The Limits of Viability: How Small Is Too Small? Istvan Seri M.D., Ph.D. USC Division of Neonatal Medicine Women’s and Children’s Hospital LAC/USC Medical Center and Children Hospital Los Angeles Keck School of Medicine University of Southern California Los Angeles, CA

The Limits of Viability: How Small Is Too Small? Gestational age at which a newborn had a 50% chance of survival 1960’s - 30-31 weeks 1980’s - 26-27 weeks 2000 - 24 weeks The issue of a limit of viability is not a static one of course and the gestational age at which a newborn had a 50% chance of survival has marched steadily downward from around 30 weeks in the 1960’s to around 27 weeks in the 1980’s to 24 weeks today.

The Limits of Viability: How Small Is Too Small? Unreasonable Mandatory Gray Zone Too small Too immature Too big Too mature So we can begin to think about a framework to guide appropriate level of intervention: On one side the group of infants who definitely have a reasonable chance of survival, where almost everyone would agree that aggressive mgmt is mandatory. On the other side infants who are so small and so immature that active intervention is considered futile…. And in between a gray zone where there is considerable controversy regarding appropriate intervention as the outcomes are very uncertain , Medical outcome for an individual infant impossible to determine in the gray zone Comfort Care Only Active Intervention ??? Intervention ???

Percent Survival by Gestational Age The Limits of Viability: How Small Is Too Small? Percent Survival by Gestational Age 23-62% Percent Survival by Gestational Age 0-55% With these caveats in mind we looked at USA/CDN studies from the 90’s using surfactant and you can see that survival is almost nil at < 22 wks, rising to 20% for 23 wks, and above 50% at 24 wks Can see range is large chreck the 22 wk survival Beginning to see an mandatory group, probably an unreasonable to intervene group with a gray zone somewhere here Hack, Seminars of Neonatology, 2000; 5 89-106 10 US, 4 Cdn, some multicenter and Lorenz Clinics in Perinatology 27, June 2000 centers with 0 survival at 23 weeks not aggressive, those with highest survival used admissions to NICU as denominator, not livebirths denominators n>1000 except for <23 weeks ;only 2 centers reported <40% survival at 24 weeks 26 weeks only had 6 studies but n=703 0-12%

Percent Survival by Birth Weight The Limits of Viability: How Small Is Too Small? Percent Survival by Birth Weight Percent Survival by Birth Weight 16-37% Hack, Semin Neonatol 2000:5:89-106; <500 gm n=663, survival at 4 centers 1%, 6%, 17%, 38%, most to discharge. Again can see probably unreasonable, mandatory Hack, Seminars of Perinatology, 2000 6 US centers 1990-1996 year of birth, n for <500=663, n for 501-600=1235, 601-700=1556 and 701-800=1478 1-38%

The Limits of Viability: How Small Is Too Small? Outcome of Neonates with Birth Weights of 401-500 g Gestational age = 23.3 ±2.1 weeks Number of Patients Hack, Semin Neonatol 2000:5:89-106; <500 gm n=663, survival at 4 centers 1%, 6%, 17%, 38%, most to discharge. Again can see probably unreasonable, mandatory Hack, Seminars of Perinatology, 2000 6 US centers 1990-1996 year of birth, n for <500=663, n for 501-600=1235, 601-700=1556 and 701-800=1478 Percent Lucey et al, Pediatrics 113:1559, 2004

The Limits of Viability: How Small Is Too Small? Outcome of Neonates with Birth Weights of 401-500 g Gestational age = 23.3 ±2.1 weeks Total Neonates Registered N = 4172 (100%) Died in Delivery Room N = 2186 (52%) Survived DR to NICU N = 1986 (48%) Hack, Semin Neonatol 2000:5:89-106; <500 gm n=663, survival at 4 centers 1%, 6%, 17%, 38%, most to discharge. Again can see probably unreasonable, mandatory Hack, Seminars of Perinatology, 2000 6 US centers 1990-1996 year of birth, n for <500=663, n for 501-600=1235, 601-700=1556 and 701-800=1478 Died in NICU N = 1253 (30%) Survived to NICU D/C N = 690 (17%) Survival Status Unknown N = 43 (1%) Gestational Age = 25.3 ±2 weeks Lucey et al, Pediatrics 113:1559, 2004

