certain diseases of fetus and mother with specific subtypes of growth retardation. Clarification of a number of issues relative to the patient data base and patient selection would be helpful before we discard two decades of elegant teaching of the pathophysiologic features of IUGR. 1. Dr. Lin and colleagues have used the definition of IUGR to be a birth weight for gestational age of < 10th percentile. I would have anticipated that the number of infants identified would approach 10% of the data base, at least markedly greater than the 3.2% screened. Why is there such a low incidence of IUGR in their population? 2. The method for assigning gestational age was not elaborated in this manuscript and remains a critical element to the definition of IUGR. Both obstetric and neonatal information can be used, but neither can assign gestational age with a greater accuracy than plus or minus 2 or 3 weeks (excluding those patients with "stellar" dates). Perhaps an even greater error is introduced with Dubowitz gestational ages <34 weeks complicated by IUGR! What method was used to determine gestational age? 3. Symmetric versus asymmetric IUGR is defined by a head circumference of> 10% or < 10%. Others in the newborn period have used the 25th percentile. The characterization of IUGR of differing symmetry reflects an attempt to understand and categorize causes of IUGR. In fact, rarely does a fetus-newborn have purely symmetric or asymmetric IUGR; more commonly, the condition would be considered "mixed," particularly at gestational ages of <34 weeks.' How many newborns were close to that asignment? 4. Risk factors for adverse fetal outcome were identified for comparison. Many are not independent factors, such as young age and pregnancy-induced hypertension. Other factors are poorly correlated with IUGR (e.g., urinary tract infection, anemia, maternal age >35 years) and still others could be more completely defined (poor obstetric history, antepartum hemorrhage, poor weight gain). More refined groupings might unmask significant correlations. 5. These high-risk factors were compared by X2 analysis with little significance identified. However, it would have been useful to evaluate the difference between the population of IUGR patients and the general data base to confirm that this population was indeed unique. 6. Perinatal events and fetal outcome would benefit from more detailed assessment. For example, the single category "intrapartum fetal distress" includes meconium-stained amniotic fluid, abnormal fetal heart rate patterns, and fetal acidosis. These three clinical findings may be independent and mayor may not reflect "distress" or fetal compromise.
1542
Lin, Su, and River
Differences in 5-minute Apgar score and neonatal death rate were statistically significant between the symmetric and asymmetric groups. However, the symmetric IVGR newborns were more likely premature. Is this association simply a reflection of prematurity? In summary, Dr. Lin and colleagues have presented interesting material from a large perinatal data base. With their patient selection no antepartum maternal or fetal factors clearly differentiated symmetric from asymmetric IVGR. I look forward to additional analysis of this information. REFERENCES 1. Goldenbery RI, Cutter GR, Hoffman MA, et al. Intrapartum growth retardation: standards for diagnosis. AM J OBSTET GYNECOL 1989;161:271-7. 2. Yogman MW, Kraemer HC, Kindlon D, et al. Identification of intrauterine growth retardation among low birth weight preterm infants. J Pediatr 1989;1I5:799-807. 3. Brar HS, Rutherford SE. Classification of intrauterine growth retardation. Semin Perinatol 1988;12:2-10. DR. L. WAYNE HESS, Jackson, Mississippi. Dr. Lin's article leaves several questions unanswered, including the following: (1) What percent of cases of antenatally suspected IVGR did not have IVGR postnatally (per Dr. Lin's definition)? (2) Was there a difference between the outcomes of the 227 antenatally diagnosed and 491 postnatally diagnosed IVGR infants; i.e., did antenatal intervention improve outcome? (3) How was the control group defined for Fig. 2? (4) What was the power of the statistics for Tables I to IV to conclude there were no statistical differences? Additionally, the study could be strengthened by the addition of a case-matched control group. A recent study contrasted all IVGR infants with a case-matched control population.' However, this study failed to contrast type I and type II IVGR infants to the control population. To date, no other large series has contrasted type I and type II IVGR infants to a control population. Dr. Lin's article provides the clinician some new insights into the problem of IVGR. However, it leaves the clinician with three problems that are difficult to reconcile. First, the clinician is interested in abnormal growth, not birth weight. A birth weight at the 10th percentile will not always define abnormal fetal growth. 2 A postterm fetus that is severely malnourished will frequently have a birth weight > 10th percentile. Second, previous studies that have "established" the 10th percentile for birth weight have demonstrated great variability in results, mainly on the basis of population differences. Lubchenco et al. 3 established neonatal growth curves on the basis of 5635 Denver (highaltitude) hospital births occurring between 1948 and
June 1991 Am J Obstet Gynecol
