PEDIATRICS Vol. 118 No. 2 August 2006, pp. 758-763 (doi:10.1542/peds.2005-2399)
SPECIAL ARTICLE |
Extremely Growth-Retarded Infants: Is There a Viability Centile?
a Neonatal Unit, Leicester Royal Infirmary, Infirmary Square, Leicester, United Kingdom
b Department of Health Sciences, University of Leicester, Leicester, United Kingdom
| ABSTRACT |
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BACKGROUND. It is known that extremely premature infants do less well than more mature infants, and this fact has led some countries to adopt a "cutoff for viability" using birth weight or gestation. Infants affected by intrauterine growth retardation are at additional risk of poor outcome. There are few data to inform decisions about viability and (dis)continuation of intensive care when both extreme prematurity and severe growth retardation are present.
OBJECTIVE. We focused on (1) premature infants affected by marked intrauterine growth retardation to determine if there was a cutoff weight centile below which the mortality sharply increased and (2) the short-term outcome of extremely premature and growth-retarded infants to determine a cutoff for viability.
METHODS. We evaluated preterm infants of 2232 weeks' gestation if they were alive at the onset of labor and born to European mothers resident in the Trent (United Kingdom) health region between 1994 and 2003. Infants were categorized into 6 weight centiles, and infants in each category were assessed for survival to discharge from the neonatal unit, duration of respiratory support, length of stay in the neonatal unit, and the age at death in nonsurvivors.
RESULTS. We identified a total of 8228 infants who met the study criteria. Of these, 4448 infants were male, 6194 were from singleton pregnancies, and 2887 were born at
28 completed weeks of gestation. Survival to discharge was markedly reduced in the infants born at
28 weeks of gestation with a birth weight less than the 2nd centile. Stillbirth was inversely related to birth weight centile in infants born before 29 weeks of gestation.
CONCLUSIONS. The survival for infants born at
28 weeks' gestation and having a birth weight in less than the 2nd centile is poor, and consideration should be given to modifying their management.
Key Words: birth weight extreme preterm intrauterine growth restriction outcome mortality
How much does he/she weigh?" is often the next question parents ask after identifying the gender of their new infant. This probably reflects a widely held lay public view that a big infant is a healthy infant. Of course, this is not unreasonable, and pediatricians have long been familiar with the increased risk of mortality and early morbidity of infants born very small or very early.14 Advances in perinatal care in recent years, along with an increased understanding of neonatal physiology, have greatly improved the chances of survival of extremely low birth weight and low gestational age infants.5 This trend, however, has presented complex medical, social, and ethical issues for families and health professionals who care for infants of borderline viability. It is very difficult to define "how small is too small" and "how much is too much" when providing intensive care to extremely small or extremely premature infants.6,7
Referring to the United Kingdom standard growth charts for boys,8 it is seen that 500 g approximately corresponds to the 10th centile at 24 weeks of gestation, 750 g corresponds to the 10th centile at 27 weeks, and 1000 g corresponds to the 10th centile at 30 weeks' gestation. The birth of an infant weighing <500 g presents a particular dilemma, because these infants are often considered to be nonviable irrespective of gestation. It is true that survival of infants born weighing <500 g is unusual, but satisfactory outcomes have been described.9,10 Currently, clinicians typically decide whether to offer or continue intensive care after considering the views of the parents and prognostic indicators such as gestational age and the appearance of cranial ultrasounds.11,12 Over the past decade several models and scoring systems have also been described as a means of predicting outcome in infants born before 32 weeks' gestation.13 However, none of the current systems of scoring have included a sufficiently large number of infants below 500 g in birth weight in their derivation cohort to allow them to be considered robust in predicting outcome for this group.
In this study we aimed to identify the outcome for the most markedly growth-retarded infants from 22 to 32 weeks' gestation from a geographically defined population and to assess whether there is a clear criterion that can define "how small is too small."
| METHODS |
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The study population was all preterm births (alive and stillborn) born between 22 and 32 weeks of gestation and born to mothers resident in the Trent region of the United Kingdom during the years 19942003.
Data were obtained from 2 sources:
- Information about infants born alive and admitted to a neonatal unit was collected as part of the Trent Neonatal Survey,14 which is an ongoing study of neonatal intensive care activity in the geographically defined population of the Trent Health Region (United Kingdom). All of the perinatal services in Trent contribute to the Trent Neonatal Survey, and units in adjacent regions also permit data collection on Trent infants. The present survey was established in February 1990. The database holds information relating to all infants of
32 weeks' gestation born to a Trent-resident mother and admitted to a neonatal unit since that time. Data for the Trent Neonatal Survey are collected by a group of 5 part-time research nurses who visit each of the neonatal units on a regular basis and complete a standardized data set about each infant. Information is obtained from the clinical records, discussions with staff, and, where appropriate, personal observation.
