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Historical Review and Recent Advances
in Neonatal and Perinatal Medicine

Edited by George F. Smith, MD and Dharmapuri Vidyasagar, MD
Published by Mead Johnson Nutritional Division, 1980
Not Copyrighted By Publisher

Chapter 23

The Developmental Outcome of Premature Infants

Lula O. Lubchenco, M. D.


Long-term follow-up of high-risk infants cannot be separated from perinatal care, since the changes in medical management have been so dramatic and have played such an important role in the outcome of the very low birth weight infant.

Problems in longitudinal follow-up studies are familiar. Aside from incomplete follow-up data, the effect of environment, especially as it compensates for neonatal injury, or aggravates it, is well-known.[1-3] Birth weight as the sole criterion for defining the sample, differing criteria for handicap, inclusion of outborn transported infants, with inborn infants, giving an unknown base population and differing racial mixtures, are all inherent problems which make evaluation of reported studies difficult.

In spite of these problems, there are distinct trends in outcome of very low birth weight infants, starting in 1922 with Hess and continuing to the present.

Hess and associates reported on the outcome of 317 survivors with birth weights of 605 to 1260 grams, at the American Academy of Pediatrics meeting in 1950. Publication of' the complete monograph occurred in 1953.[4] The infants studied were those admitted to the Sarah Morris Hospital during the years 1922-1950. The overall mortality in this weight group was 73%. The follow-up was remarkably complete (92%) and carefully done with psychometric and physical examinations being reported (Table 1). Only 15% of the children were severely handicapped, although 41% had some problem. Referring to mortality and outcome, Hess said "Nature has been kind to many who did not survive the ordeals of the early days . . ."

In the late 1940's and early 1950's premature centers were being developed throughout the United States, following the experience of Hess in Chicago and all expected similar results with improved care for this vulnerable population.

It was not until the late 1950's that the incidence of handicaps in our graduates was suspected to be greater than the incidence reported by Hess. In Colorado, survivors with birth weights of 1500 grams or less who were born between July 1947 and July 1950 were reported on.[5] An incidence of 68% of central nervous system and visual handicaps was found in 63 of 94 survivors. In addition, growth retardation and social and emotional problems were encountered, and school failure occurred in 30% of children with normal intelligence.

At the same time, reports from Dann[6] and Drillien[7] confirmed an increasing incidence of handicaps in survivors of very low birth weight. Even after reduction of oxygen (Table 2), the incidence of handicaps did not change, except for the severity of retrolental fibroplasia. This era in premature infant care was best described as the "hands-off" period. There were Gordon Armstrong incubators and a few isolettes. The infants were under the watchful eyes of the nursing and medical staffs, who were concerned with cyanosis and apnea and the need for stimulation. Warmth and oxygen were provided and gavage feeding was well-established, though feedings were delayed. There were few IV's given. Chemistry and hematology laboratories, as well as x-ray examination were available, but not geared to these infants. Attending physicians and nurses depended on clinical findings and a modicum of intuition to guide them in management. And parents were estranged from their infants. By 1950, the specter of retrolental fibroplasia had appeared.

The tragic associations between oxygen administration and retrolental fibroplasia, chloramphenicol and the Gray Baby Syndrome, sulfonamides, Vitamin K and kernicterus are well-known. As though these were not sufficient setbacks in themselves, the epidemics of staphylococcal disease in newborn infants and rubella in pregnant women followed on their heels.

It is a wonder that premature infant care survived this decade. This period of introspection raised a number of questions about postnatal management as it related to outcome; some gave hope that more vigorous metabolic support could improve outcome. It was clear, from the tragedies described above, that postnatal care could adversely alter outcome; therefore, it might be possible for vigorous metabolic support to positively alter outcome.

In the 1960's, care of premature infants had become more aggressive. Metabolic problems, such as hypoglycemia and acidosis, were being treated. "Prematures" were now categorized by those with short gestations and those with intrauterine growth retardation, and "intensive care" became a well-known byword.