1961. The "dates" in this study were based on mother's last menstrual period without correction for clinical criteria. Nonwhite and diabetic patients were excluded from the study. Goldenberg et al! noted a 192 gm (at 28 weeks) to 823 gm (at 42 weeks) difference in the 10th percentile birth weights in 38 summarized studies. Third, defining IVGR as a birth weight < 10th percentile assumes: (1) that adverse outcome and birth weight percentile remain constant at all gestational ages and (2) that the 10th percentile is a meaningful, discrete cutoff level. Myers and Ferguson' have demonstrated that neither of these assumptions is true. The birth weight percentile at which the stillbirth rate is quadrupled is the 1.5th percentile at 28 weeks versus the 16.5th percentile at 42 weeks. IVGR must be more objectively defined before standard obstetric interventions or newly suggested therapies (such as fetal substrate augmentation with nutrients and oxygen or lowdose maternal aspirin therapy) can be objectively, scientifically evaluated. REFERENCES 1. Callan NA, Witter FR. Intrauterine growth retardation: characteristics, risk factors and gestational age. Int J GynaecolObstet 1990;33:215. 2. Altman DG, Hytten FE. Intrauterine growth retardation: let's be clear about it. Br J Obstet Gynaecol 1989;96: 1127. 3. Lubchenco LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics 1963;32:793. 4. Goldenberg RL, Cutter GR, Hoffman HJ, Foster JM, Nelson KG, Hauth JC. Intrauterine growth retardation: standards for diagnosis. AM J OBSTET GYNECOL 1989; 161 :271. 5. Myers SA, Ferguson R: A population study of the relationship between fetal death and altered fetal growth. Obstet Gynecol 1989;74:325. DR. DANIEL A. RIGHTMIRE, Springfield, Illinois. I am quite curious as to why Dr. Lin did not use a head circumference/abdominal circumference ratio in his definition of symmetric versus asymmetric growth retardation. Head circumference, compared to abdominal circumference, may be a late indicator of poor fetal growth. Think of the causes of growth retardation as being divided into placental factors, maternal factors, and fetal factors. I am afraid that Dr. Lin's definition may have preselected a group of small-to-be fetuses who had fetal factors early on, either pathologically or normally. In other words, he may have a mix of constitutionally small babies who will do well and babies with birth defects or other constitutional factors, all of whom may be predetermined to be small throughout pregnancy. I am afraid that many of his findings might be simple, logical extensions of his definitions rather than reflections of pathologic conditions of gestation.
Key words: Symmetric IUGR, asymmetric IUGR, associated high-risk factors, perinatal outcome Intrauterine growth retardation (IUGR) is recognized as an important cause oflow birth weight, second only to the problem of preterm birth. I The IUGR infant is associated with multiple causative factors 2 ,3 and with high levels of perinatal mortality and morbidity!-7 Two types of IUGR infants have been identified clinically: symmetric and asymmetric." 6, 7 The purpose of this study was to compare associated high-risk factors and perinatal outcome between symmetric and asymmetric IUGR infants. Patients and methods Between July 1979 and December 1985, 718 IUGR infants among a total of 22,616 infants were delivered at the Chicago Lying-In Hospital, The University of Chicago. During the study period, all patients with high-risk factors were enrolled prenatally in either the From the DivislOn of Maternal-Fetal Medlczne, Department of Obstetrics and Gynecology, Pntzker School of Medicine, The Unzversity of Chicago. Supported in part by the Mother's AId Fund of the ChIcago LyingIn Hospital. Presented at the Fifty-eIghth Annual Meetzng of the Central AssoClatlOn ofObstetnclans and Gynecologzsts, LouisVIlle, Kentucky, October
II-13, 1990.
Reprint requests: Chin-Chu Lin, MD, Department of Obstetncs and Gynecology, The University of Chicago, 5841 South Maryland Ave., Box 446. ChIcago, IL 60637,
6/6/28942
Obstetric High-Risk Clinic or the Medical High-Risk Clinic. Historic high-risk factors were recorded during the initial visit, and high-risk factors that developed during gestation were identified in subsequent clinical visits. Clinical data for all high-risk patients during pregnancy were entered into the University of Chicago OB-File computer system whenever a high-risk factor was identified. High-risk patients then had close followup, with intervals of 1 to 2 weeks at our high-risk clinics. Clinical data of low-risk obstetric patients during pregnancy were not entered into the computer system. However, clinical data of labor and delivery and newborn data for both high- and low-risk patients who were delivered at our institution were entered into the computer system. During the study period, 3788 patients had prenatal care at our high-risk clinics. Clinically suspected IUGR cases, such as those with retarded uterine fundal height, were further evaluated by serial ultrasonographic measurements to establish the diagnosis of suspected IUGR. Multiple static axial and longitudinal images of the fetus and uterus were taken during each ultrasonographic examination. Each examination included fetal measurements such as biparietal diameter, head circumference, abdominal circumference, femur length, calculation of head circumference / abdominal circumference ratio, and estimated fetal weight. Each patient also was screened for gross fetal anomalies and quantitative amniotic fluid volume.
1535
1536 Lin, Su, and River
June 1991 Am J Obstet Gynecol
Table I. Comparison of incidences of various high-risk factors between symmetric and asymmetric IUCR* High-risk factor
Symmetric
Asymmetric
Total cases Demographic-behavioral risk factor Primigravid Age <17 yr Age >35 yr Smoking Alcohol Drug abuse Obstetric risk factor Preeclampsia Twin gestation Poor obstetric history Poor weight gain Antepartum hemorrhage Medical risks in current pregnancy: Chronic hypertension Anemia (hemoglobin <10 gm/dl) Urinary tract infection (symptomatic) Asthma Hemoglobinopathy Cardiac disease Diabetes mellitus
273
445 100 26 12 136 37 33
(22.4%) (5.8%) (2.7%) (30.6%) (8.3%) (7.4%)
X2 Test
P= P= P= P= P= P=
64 24 8 77 24 28
(23.4%) (8.8%) (2.9%) (28.2%) (8.8%) (10.3%)
52 24 39 40 II
(19.0%) (8.8%) (14.3%) (14.7%) (4.0%)
55 (12.4%) 36(8.1%) 44 (9.9%) 70 (15.7%) 15 (3.4%)
P < 0.025 P = NS P = NS P = NS P = NS
25 (9.2%) 44 (16.1%) 14 (5.1 %) 11 8 5 1
28 (6.3%) 82 (18.4%) 36 (8.1%) 14 17 6 12
P= P= P=
NSt NS NS NS NS NS
NS NS NS
*Each case of rUCR may have one or more high-risk factors. tPower of statistics for 13 items with p = NS. We had a 7% chance of detecting a 20% difference in the groups.