- Data regarding immature infants who died outside a neonatal unit were obtained from the Confidential Enquiry Into Stillbirths and Death in Infancy (now the Confidential Enquiry Into Maternal and Child Health) for the region. This is a similarly longstanding national study that, at the time, had 2 functions: (1) to collect a minimum data set for all infants delivered after 20 weeks' gestation either born dead or who die in the first year of life and (2) to carry out confidential inquiries into specified groups of deaths to improve the quality of obstetric, perinatal, and infant care.
Subjects and Design
Infants were included in the study if they were alive at the onset of labor and born
- to mothers of European ethnic origin resident in the Trent region;
- between 22 and 32 weeks' gestational age; and
- without a major congenital anomaly.
Analysis was performed for the entire cohort, and the cohort was subdivided further according to gestational age into infants who were
28 or >28 weeks' gestation. This division was chosen because the problems of growth restriction would be compounded by more marked problems of prematurity in the first group.
To consider the effect of growth restriction we considered the behavior of infants in 6 centile bands: <1st, 1st to 2nd, 2nd to 3rd, 3rd to 4th, 4th to 5th, and >5th. These centiles were derived by using the methodology described by Cole et al.8
Only short-term outcome data were analyzed and are presented as numbers and percentages. No attempt was made to apply statistical methods because of the small numbers in some of the lower centile groups.
Double data entry and regular audits were performed to ensure data quality.
Outcome Measures
The outcomes of the differing centile groups were compared for:
- death during labor (stillbirths);
- deaths on a labor ward without admission to a neonatal unit;
- survival to discharge from neonatal care;
- duration of respiratory support (mechanical ventilation, continuous positive airway pressure, or oxygen); and
- lengths of stay for survivors and age at death for infants who died before discharge from neonatal care.
| RESULTS |
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Over the 10 years of the study there were 8228 infants who met the study criteria. Of these, 4448 infants (54%) were male, 6194 (75%) were from singleton pregnancies, and 2887 (35%) were born at
28 completed weeks of gestation. Of the infants born at
28 completed weeks of gestation, 1503 (52%) were male and 2219 (77%) were from singleton pregnancies. Of those born at
28 completed weeks, 2945 (55%) were male and 3975 (74%) were from singleton pregnancies. There was no indication that any centile contained significantly more multiple infants. Additional information on these births according to birth weight centile is shown in Table 1.
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Survival to discharge was markedly reduced in the infants born at
28 weeks with birth weight <2nd centile. This pattern was not seen, however, in the infants born after 28 weeks, although a less dramatic association of birth weight centile and survival was seen. Stillbirth was inversely related to birth weight centile in infants born before 29 weeks, but this pattern was not seen in the infants born after 28 weeks (Table 2). Looking further, just 4 infants in the lower centiles died after they were admitted to a neonatal unit and received no respiratory support (Table 3). It would seem that these 4 were the only ones admitted to the neonatal unit on purely compassionate grounds. As can be seen from Table 4, the length of stay for infants who died was similar across all the different gestational-age groups, as was the length of ventilation. In infants who survived, however, the length of stay and ventilatory support were inversely related to birth weight centile for infants born before 29 completed weeks of gestation. In infants of >28 weeks' gestation, this finding was also seen for length of stay but not length of respiratory support.
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| DISCUSSION |
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In this study we focused on the short-term outcome of extremely premature and growth-retarded infants. Our objective for this study was to determine the mortality and resource use of infants with intrauterine growth failure who were alive at the onset of labor according to the severity of growth failure. We tested the hypothesis that a threshold level in severity of growth restriction was associated with a very poor outcome. This study indicates that infants weighing <2nd centile and born before 29 completed weeks of gestation are at high risk of death from the onset of labor until discharge from the neonatal unit. The rate of death in these infants in our study is similar to that reported for infants weighing <500 g.10,15,16 The approach of some neonatologists who do not treat infants born at <500 g17,18 could therefore be adopted for these infants, too. Reassuringly, however, the vast majority of growth-retarded infants born after 28 weeks' gestation did extremely well.