The Limits of Viability: How Small Is Too Small? Outcome of Neonates with Birth Weights of 401-500 g Gestational age = 23.3 ±2.1 weeks Compared to patients who died in the DR, neonates who survived to be admitted to the NICU were more likely to Be female (58% vs 49%) Be small for gestational age (56% vs 11%) Have received prenatal steroids (61% vs 12%) Have been delivered via cesarean section (55% vs 5%) Hack, Semin Neonatol 2000:5:89-106; <500 gm n=663, survival at 4 centers 1%, 6%, 17%, 38%, most to discharge. Again can see probably unreasonable, mandatory Hack, Seminars of Perinatology, 2000 6 US centers 1990-1996 year of birth, n for <500=663, n for 501-600=1235, 601-700=1556 and 701-800=1478 Lucey et al, Pediatrics 113:1559, 2004

The Limits of Viability: How Small Is Too Small? Percent Survival by Gestational Age and Birth Weight Birth weight and gestation work independently in predicting survivaL.Within a certain range, increasing birth weight at a given gestational age can have a profound effect on survival. % survival on the x axis and birth weight on the y axis, with green being 23 weekers, blue 24 and lavender 25 weeks, Survival rates for each gestational age increased quite dramatically with increasing birth weight, unless the infant was so large to be LGA as in these 24 wkers For instance the survival for a 23 wker weighing 600 gm was double that of one weighing 500 gm and the survival of a 24 wker weighing 700 gm was more than 3 x that of one weighing 500 gm. and you can see that in these extremely premature infants, survival doubles or more than doubles for a given gestational age when you move from 500 grams to 700 grams BW. BC Children’s and Grace maternity, 56- 23 wkers and 108- 24 wkers, 160 25 wkers1983-89. …So that’s mortality data, but what about morbidity – reasonable quality of life is maybe even more important than survival.For QOL indicators, we usually look at neurodevelopmental outcome. Synnes et al, 1994

The Limits of Viability: How Small Is Too Small? Burdens of Prolonging Support in Infants at the Limits of Viability % Hack and Fanaroff (NEJM, 1989); infants born 82-87; altho aggressive therapy did not improve survival in infants with BW<750 gm, it did increase mean age of death from 72-880 hours

The Limits of Viability: How Small Is Too Small? Infants born <23 weeks too immature to survive Comfort care only

The Limits of Viability: How Small Is Too Small? Effect of Fetal Compromise on Survival Certain infants in any age or weight group usually have a better chance of survival than others, and this is very true in infants born at the limits of viability. some of these factors can even be determined antenatally. Fetal compromise included : major congenital anomaly, congenital sepsis, chronic intrauterine infection, intrauterine drug exposure, congenital anemia, severe IUGR, significant fetal distress, cardiorespiratory and neurologic depression at delivery gan, - information such as this has led neonatologists toward providing limited pulmonary, but not full cardiopulmonary resuscitation for depressed ELBW infants in the DR 142 babies born between 1990-1995,William Beaumont Hospital, Mich Concern about self fulfilling prophesy if reluctance to resuscitate if presence of these factors Batton et al, 1998

The Limits of Viability: How Small Is Too Small? Gestational Age-Dependent Mortality (1991-1999) Pediatrics 110:143, 2002 Vermont-Oxford Network (362 Institutions)

The Limits of Viability: How Small Is Too Small? Birth Weight-Specific Survival of VLBW Neonates (1977-2000) Parkland Memorial Hospital, Dallas, TX Kaiser et al, J Perinatol 24:343, 2004

Decision-Making at the Threshold of Infant Viability Estimating Survival & Intact Survival GA BW Survival Intact Survival* (weeks) (g) ( % ) ( % ) 23 600 50 % 25 % 24 700 70 % 70 % 25 800 80 % 80 % 26 900 90 % 70 % 27 1000 95 % 80 % * Among Survivors

The Limits of Viability: How Small Is Too Small? Infants born >25 weeks are mature enough Full support warranted

The Limits of Viability: How Small Is Too Small? Target range for “Gray Zone” based on survival: 23-24 6/7th weeks and 500-600 g What are the complications and outcome data of premature neonates in the “Gray Zone”?