A fetus with two abnormal results among the three parameters, such as abdominal circumference of < 10th percentile, with a head circumference/abdominal circumference ratio of >2 SD above the mean, (e.g., 1.21 at 34 weeks, 1.05 at 40 weeks) or an estimated fetal weight < 10th percentile was diagnosed as having suspected IUCR. Ultrasonographic evaluation, however, was not performed routinely for all of our obstetric patients, particularly during the first half of the study period, 1979 to 1982. Prenatally suspected IUCR cases were subjected to a weekly high-risk clinic visit and a nonstress test. A nonreactive nonstress test was followed by a contraction stress test,S a biophysical profile scoring evaluation,9 or both. Antenatally suspected IUCR pregnancies were terminated at 38 weeks of gestation after documentation of fetal lung maturity. Earlier termination was carried out either for fetal indications or because of maternal deterioration, consistent with our management protocol. 10 During labor and delivery, various signs of fetal distress, including abnormal fetal heart rate patterns, meconium-stained amniotic fluid, and fetal acidosis, were intensively monitored. At the time of delivery all IUCR infants were evaluated by two pediatricians. All of the preterm IUCR infants in the study series received neonatal care at The University of Chicago's intensive care nursery. After the infant was discharged from the intensive care nursery, the medical record of each preterm IUCR neonate was carefully reviewed and various neonatal morbidities such as respiratory distress syndrome, neonatal infection, neonatal acidosis, hypoglycemia, and hyperbilirubinemia were identified.
At the conclusion of data collection, all 718 IUCR infants were assigned to one of two groups, symmetric or asymmetric IUCR. The symmetric IUCR group was defined as < 10th percentile for both body weight and head circumference for the gestational age at birth. The asymmetric IUCR group was defined as a birth weight of < 10th percentile but head circumference of > 10th percentile for gestational age, on the basis of our own fetal growth curve, which has been in existence since 1983. 3 Preterm IUCR was defined as <10th percentile for birth weight with a gestational age of <37 weeks. For a comparison of associated high-risk factors, 18 factors (including seven medical complications, five obstetric factors, and six environmental-behavioral factors) were compared between the two groups. Fourteen factors were compared statistically by the X2 test for their incidence in each group. Four other factors were not analyzed because of the small number of cases in each category. Further analysis was performed for the 57 IUCR infants whose mothers developed preeclampsia; all of these cases had at least 4 weeks of prenatal care before delivery. Several parameters of perinatal outcome were compared between symmetric and asymmetric IUCR infants by means of either the t test or the X2 test for statistical analysis. Results
Associated high-risk factors. The overall incidence of IUCR during the study period was 3.2% (718 cases ofIUCR per 22,616 total births). Among the 718 IUCR infants, 273 (38%) were symmetric and 445 (62%) were asymmetric IUCR according to the criteria mentioned
Symmetric and asymmetric IUGR
Volume 164 Number 6, Part I
previously. Approximately 80% of symmetric IUGR (217/273) and 70% of asymmetric lUGR (312/445) had one or more identifiable high-risk factors. A comparative analysis of the 18 associated risk factors is shown in Table 1. The incidence of each of the following risk factors was not statistically different between symmetric and asymmetric IUGR: chronic hypertension, anemia, symptomatic urinary tract infection, twin gestation, poor obstetric history, poor weight gain, antepartum hemorrhage, maternal age < 17 years, smoking, use of alcohol, and drug abuse. For those risk factors with a small number of cases in each category, such as asthma, hemoglobinopathy, cardiac disease, diabetes mellitus, and maternal age >35 years, there was no difference in the incidence of symmetric and asymmetric IUGR. Preeclampsia was the only high-risk factor that exhibited a higher incidence of symmetric than asymmetric IUGR (19% vs 12%, P < 0.025). Table II compares symmetric and asymmetric IUGR infants whose mothers had preeclampsia before delivery. The mean gastational age at the diagnosis of IUGR, the mean gestational age at delivery, and the mean birth weight all were significantly lower in the symmetric IUGR group when compared with the asymmetric IUGR group. Most symmetric IUGR infants were delivered of women with either early onset of moderate to severe preeclampsia or chronic hypertension with superimposed preeclampsia. One symmetric and 12 asymmetric IUGR infants were born to diabetic mothers. Seven of the 12 asymmetric IUGR infants were the products of mothers with juvenile diabetes (three with class C, three with class D, and one with class F diabetes). Antenatal diagnosis of IUGR. Approximately one third of the IUGR cases in the study were identified clinically and confirmed by ultrasonography during pregnancy in both groups (93 cases or 34.0% in the symmetric group and 134 cases or 30.1 % in the asymmetric group, p = NS). Among IUGR fetuses diagnosed antenatally, the difference in the timing of clinical detection between symmetric and asymmetric IUGR was quite striking: before 32 weeks, 23% (21 cases) symmetric versus 2% (3 cases) asymmetric (p < 0.001, X' test); at 34 weeks, 46% (43 cases) symmetric versus 14% (19 cases) asymmetric (p < 0.001, X' test); and at 36 weeks, 82% (76 cases) symmetric versus 64% (86 cases) asymmetric (p < 0.01, X' test). Fig. 1 illustrates cumulative curves of the incidences of clinical detection of the two types of IUGR according to gestational age. Preterm delivery, birth weight, and placental weight. As shown in Table III, the incidence of preterm delivery was higher for symmetric than for asymmetric lUGR (32.6% vs 12.4%, P < 0.001). Fig. 2 shows the mean birth weight according to gestational week for both symmetric and asymmetric pre-
1537
0
III ~
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III ~
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Symmetrical Asymmetrical
80
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60
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CI
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III
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0 25
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GESTATIONAL AGE
Fig. 1. Cumulative curves of incidences at time of clinical detection for symmetric and asymmetric IUGR according to weeks of gestation (see text for details).