The clear association between severity of growth restriction and mortality demonstrated by this study is in agreement with those of other recent studies.1921 Similarly, this study provides evidence that the most growth-restricted infants require longer hospital stays and respiratory support. Early reports suggested that growth-restricted infants had better survival and less respiratory and other complications than appropriately grown peers resulting from being matured by endogenous stress hormones.22,23 These comparisons, however, were flawed in that they compared growth-restricted infants with appropriately grown infants of similar birth weight.20 Control infants, therefore, were more immature and consequently suffered higher rates of complications. Our data agree with more recent studies that have shown an increase in the length of stay in small-for-gestational-age infants when compared with appropriate-for-gestational-age infants.2426 This is likely to be a result of many factors, including poorer growth and higher rates of complications such as necrotizing enterocolitis, chronic lung disease of prematurity, and intraventricular hemorrhage.19,21
An important explanation for the poor survival in the extremely premature, severely growth-restricted infants is that the obstetric management may have been conservative, with limited monitoring and intervention in view of the perceived prognosis for the infant. When the prognosis is poor, obstetricians often try to limit maternal morbidity by avoiding a cesarean section and allowing the infant to deliver naturally without active monitoring.2729 Data on obstetric decisions for mode of delivery, the presence or absence of a neonatologist, and the exact approach to resuscitation in the delivery room were not available. Also, information regarding subsequent withdrawal of intensive care on compassionate grounds was not available.
For those infants who died in this study, the length of stay was similar across all the different birth weight centile groups, indicating that the time of death was not affected by the size of the infants. We had postulated that the very small infants would have a lower chance of survival but that some of these infants would survive for a prolonged period before dying. A study by Meadow et al30 of 1142 extremely low birth weight infants from a tertiary unit born between 1991 and 2001 demonstrated an increase in the median length of stay of infants who eventually died before discharge from 2 days in 1991 to 10 days in 2001. This finding could be the result of a change in resuscitation of very small infants; our data, however, do not indicate a different approach to resuscitating severely growth-restricted infants, with each of the centiles having similar numbers of live-born infants dying on the labor ward without admission to a neonatal unit in Trent.
As a consequence of the exclusion criteria used in our study, we analyzed the outcome of European fetuses that were alive at the onset of labor. Asian infants have been shown previously to be smaller but have better survival than European infants of similar weight.1 Black premature infants are also known to have an improved prognosis in comparison to similar white infants.2,3 However, we have no evidence to suggest why the results cannot be applied to nonwhite populations. Excluding infants who were not alive at the beginning of labor was important to remove the distorting effect of stillborn infants who may have spent some time either dead or growing very poorly in the womb. Our data, therefore, should be applicable to all infants alive at the onset of labor or elective cesarean section. These data should be useful for counseling expectant parents in a similar situation.
Other potentially confounding factors were not excluded, including Doppler abnormalities, minor or nonlethal congenital malformations, and the indication for delivery. Unfortunately, these data were not available from the Confidential Enquiry Into Stillbirths and Death in Infancy data set and thus could not be included in the study. Another weakness of the study was the small numbers present in some of the groups; a larger sample size would improve the precision of estimates of outcome. Our study group, however, was derived from the lightest 5% of infants from a large cohort of >8000 infants born before 32 weeks' gestation; little data on a similar scale are available in Europe.
Major strengths of our study include the use of a geographically defined population (Trent), the use of a gestational-age cutoff, and the inclusion of stillborn infants.2 Using a geographically based population avoided the potential for selection bias to affect our results. In contrast to population-based geographic cohorts, tertiary-unit cohorts contain infants that have been transferred for tertiary care, because they are too sick or premature for the local unit. This leads to a reduction in the number of controls, and their health tends to be worse than expected, potentially introducing bias into the comparison of outcomes.31 Using a gestational-age cutoff is also important, because using a birth weight criterion (eg, under 1500 g) for inclusion in a study leads to the selection of infants who are small for their gestational age. Because suitable control infants of the same gestational age who are normally grown were excluded for having a birth weight above the cutoff, selection bias is inevitable with birth weightdefined inclusion criteria.32
In addition to higher mortality, growth restriction may be associated with a poorer neurodevelopmental prognosis.4 We were unable to study this because of incomplete follow-up, although it would be of great interest; a high risk of death matched with poor neurologic outcome in survivors may further inform decisions about appropriateness of intensive care for infants with severe growth restriction. Centiles were defined by the data and methods used to derive the widely used growth charts of Cole et al.8 The use of these definitions should allow the data in this article to be more easily applied to other newborn infants.
| CONCLUSIONS |
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Survival for infants born at
28 weeks' gestation who weigh <2nd centile is poor, and consideration should be given to not providing intensive care or to withdrawing intensive care at an early stage in these infants. Additional studies of neurodevelopmental outcome in extremely premature infants with severe growth restriction are needed and may further strengthen the case for this conservative approach.33,34
| FOOTNOTES |
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Accepted Mar 2, 2006.
Address correspondence to Vishwanath M. Kamoji, MD, MRCPCH, Neonatal Unit, Level 5 Kensington Building, Leicester Royal Infirmary, Infirmary Square, Leicester LE1 5WW, United Kingdom. E-mail : vmkamoji{at}doctors.org.uk
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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