The first data from the Colorado center suggesting that aggressive management could positively alter outcome are shown in Figure 1 and Table 3. Data from other centers showed a relationship between intensive care and outcome, both for mortality and long-term morbidity (Figures 2 and 3).[8]

The use of continuous positive airway pressure and respirators then made neonatal care truly "intense." The radiant warmer contributed to the ease with which aggressive care could be given and nearly all centers reporting on outcome began showing improved long-term results (Figure 4).[9]

The hypothesis was proclaimed throughout perinatal circles that the efforts needed to improve survival of the very low birth weight infant enhanced the chances of improved, long-term outcome.

In our institution a dramatic fall in mortality occurred when a combined effort of obstetricians and neonatologists, aimed at prevention of intrapartum and neonatal asphyxia, occurred (Table 4). Follow-up of these infants, i.e., those born before and after intrapartum intensive care (Table 5),[10] showed no difference before and after decrease in mortality in the incidence of handicaps at one year of age. However, this brings up one of the problems in follow-up studies (Figure 5). Does one compute outcome from the total sample of births or does one disregard the infants who die in the neonatal or postneonatal period?

If one looks at total births, it is obvious that many more children survived the neonatal period in 1975 and just as impressive are the normal children at one year of age in 1975. But, if one looks only at percentage of handicaps in survivors to one year of age, the incidence is the same. There were only 16 survivors to one year of age in 1974 and 58 in 1975. There were also greater numbers of handicapped children in 1975, 19 versus 5.

At this juncture, a word concerning the types and severity of handicaps in preterm infants is pertinent. The handicaps described in preterm infants are real but they are not of the type or severity one sees with congenital infection or chromosomal abnormalities. Only rarely are the problems sufficient to require institutionalization, although some may require special education. In general, they-the handicapped premature infants-are integrated easily into the families.

Hess apparently had a similar experience: "the clinical tabulation . . . gives a more severe impression than the children themselves."[4]

Spastic diplegia is the most common finding. Although it has decreased in frequency and severity, it is still with us. Hemiplegia was rarely seen in the earlier studies, but rivals spastic diplegia in incidence now. Hydrocephalus is much more frequent today.

Congenital anomalies account for some of the handicaps. A 3% incidence of significant malformations is found in newborns at University Hospital (Figure 6). The highest incidence occurs in small for gestational age infants. Emerging as new problems are bronchopulmonary dysplasia (15-30% of survivors), patent ductus arteriosus (50-70%) and necrotizing enterocolitis. Not included in most statistics of handicaps are the numerous scars from complications of treatment, growth retardation and prolonged hospitalizations. Children who are neglected or abused and those who die of Sudden Infant Death Syndrome are handicaps of the present.

The small for gestational age infant has been reported to have a poor prognosis.[11] In the data from the University of Colorado Health Sciences Center, however, the outcome of small for gestational age infants is as good as it is for infants appropriately grown for gestational age. This may be an indication that the small infants derived maximum benefits from the intensive intrapartum care given to them.

The most significant finding in recent studies, i.e., children who have had the advantages of obstetric and neonatal care, is that outcome is no longer dependent on birth weight or gestational age (Table 6).12 Unlike neonatal mortality, which is still strongly related to birth weight, the longterm outcome of very low birth weight infants is dependent more upon intrapartum and neonatal care.

The problem in comparing transport patients with inborn babies is in great part due to uncertainty regarding the base population of the transported group. Is there a selection in this group which accounts for their outcome? Do the babies at highest risk die prior to transport? Do the larger infants remain in the hospital of birth?

With the development of regional services and transport of infants and mothers for special care, evaluation of the transport system is sorely needed. State and national figures on neonatal mortality show a downward trend, but the factors contributing to this trend are not yet available.

Regionalization of perinatal care began many years ago in Colorado[13] and, by 1975, was working efficiently within Metro Denver, as well as throughout the entire region.