Table II. Comparison between symmetric and asymmetric IUGR associated with maternal preeclampsia* _ _ _ _ _ _ _ I-s-y-m-~-ne-tnc-·-,..--A-sy-m-71-!e-t-nc- t Test Total No. of cases Gestational week IUGR Diagnosed Gestational week at delivery Interval between diagnosts and delivery (wk) Birth weight (gm)
31
26
29.5 ± 2.0
34.1 ± 1.5
p < 0.001
32.7 ± 3.1
36.7 ± 2.2
p < 0.001
3.2 ± 2.8
2.6 ± 2.2
1300 ± 418
2050 ± 338
p
=
NS
p < 0.001
*All patients had at least 4 weeks of prenatal care before delivery. All data expressed as mean ± SO. term IUGR infants. For the purpose of comparison, a control curve of the mean birth weight by gestational week on the basis of a total of 3216 preterm non-IUGR infants delivered prematurely at out institution during the study period, ranging from 28 to 36 weeks, also is illustrated. As expected, the mean weight curves for both symmetric and asymmetric IUGR infants are far below the control curve. It is of interest to note that the mean weight curve for symmetric IUGR runs below that of asymmetric IUGR at each gestational week before 37 weeks. Of those IUGR infants who were delivered at term (:::37 weeks' gestation), the mean birth weight of symmetric IUGR infants was significantly lower than that of asymmetric IUGR infants (2167 ± 260 vs 2385 ± 105 gm, p < 0.001 by t test). The incidence of small placenta at term gestation (defined as a placental weight of <400 gm) was significantly higher in symmetric than
1538 Lin, Su, and River
June 1991 Am J Obstet Gyneco1
3000
iil :E
lI: C)
2000
I:I: C)
iii
3:
:I: lll:
1000
CONTROL
iii
_ _ ASYMMETRICAL _ _ SYMMETRICAL
O+-..--......-,,-.---r..,...............,---r-......-,,-.---r..,..............., 26
30
28
32
36
34
38
Comment
GESTATIONAL AGE (WEEKS)
Fig. 2. Mean body weight by weeks of gestation for preterm symmetric and asymmetric IUCR. Control curve is obtained from mean birth weight data for our 3216 preterm appropriate-for-gestational-age population during the study period. Mean birth weight data were calculated week by week according to gestational age between 28 and 36 weeks.
Table III. Perinatal events and fetal outcome Symmetric
Total No. of cases Preterm birth Total intrapartum fetal distress* Abnormal FHR with MSAF Abnormal FHR with pH <7.20 Cesarean section Apgar score $6 1 min 5 min Neonatal death Fetal anomaliest
I Asymmetric
I
X2 Test
445 273 89 (32.6%) 55 (12.4%) P < 0.001 117 (42.9%) 153 (34.4%) P = NS 54 (19.8%)
69 (15.5%) P = NS
36 (13.1%)
23 (5.2%)
55 (20.1%)
71 (16.0%) P = NS
87 43 24 16
91 (20.4%) 35 (7.9%) 8 (1.8%) 13 (2.9%)
(31.9%) (15.8%) (8.8%) (5.9%)
tum fetal distress, cesarean delivery, and gross fetal anomalies were not significantly different between the two groups. Neonatal morbidity among preterm IUGR infants. Neonatal morbidity among the 89 preterm symmetric IUGR and the 55 preterm asymmetric IUGR infants is compared in Table IV. The incidences of low 5-minute Apgar score, respiratory distress syndrome, neonatal infection, and neonatal acidosis were higher for symmetric than for asymmetric preterm IUGR infants. There were no significant differences between the two groups in the incidence of hyperbilirubinemia, hypoglycemia, or low I-minute Apgar score.
