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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Pediatrics. Author manuscript; available in PMC Oct 25, 2011.
Published in final edited form as:
PMCID: PMC3201804
NIHMSID: NIHMS279585
Evidence-Based Treatment Decisions for Extremely Preterm Newborns
Nehal A. Parikh, DO, MS,a Cody Arnold, MD, MSc, MPH,a John Langer, MS,b and Jon E. Tyson, MD, MPHac
a Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas
b Research Triangle Institute, Research Triangle Park, North Carolina
c Center for Clinical Research and Evidence-Based Medicine, University of Texas Medical School at Houston, Houston, Texas
Address correspondence to Jon E. Tyson, MD, MPH, University of Texas Medical School at Houston, 6431 Fannin St, MSB 2.106, Houston, TX 77030. jon.e.tyson/at/uth.tmc.edu
Few treatment decisions in any area of medicine have greater consequences than the decisions made shortly after birth to give intensive care or comfort care to extremely preterm infants. Obstetricians and neonatologists continue to struggle with ethical questions such as “How can we formulate better evidence-based treatment thresholds in judging when intensive care is ethically mandatory, unwarranted, or optional?”1 and “How can parents be best informed and counseled?”
Results of the cohort study by Bader et al, published in this issue of Pediatrics,2 are an important addition to the evidence base for these decisions. Theirs is one of only a few recent population-based studies that are free of the referral biases in virtually all center-based studies. Other important strengths include prospective data collection and entry into a computerized database with error checks. Prenatal and post-natal risk factors were related to predischarge mortality for >99% of the 3768 infants born alive at 23 to 26 weeks’ gestational age (GA) in Israel between 1995 and 2006. A limitation of the study is their lack of analyses to assess the extent to which mortality was affected by center differences or decisions to forego intensive care. In addition, there were no data about longer-term outcomes, including profound impairment, an outcome that some people consider worse than death.3,4
In multivariable regression models, the likelihood of death decreased with not only increasing GA but also higher birth weight (BW), female gender, singleton gestation, and antenatal steroid treatment. These same factors were also associated recently with a reduced mortality rate in large population-based analyses in California5 and center-based analyses in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN).6
Bader et al2 found that the decrease in mortality rate with antenatal steroid treatment and with a higher BW (per 100-g increase) was comparable to that of a 1-week increase in GA. In the California5 and NRN studies,6 this was true for not only higher BW and antenatal steroid treatment but also for female gender and singleton gestation. The reduction in risk of impairment and of profound impairment at 18 to 22 months’ corrected age (postterm) associated with each of these 4 factors was also comparable to a 1-week increase in GA in the NRN study.
Bader et al2 used BW and gender to classify infants into 3 categories on the basis of gender-specific BW percentiles and then developed simple tables for clinicians to use in assessing prognosis. This approach involves some uncertainty in determining appropriate BW standards7 and introduces approximations in grouping infants with different percentiles into the same category. Although this categorization was necessary for prediction tables, the infant’s exact BW can be used as one of multiple factors in assessing prognosis on Web-based tools such as that on the NICHD Web site (www.nichd.nih.gov/neonatalestimates).8
What are the implications of these and other recent outcome studies912 for decision-making in the care of extremely preterm fetuses or newborn infants? With the editors’ encouragement, we offer the following thoughts.
  • In the absence of randomized trials that evaluate the benefits of antenatal corticosteroids before 26 weeks’ gestation,16 large, carefully risk-adjusted cohort studies allow the most rigorous assessment. Results of the 3 studies noted above support administration of antenatal corticosteroids before delivery at 23 to 25 weeks’ gestation, although the associated benefits are likely to be partly a result of an obstetric commitment to optimize pregnancy outcome.
  • Several problems make it difficult to use the results of published studies to infer the probability that initiating intensive care will benefit extremely preterm infants. This probability is likely to be intermediate between the percentage with a favorable outcome among all these infants (some of whom died without receiving intensive care) and the percentage among those selected to receive intensive care. At a minimum, researchers in future studies should report both percentages. More sophisticated approaches, such as those used for the NICHD Web site, can be used to address this problem.6 Another problem is that outcome with intensive care differs in different centers. In principle, the likelihood of a favorable outcome estimated from multi-center studies could be adjusted on the basis of local outcomes. However, few centers have the large populations, standardized follow-up assessments, and low attrition rates needed to adjust estimates for survival without impairment or profound impairment. A low predischarge mortality rate does not necessarily indicate a high rate of survival without profound impairment.6
  • There is a need to replace GA-based guidelines with probability-based guidelines to promote decisions to initiate intensive or comfort care that are better informed, more individualized, and less influenced by the frequent errors in assessing GA.1719 The most recent guidelines from the American Academy of Pediatrics emphasized the need for each institution to develop “comprehensive and consistent guidelines for antenatal counseling” that are based on multiple factors.13
Approaches such as the following can be considered.