This gave us an opportunity to investigate the effect of regionalization in Denver through a combined effort of 5 Metro Denver hospitals, Denver Children's Hospital and University Hospital. The 5 Metro hospitals, then with Level I nurseries, routinely transported high-risk infants to Denver Children's Hospital. Data on fetal deaths, neonatal deaths and long-term outcome were gathered on this population, which was then compared with the University Hospital inborn infants (Tables 7 and 8). Fetal deaths occurred twice as often in the Metro hospitals as in the University Hospital. Neonatal deaths and long-term outcome were no different in the two populations. However, many inborn infants were transferred in utero to this perinatal center; therefore, this subpopulation was examined. It is a large group since 57% of the admisssions with birth weights less than 1500 grams, entering University Hospital during the period of this study, were from maternal transports. The fetal death rate in this population, i.e., in utero transports, was similar to that of the University Hospital clinic population and both were significantly lower than in the Metro hospitals. The neonatal death rate was lowest in the maternal transport infants. Birth weight and gestational age were essentially the same in all 3 populations. In each group, fetal deaths had the lowest mean birth weight, neonatal deaths next and survivors had the largest mean weight.

A number of neonatal morbidities appear to be lower in the Metro hospital population (respirator care, shock following delivery, and incidence of patent ductus arteriosus), but data on these findings were not uniformly reported, especially when the infant died prior to transport.

Multiple births were much more frequent in this weight group, in all 3 populations, than in full-term infants, averaging 19% of the infants studied or occurring in about 9% of mothers.

The cesarean section rate was highest in the in utero transport population (43%) which was significantly higher than the rate in the University Hospital clinic population (28%). Both University Hospital populations were higher than the rate in Metro hospitals (16%).

Regionalization of perinatal care in this metropolitan area has resulted in acceptable survival rates for 1975-1978, compared with other institutions, for liveborn infants and comparable long-term outcome. The incidence of severe handicaps occurred in 19% of University Hospital babies and in 22% of those born in the Metro hospitals.

The high fetal death rate in the Metro hospitals becomes the responsibility of the obstetrician and the maternal patient.


Table 1
Long-Term Follow-up of Very Low Birth Weight Infants*
(735-1260 Grams)







Slight deviation









Very bad



Some handicap in 41% of children
Severe handicap in 15% of children
* Hess 1949


Table 2
Premature Infant Follow-Up Study
1 July 1947-1 July 1953

Summary of Handicaps

Group "A" High Ambient O2 Concentration

Group "B" Low Ambient O2 Concentration

Retrolental Fibroplasia (blind in both eyes)

19 (8)

14 (1)

Central Nervous System Disorders



IQ Less than 90



Neurosensory Hearing Loss



Total Number of Children Examined



Total Number of Handicapped Children

47 (70%)

46 (70%)


Table 3
Long-term Outcome of Preterm AGA Infants
Birth Weights 1500-2500 Grams, Born 1962-1965


ICN with IV

ICN without IV

Regular Nursery

No. infants followed




Def. CNS Abn.




Def. + Min. CNS Abn.




Mean IQ





Table 4
Reduction in Neonatal Morbidity
Liveborn Very Low Birthweight Infants


No. Adms.

% Neonatal Mortality

Jul 70-Jun 71



Jul 71-Jun 72



Jul 72-Jun 73



Jul 73-Dec 74



Jan 75-Dec 75



Jan 76-Dec 76



Jan 77-Dec 77



Jan 78-Dec 78



Jan 79-Dec 79




Table 5
Summary of Outcome
Survivors to One Year
Birth Weights <1500 Grams




No. Survivors to 1 Yr.