P < 0.05
P < 0.01 P < 0.05 P < 0.001 P = NS
FHR, Fetal heart rate; MSAF, meconium-stained amniotic fluid. *Intrapartum fetal distress. All cases had abnormal fetal heart rate patterns, some of them combined with meconiumstained amniotic fluid and fetal acidosis. tTwo cases of chromosomal abnormalities and one case of cytomegalovirus in the symmetric group and three cases of chromosomal abnormalities in the asymmetric group.
in asymmetric lUGR (37.5% vs 12.6%, P< 0.001 by X2 test). Perinatal events and fetal outcome. As shown in Table III, fetal outcome for symmetric IUGR was much worse than for asymmetric IUGR infants. There was a higher incidence of preterm delivery, depressed Apgar scores at both 1 and 5 minutes, fetal acidosis, and neonatal death. However, the incidences of total intrapar-
An IUGR infant is commonly defined as one weighing < 10th percentile in birth weight for gestational age. ll However, because there is no standard population from which to derive these percentiles, the birth weights that serve as the cutoff point by various published studies may differ as much as several hundred grams at any gestational week during the third trimester. [2 This variability may result from population differences in sex, or race and from different geographic areas studied, as well as differences in study methods. In this study we used a fetal growth curve (constructed by Lowensohn and based on total live births between 1978 and 1982 at our institution) to define IUGR if the birth weight fell below the 10th percentile line for each gestational week (Fig. 3).3 A comparison of the 10th percentile line of two different fetal growth curves shows a close similarity between the Chicago and the Colorado curve. l l The 10th percentile growth curve from the state of California,[3 however, suggests that their newborns at the cutoff point for IUGR between 26 and 36 weeks of gestation are heavier than ours. When we used the Chicago curve to study a total of 7177 deliveries at our institution between January 1979 and May 1981, there were 426 IUGR newborn infants, an incidence of 5.9%.3 In this study the incidence of IUGR was 3.2% according to the same study method in the same institution but during a different study period. The reason for this difference in the incidence of IUGR during two time periods is not well understood. Among 718 IUGR infants in this study series, 189 (26.3%) were not associated with any high-risk factors. We believe that many of them, particularly those with symmetric IUGR, may belong to the group of so-called "constitutionally small" babies. On the basis of a four times increased risk of stillbirth, Myers and Ferguson" studied a population in the state of Illinois and argued that the 3rd percentile should be used to define IUGR in preterm gestations before 31 weeks, whereas the 15th to 17th percentile should be used to define IUGR
Symmetric and asymmetric IUGR
Volume 164 Number 6, Part 1
1539
WEIGHT - GESTATION GROWTH CURVES
---- University of Chicago Live Births: 1978-1982 0-0-0 California Total Single Live Births: 1966-1970 Colorado General Hospital Live Births: 1948-1960
5.0 4. 5 4.0 ~
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Weeks of Gestation Completed
Fig. 3. Weight-gestational age fetal growth curves of the University of Chicago, state of California, and Colorado General Hospital. Both 10th and 90th percentile lines are shown. Note Chicago and Colorado 10th percentile lines are in close agreement. (Courtesy of R.I. Lowensohn. From Lin C-C, Evans MI, eds. Intrauterine Growth Retardation: Pathophysiology and Clinical Management. New York: McGraw-Hill, 1984:40. Reproduced with permission from McGraw-Hill, Inc.)
in those pregnancies approaching term gestation. In view of the heterogeneity of the various causes of IUGR, there are some inevitable limitations to using the 10th percentile of birth weight as the sole criterion for diagnosing IUGR. Among six infants with chromosomal abnormalities and congenital viral infection, three cases were in the symmetric IUGR group and the other three cases were in the asymmetric IUGR group. In all three cases in the asymmetric group, the head circumference measurements were between the 10th and 25th percentiles. Using a definition of less than the 25th instead of the 10th percentile for head circumference to define symmetric IUGR would place all of these cases in the symmetric group. This idea is consistent with the findings of Sabbagha,15 who reported an incidence of IUGR infants of >50% in cases associated with a small biparietal diameter «25th percentile) in early pregnancy. However, if adopting a definition of <25th percentile for head circumference to differentiate symmetric from asymmetric IUGR would lead to an unrealistically high incidence of symmetric IUGR in our study population. If a criterion of < 10th percentile for head circumference is used to define symmetric IUGR, the 38% incidence of symmetric IUGR in this study series is already somewhat higher than the 20% to 25% incidence of symmetric IUGR cited in the literature!' 3.16 Obviously, this dilemma of whether to use the 10th or
Table IV. Neonatal morbidity among preterm IUGR infants _ _ _ _ _ _ _-J._S;,.ym_m_et_rl_c
Total No. of preterm births Apgar score ::;:6 1 min 5 min RDS Neonatal infection Neonatal acidosis Hyperbilirubinemia Hypoglycemia
89
57 39 44 22 20 29 39
(64%) (43.8%) (49.4%) (24.7%) (22.5%) (32.6%) (3.4%)
Asymmetric
I
X2 Test
55
27 (49.1%) 11(20.0%) II (20.0%) 8 (14.5%) 4 (7.3%) 13 (23.6%) 5 (9.1%)
p = NS
P<
0.025
P < 0.025
P < 0.05 P < 0.025 P = NS P = NS
RDS, Respiratory distress syndrome. Neonatal acidosis, pH <7.20. Hyperbilirubinemia, serum bilirubin level> 10.0 mg/dl. Hypoglycemia, plasma glucose level <30.0 mg/dl.