  • Use probability thresholds that are implicit in current GA-based treatment guidelines already being used. GA has been used as a proxy (albeit imperfect) to indicate the overall probability of a favorable (or unfavorable) outcome with intensive care. Current GA-based guidelines take into consideration parental autonomy, infant suffering, and resource availability and reflect implicit clinical judgments about when the probability of benefit is so high that intensive care should be mandatory and when the probability is so low that intensive care is unwarranted.1 These judgments can be better applied to individual infants when their probability of a favorable outcome is assessed more accurately.
    In many centers, intensive care has been viewed as mandatory for infants born at ≥25 weeks’ GA.20 With the NRN data, the overall probability of survival with intensive care for 401- to 1000-g infants born at 25 weeks’ gestation would be estimated to be 75% to 76%; the probability of survival without profound impairment, 62% to 63%; and the probability of survival without impairment, 46%.6 In centers with outcomes equivalent to those across the NRN and in which intensive care has been considered mandatory at ≥25 weeks’ gestation, such care might be considered mandatory, irrespective of GA, when the estimated probability of a favorable outcome exceeded values such as those discussed above.
    At 22 weeks, a GA at which intensive care has often been considered unwarranted, the probability of survival with intensive care was estimated to be 5% to 20%; the likelihood of survival without profound impairment was estimated to be 2% to 10%; and the likelihood of survival without impairment was estimated to be 1% to 5% in the NRN study.8 As a measure of both the total infant suffering and resource use resulting from intensive care at this GA, a mean of 197 ventilator-days and 365 hospital-days (including days for infants who died) were needed per infant who survived without profound impairment (values represent estimates for male and female infants combined; for gender-specific values, see Table 4 in ref 6). In centers at which intensive care has been judged to be unwarranted at ≤22 weeks’ gestation, such care might be judged to be unwarranted irrespective of GA when, say, the estimated probability of survival without profound impairment is ≤10% (ie, a >90% likelihood of death or profound impairment). Whatever thresholds were used, intensive care would then be considered optional (as decided with the parents) at probability estimates intermediate between the thresholds for mandatory and unwarranted care.
  • Develop probability thresholds on the basis of a broad consensus. Development of new guidelines within individual centers or groups of centers may be best done by actively engaging obstetric and neonatal caregivers, follow-up clinic personnel, and parents in a process similar to that used by Kaempf et al.21,22 It is difficult to weigh the infant suffering, parental distress, and short-term and long-term resource needs associated with intensive care against the potential benefits. Different centers may differ in the importance ascribed to different outcomes and the probability thresholds that would be selected in designating intensive care as unwarranted, mandatory, or optional. An argument can be made that intensive care should be considered investigational in the lower portion of what might otherwise be the optional range.1 (This designation could help foster a well-defined approach to informing parents and involving them in decision-making and a commitment to carefully assess and publish neonatal and follow-up outcomes.)
Table 1 lists probability estimates of outcome and resource use of ventilated infants in the NRN. It is provided to stimulate discussion of the threshold probability estimates that may be considered in designating intensive care as unwarranted, investigational, or optional. Whatever guidelines are developed, they obviously should be reconsidered as new information emerges.
TABLE 1
TABLE 1
Outcomes and Resource Used According to Estimated Probability of Survival Without Profound Neurodevelopmental Impairments Among Infants of 22 to 25 Week’ Gestation (401–1000 g) Treated With Mechanical Ventilation in the NICHD NRN Study (more ...)
NEED FOR ADDITIONAL RESEARCH
Despite the advances in assessing the prognosis of extremely preterm infants, much additional study is needed to promote better informed parental counseling and treatment decisions for extremely preterm infants. Although beyond the scope of this commentary, promising areas of investigation have been suggested elsewhere.1,23
Acknowledgments
This work was supported in part by National Institutes of Health grant U10HD021373-22.
Funded by the National Institutes of Health (NIH).
ABBREVIATIONS
GAgestational age
BWbirth weight
NICHDEunice Kennedy Shriver National Institute of Child Health and Human Development
NRNNeonatal Research Network

Footnotes
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
Opinions expressed in this commentary are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.
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