No. Followed



No. Handicap



Mild Handicap



Mod-Severe Handicap






** 2 were abused and 1 had Down Syndrome [Trisomy 21]


Table 6
Long-Term Outcome (to Date)
Birth Weights < 1500 Grams

B Wts

UCMC 75-76
DCH 75









NMR 70%



NMR 56%











NMR 33%



NMR 18%











NMR 4%



NMR 20%




Table 7
Outcome of Inborn Versus Transported High-Risk Infants
Birth Weights 800-1499 Grams
Birth Dates 1/1/75-1/1/78


University Hospital

5 Metro Denver Hospitals*

Total Births



Fetal Deaths

49 (12.4%)

77 (26.0%) **




Neonatal Deaths

105 (30.4%)

84 (37.9%)

Neonatal Survivors



* St. Anthony, St. Mark's, Mercy, Swedish, Lutheran
** p < 0.005


Table 8
Outcome of Inborn Versus Transported High-Risk Infants
Birth Weights 500-1499 Grams
Birth Dates 1/1/75-1/1/78
Results of Follow-up


University Hospital

Transport Hospital





179 (80%)

78 (59%)

No Handicap



1+ Handicap



2+ Handicap



3+ Handicap

34 (19%)

17 (22%)



Fig. 1. Incidence of handicaps in premature survivors in Colorado, 1962-65.

Fig. 2. University of California at San Francisco -- Inborn neonatal survival, 1961-1970.

Fig. 3. University of California at San Francisco Inborns: Incidence of handicaps for 26-34 weeks gestational age infants, 1965-70. (From unpublished data, Tooley et al., University of California at San Francisco.)

Fig. 4. Percent of normals among survivors, as reported by various investigators for 30 year period.

Fig. 5. Colorado Medical Center low birth weight infants, 1974-75.

Fig. 6. Congenital anomalies distribution, University of Colorado Medical Center, July 1966 - June 1968. (*In addition, there were 8 infants with anomalies out of 403 with unknown gestational ages (2%).)



1. Drillien C. M.: The Growth and Development of the Prematurely Born Infant. Edinburgh, E. & S. Livingstone, Ltd., 1964.

2. Cohen S. E., Beckwith, L., Parmelee, A. H.: Receptive language development in preterm children as related to caregiver-child interaction. Pediatrics 61:16, 1978.

3. Werner E., Bierman J. M., French F. E., et al.: Reproductive and environmental casualties: A report on the 10-year follow-up of the children of the Kauai Pregnancy Study. Pediatrics 42:112, 1968.

4. Hess J. H.: Experiences gained in a thirty year study of prematurely born infants. Pediatrics 11:425, 1953.

5. Lubchenco L. O. et al.: Sequelae of premature birth. Amer. J. Dis. Child. 106:101, 1963.

6. Dann M., Levine S. Z., New E.: The development of prematurely born children with birth weights or minimal postnatal weights of 1000 grams or less. Pediatrics 22:1037, 1958.

7. Drillien C. M.: Physical and mental handicaps in the prematurely born, J. Obstet. Gynaeeol. Brit. Comm. 66:721, 1959.

8. Phibbs R. N., Tooley W. H.: Relationship of long-term development to cardiopulmonary status at birth. Presented at 13th International Congress of Pediatrics, Vienna, 1971.

9. Bowes W. A.: Results of the intensive perinatal management of very low birth weight infants (501-1500 GM). In Preterm Labour, Proceedings of the Fifth Study Group of the Royal College of Obstetricians and Gynaecologists, October 5-6, 1977. Anderson A., Beard R., Brudenell J. M. et al. (eds.). London, England, pp. 331-355.

10. Lubchenco L. O., McGuinness G. A., Tomlinson A. L. et al.: Aggressive obstetric neonatal management: Long-term outcome, new techniques and concepts. In Maternal and Fetal Medicine, Kaminetzky and Iffy (eds.) New York: Van Nostrand Reinhold Company, 1979, p. 123.

11. Fitzhardinge P. M., Kalman E., Ashby S. et al.: Present status of the infant of very low birth weight treated in a referral neonatal intensive care unit in 1974. Ciba Found. Symp. 59: 139, 1978.

12. Hack M., Fanaroff A. A., Merkatz 1. R.: The low birth weight infant -- Evolution of a changing outlook. N. Engl. J. Med. 301:1162, 1979.

13. Butterfield L. J.: Newborn Country USA. Clinics in Perinatol. 3: 281, 1976.

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