the 25th percentile for head circumference to define symmetric IUGR is difficult to resolve. Eighteen high-risk factors that my be attributed to the development of fetal growth retardation were found in 80% of symmetric and 70% of asymmetric IUGR in our study population. Our data are consistent with Galbraith et al.,e who found that two thirds of IUGR infants come from the population with risk factors. It is interesting to find that an almost equal incidence of symmetric and asymmetric IUGR infants were produced by pregnancies associated with such high-risk
1540 Lin, Su, and River
factors as chronic hypertension, anemia, antepartum hemorrhage, and twin gestation. These factors were previously thought to be related only to the production of asymmetric IUGR!·S,17 In addition, more symmetric than asymmetric IUGR infants were associated with preeclampsia. The majority of the preeclampsia cases in this study series, however, was cases involving either an early onset of preeclampsia (before 32 weeks of gestation) or chronic hypertension with superimposed preeclampsia. The extremely poor fetal outcome seen in severe cases of preeclampsia during midpregnancy and in chronic hypertension with superimposed severe preeclampsia has been well documented. lB. 19 The preterm growth-retarded fetus so produced resembles symmetric rather than asymmetric IUGR in its appearance. On the basis of the results of the present study, medical, obstetric, and environmental-behavioral high-risk factors do not produce predominantly symmetric or asymmetric IUGR infants. We speculate that the timing of the interaction between high-risk factors and the stage of gestation, rather than the nature of each highrisk factor, plays the more important role in determining whether symmetric or asymmetric IUGR will occur in human pregnancies. Intrauterine fetal growth can be viewed as series of incremental changes in the size of the fetus, as well as in the function of various fetal organ systems, throughout the entire period of pregnancy. These changes are influenced by both genetic and environmental factors, which interact with cell proliferation, organ differentiation, and metabolic development in the process of fetal growth. On the basis of animal experiments and human observations, Rosso and Winick l7 ,20 have described three phases of fetal cellular growth. The first phase is cellular hyperplasia, which includes an increase in cell number occurring during the first 16 weeks of embryonic and fetal life. Fetal insult during this phase leads to the development of symmetric IUGR with the primary effect being a reduced cell number. These infants are usually small in size with a reduction in all external measurements, e.g., weight, length, and head circumference, thus producing a normal ponderal index. This type of growth retardation is frequently associated with congenital malformations. The second phase of fetal growth is concomitant hyperplasia and hypertrophic cellular growth. This phase encompasses the period from 16 to 32 weeks' gestation, during which time there is progressive decrease in the rate of cell hyperplasia and a progressive increase in hypertrophic cell growth. Fetal insult during this phase usually produces a mixed or intermediate type of IUGR with features resembling symmetric IUGR if the insult occurs earlier and asymmetric IUGR if the insult occurs in the latter half of this phase. The third phase of fetal growth extends from 32 weeks to term. During this time period, cell size rapidly increases, along with the rate of glycogen and fat deposition. An insult during this phase
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June 1991 Obstet Gynecol
leads to the development of asymmetric IUGR with its relative brain-sparing phenomenon. This well-known hypothesis serves as a basis to support our speculation that the timing of the interaction between high-risk factors and the stage of gestation is far more important than the nature of each high-risk factor. Thus a symmetric IUGR fetus can be produced by the pregnant woman with an early onset of severe preeclampsia. Approximately one third of both the symmetric and asymmetric IUGR cases in our study series were identified by prenatal examination and subsequent ultrasonographic examination during pregnancy. Using serial ultrasonography for prenatal detection of IUGR in a large study population in London, Warsof et aJ.21 were able to detect IUGR with an accuracy of 48%. Hughey22 was able to detect only 23% of IUGR fetuses by means of clinical methods and selective screening, but he was able to increase his IUGR detection rate to 57% by using routine ultrasonographic screening. The relatively low prenatal IUGR detection rate in this study series is mainly due to the fact that routine ultrasonographic screening is not performed on our entire obstetric population. The major findings in the comparison of perinatal outcome between symmetric and asymmetric IUGR in this study series include: (1) that the onset of symmetric IUGR occurs much earlier in the course of pregnancy than that of asymmetric IUGR, (2) that more symmetric than asymmetric IUGR results in preterm delivery, (3) that the morbidity rate for symmetric IUGR is higher than that for asymmetric preterm IUGR neonates, and (4) that term symmetric IUGR infants tend to have a lower body weight and a smaller placenta than do term asymmetric IUGR infants. Recently, investigators 2s. 2' have paid special attention to the preterm growth-retarded infant because, in general, infants in this category have the worst prognosis. In addition to the knowledge of a worse prognosis for preterm IUGR than for preterm appropriate-forgestational-age infants, this study has further documented that the neonatal morbidity rate among preterm symmetric IUGR infants is significantly higher than that of preterm asymmetric IUGR infants. However, some of these differences in neonatal morbidity rates may be attributed in part to the difference in preterm birth rate observed between the two groups. REFERENCES I. Goldenberg RL, Nelson KG, Koski JF, Cutter GR. Low birth weight, intrauterine growth retardation, and preterm delivery. AM J OBSTET GYNECOL 1985; 152:980-4. 2. Galbraith RS, Karchmar EJ, Piercy WN, Low jA. The clinical prediction of intrauterine growth retardation. AM J OBSTET GYNECOL 1979;133:281-6. 3. Lin C-C, Evans Ml, eds. Intrauterine growth retardation: pathophysiology and clinical management. New York: McGraw-Hill, 1984:385. 4. Lin C-C, Moawad AH, Rosenow Pj, River LP. Acid-base characteristics of fetuses with intrauterine growth retar-
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dation during labor and delivery. AM J OBSTET GYNECOL 1980;137:553-9. Cefalo RC. The hazards of labor and delivery for the intrauterine growth retarded fetus. J Reprod Med 1978; 21 :300-4. Daikoku NH, Johnson JWC, Graf C, Kearney K, Tyson JE, King TM. Patterns of intrauterine growth retardation. Obstet Gynecol 1979;54:211-9. Kurjak A, Latin V, Polak J. Ultrasound recognition of two types of growth retardation by measurement of four fetal dimensions. J Perinat Med 1978;6:102-8. Lin C-C, Devoe LD, River LP, Moawad AH. Oxytocin challenge test and intrauterine growth retardation. AM J OBSTET GYNECOL 1981;140:282-8. Manning FA, Baskett TF, Morrison L, Lange 1. Fetal biophysical profile scoring: a prospective study in 1,184 highrisk patients. AM J OBSTET GYNECOL 1981; 140:289-94. Lin COCo Intrauterine growth retardation: In: Wynn RM, ed. Obstetrics and gynecology annual. New York, Connecticut: Appleton-Century-Crofts, 1985 vol 4:127-221. Lubchenco LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics 1963; 32:793-800. Goldenberg RL, Cutter GR, Hoffman HJ, FosterJM, Nelson KG, HauthJC. Intrauterine growth retardation: standards for diagnosis. AM J OBSTET GYNECOL 1989;161: 271-7. William RL. Intrauterine growth curve: intra- and international comparisons with different ethnic groups in California. Prev Med 1975;4: 163-8. Myers SA, Ferguson R. A population study of the relationship between fetal death and altered fetal growth. Obstet Gynecol 1989;74:325-31. Sabbagha RE. Intrauterine growth retardation: antenatal diagnosis by ultrasound. Obstet Gynecol 1978;52:252-6. Brar HS, Rutherford SE. Classification of intrauterine growth retardation. Semin Perinatol 1988;12:2-10. Rosso P, Winick M. Intrauterine growth retardation: a new systematic approach based on the clinical and biochemical characteristics of this condition. J Perinat Med 1974;2:147-60. Lin C-C, Lindheimer MD, River LP, Moawad AH. Fetal outcome in hypertensive disorders of pregnancy. AM J OBSTET GYNECOL 1982; 142:255-60. Anderson GD, Sibai BM. Hypertension in pregnancy. In: Gabbe SG, NiebylJR, SimpsonJL, eds. Obstetrics: normal and problem pregnancies. New York: Churchill Livingstone, 1986:819-63. Winick M. Cellular changes during placental and fetal growth. AM J OBSTET GYNECOL 1971; 109: 166-76. Warsof SL, Cooper DJ, Little 0, Campbell S. Routine ultrasound screening for antenatal detection of intrauterine growth retardation. Obstet Gynecol 1986;67:33-9. Hughey MJ. Routine ultrasound for detection and management of the small-for-gestational-age fetus. Obstet Gynecol 1984;64:101-7. Koops BL, Morgan LJ, Battaglia FC. Neonatal mortality risk in relation to birthweight and gestational age: update. J Pediatr 1982;101:969-77. Nishida H. Is intrauterine growth retardation worse than prematurity? In: Maeda K, Okyyama K, Takeda Y, eds. Recent advances in perinatology. Amsterdam: Excerpta Medica, 1986:63-7; international congress series 712.
Editors' note: This manuscript was revised after these discussions were presented. Discussion DR. ALFRED B. KNIGHT, Temple, Texas. This article is a review of IUGR newborns in a data base of 22,616 patients delivered between 1979 and 1985. I have presumed in this discussion that information was collected on all patients in the data base.
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There many complex issues regarding abnormal fetal growth yet to be answered, not the least of which is the definition.' The further classification of IUGR as symmetric or asymmetric was an attempt to associate cause and prognosis after the child was born with a gestational pathophysiologic condition. This concept could then be extended to in utero diagnosis. Lin and colleagues were unable to confirm the classic clinical association of certain diseases of fetus and mother with specific subtypes of growth retardation. Clarification of a number of issues relative to the patient data base and patient selection would be helpful before we discard two decades of elegant teaching of the pathophysiologic features of IUGR. 1. Dr. Lin and colleagues have used the definition of IUGR to be a birth weight for gestational age of < 10th percentile. I would have anticipated that the number of infants identified would approach 10% of the data base, at least markedly greater than the 3.2% screened. Why is there such a low incidence of IUGR in their population? 2. The method for assigning gestational age was not elaborated in this manuscript and remains a critical element to the definition of IUGR. Both obstetric and neonatal information can be used, but neither can assign gestational age with a greater accuracy than plus or minus 2 or 3 weeks (excluding those patients with "stellar" dates). Perhaps an even greater error is introduced with Dubowitz gestational ages <34 weeks complicated by IUGR! What method was used to determine gestational age? 3. Symmetric versus asymmetric IUGR is defined by a head circumference of> 10% or < 10%. Others in the newborn period have used the 25th percentile. The characterization of IUGR of differing symmetry reflects an attempt to understand and categorize causes of IUGR. In fact, rarely does a fetus-newborn have purely symmetric or asymmetric IUGR; more commonly, the condition would be considered "mixed," particularly at gestational ages of <34 weeks.' How many newborns were close to that asignment? 4. Risk factors for adverse fetal outcome were identified for comparison. Many are not independent factors, such as young age and pregnancy-induced hypertension. Other factors are poorly correlated with IUGR (e.g., urinary tract infection, anemia, maternal age >35 years) and still others could be more completely defined (poor obstetric history, antepartum hemorrhage, poor weight gain). More refined groupings might unmask significant correlations. 5. These high-risk factors were compared by X2 analysis with little significance identified. However, it would have been useful to evaluate the difference between the population of IUGR patients and the general data base to confirm that this population was indeed unique. 6. Perinatal events and fetal outcome would benefit from more detailed assessment. For example, the single category "intrapartum fetal distress" includes meconium-stained amniotic fluid, abnormal fetal heart rate patterns, and fetal acidosis. These three clinical findings may be independent and mayor may not reflect "distress" or fetal compromise.
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Differences in 5-minute Apgar score and neonatal death rate were statistically significant between the symmetric and asymmetric groups. However, the symmetric IVGR newborns were more likely premature. Is this association simply a reflection of prematurity? In summary, Dr. Lin and colleagues have presented interesting material from a large perinatal data base. With their patient selection no antepartum maternal or fetal factors clearly differentiated symmetric from asymmetric IVGR. I look forward to additional analysis of this information. REFERENCES 1. Goldenbery RI, Cutter GR, Hoffman MA, et al. Intrapartum growth retardation: standards for diagnosis. AM J OBSTET GYNECOL 1989;161:271-7. 2. Yogman MW, Kraemer HC, Kindlon D, et al. Identification of intrauterine growth retardation among low birth weight preterm infants. J Pediatr 1989;1I5:799-807. 3. Brar HS, Rutherford SE. Classification of intrauterine growth retardation. Semin Perinatol 1988;12:2-10. DR. L. WAYNE HESS, Jackson, Mississippi. Dr. Lin's article leaves several questions unanswered, including the following: (1) What percent of cases of antenatally suspected IVGR did not have IVGR postnatally (per Dr. Lin's definition)? (2) Was there a difference between the outcomes of the 227 antenatally diagnosed and 491 postnatally diagnosed IVGR infants; i.e., did antenatal intervention improve outcome? (3) How was the control group defined for Fig. 2? (4) What was the power of the statistics for Tables I to IV to conclude there were no statistical differences? Additionally, the study could be strengthened by the addition of a case-matched control group. A recent study contrasted all IVGR infants with a case-matched control population.' However, this study failed to contrast type I and type II IVGR infants to the control population. To date, no other large series has contrasted type I and type II IVGR infants to a control population. Dr. Lin's article provides the clinician some new insights into the problem of IVGR. However, it leaves the clinician with three problems that are difficult to reconcile. First, the clinician is interested in abnormal growth, not birth weight. A birth weight at the 10th percentile will not always define abnormal fetal growth. 2 A postterm fetus that is severely malnourished will frequently have a birth weight > 10th percentile. Second, previous studies that have "established" the 10th percentile for birth weight have demonstrated great variability in results, mainly on the basis of population differences. Lubchenco et al. 3 established neonatal growth curves on the basis of 5635 Denver (highaltitude) hospital births occurring between 1948 and
June 1991 Am J Obstet Gynecol
1961. The "dates" in this study were based on mother's last menstrual period without correction for clinical criteria. Nonwhite and diabetic patients were excluded from the study. Goldenberg et al! noted a 192 gm (at 28 weeks) to 823 gm (at 42 weeks) difference in the 10th percentile birth weights in 38 summarized studies. Third, defining IVGR as a birth weight < 10th percentile assumes: (1) that adverse outcome and birth weight percentile remain constant at all gestational ages and (2) that the 10th percentile is a meaningful, discrete cutoff level. Myers and Ferguson' have demonstrated that neither of these assumptions is true. The birth weight percentile at which the stillbirth rate is quadrupled is the 1.5th percentile at 28 weeks versus the 16.5th percentile at 42 weeks. IVGR must be more objectively defined before standard obstetric interventions or newly suggested therapies (such as fetal substrate augmentation with nutrients and oxygen or lowdose maternal aspirin therapy) can be objectively, scientifically evaluated. REFERENCES 1. Callan NA, Witter FR. Intrauterine growth retardation: characteristics, risk factors and gestational age. Int J GynaecolObstet 1990;33:215. 2. Altman DG, Hytten FE. Intrauterine growth retardation: let's be clear about it. Br J Obstet Gynaecol 1989;96: 1127. 3. Lubchenco LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics 1963;32:793. 4. Goldenberg RL, Cutter GR, Hoffman HJ, Foster JM, Nelson KG, Hauth JC. Intrauterine growth retardation: standards for diagnosis. AM J OBSTET GYNECOL 1989; 161 :271. 5. Myers SA, Ferguson R: A population study of the relationship between fetal death and altered fetal growth. Obstet Gynecol 1989;74:325. DR. DANIEL A. RIGHTMIRE, Springfield, Illinois. I am quite curious as to why Dr. Lin did not use a head circumference/abdominal circumference ratio in his definition of symmetric versus asymmetric growth retardation. Head circumference, compared to abdominal circumference, may be a late indicator of poor fetal growth. Think of the causes of growth retardation as being divided into placental factors, maternal factors, and fetal factors. I am afraid that Dr. Lin's definition may have preselected a group of small-to-be fetuses who had fetal factors early on, either pathologically or normally. In other words, he may have a mix of constitutionally small babies who will do well and babies with birth defects or other constitutional factors, all of whom may be predetermined to be small throughout pregnancy. I am afraid that many of his findings might be simple, logical extensions of his definitions rather than reflections of pathologic conditions of gestation.