The Limits of Viability: How Small Is Too Small? Percent Severe Head Ultrasound Abnormalities by Gestational Age % Most authors included Grade 3-4 IVH or major PVL Although there are wide ranges in incidence, most authors report a moderate to marked decreased incidence in severe brain injury from 23 to 25 wks N’s in the 23 week gestation group were very small: 5-10 Hussain did not look at PVL, Cooke used only intraparenchymal lesions, ie Grade IV or PVL

The Limits of Viability: How Small Is Too Small? Percent Chronic Lung Disease at 36 weeks by Gestational Age at Birth % The association with CLD and gestational age is a little more convincing, with virtually all studies showing a stepwise decrease with increasing gest age

The Limits of Viability: How Small Is Too Small? Percent Survival and Intact Survival by Gestational Age % 5 year outcome, Regional study Australia, 401 liveborn infants 1991 to 1993; not all offered intensive care; ?selectively intervene in youngest infants who are vigorous and in good condition, will have fewer survivors but majority will have intact survival Doyle et al Pediatrics, 2001

Bottoms et al, NICHD Network, 1997 The Limits of Viability: How Small Is Too Small? Percent Survival and Intact Survival by Birth Weight % Included only infants in which there was active managemnet of labor; intact survival meant no ROP stage 3 or 4, no IVH >stage 2, no seizures, no surgical NEC, no oxygen dependence at 120 days or discharge Bottoms et al, NICHD Network, 1997

The Limits of Viability Impact of BPD, Brain Injury and ROP on 18-Month Outcome of ELBW Infants Outcome Variable Odds Ratio 95 % CI BPD 2.4 1.8 – 3.2 Brain Injury 3.7 2.6 – 5.3 Severe ROP 3.1 1.9 – 5.0 These 3 common neonatal morbidities strongly predict the risk of later death or disability Schmidt et al: JAMA 289:1121, 2003

The Limits of Viability Impact of BPD, Brain Injury and ROP on 18-Month Outcome of ELBW Infants Overall probability of poor outcome at 18 m (35%) These 3 common neonatal morbidities strongly predict the risk of later death or disability Schmidt et al: JAMA 289:1121, 2003

The Limits of Viability Pulmonary Outcome VON 2000

The Limits of Viability IVH and PVL: Incidence by Birth Weight VON 2000

The Limits of Viability Sequelae of Prematurity (1) Place of Birth and Mortality in Canadian NICUs Number of NICU Admits 17 NICUs Admits = 19,265 Period = 1996-97 Health care personnel’s view were extremely out of line compared with views of teens and their parents Denial? Or focusing on the positive aspects of an imperfect QL and deriving high satisfaction from own life Adult data matches this data and suggests strong coping mechanisms for those with disabilities Birth Weight (kg) Sankaran K et al; CMAJ 166:173-8, 2002

The Limits of Viability Sequelae of Prematurity (2) Place of Birth and Mortality in Canadian NICUs Health care personnel’s view were extremely out of line compared with views of teens and their parents Denial? Or focusing on the positive aspects of an imperfect QL and deriving high satisfaction from own life Adult data matches this data and suggests strong coping mechanisms for those with disabilities Sankaran K et al; CMAJ 166:173-8, 2002

The Limits of Viability Sequelae of Prematurity (3) Place of Birth and Mortality in Canadian NICUs Health care personnel’s view were extremely out of line compared with views of teens and their parents Denial? Or focusing on the positive aspects of an imperfect QL and deriving high satisfaction from own life Adult data matches this data and suggests strong coping mechanisms for those with disabilities Sankaran K et al; CMAJ 166:173-8, 2002

The Limits of Viability Place of Birth and Mortality in Infants with Birth Weight of 500-1499 g Non-SPC SPC* Death (%) 16.9 14.3 BPD (%) 20.1 17.5 IVH-III-IV 15 8.4 ROP (Treated) 5.6 4.8 NEC 6.1 7.2 * SPC=Subspecialty Perinatal Center Warner et al; Pediatrics 2004; 113:35-41

The Limits of Viability Survival and 2-year Outcome in Infants <27 wks (1996-1997) Gestational Age (weeks) Adverse Outcome (Died or abnormal at 2 years) 23 – 24 92% 25 64% 26 35% 27 – 32 18% Rijken et al; Pediatrics 2003; 112:351-58

Gestational Age (weeks) The Limits of Viability Survival and Outcome of ELBW infants born at 23-26 weeks (1986-2000) Gestational Age (weeks) Survival (%) % Normal at 47.5 months (n=675) % Normal at 8 years (n=147) 23 66 52 33 24 81 59 55 25 85 67 26 93 65 Hoekstra et al; Pediatrics 2004; 113:e1-e6

The Limits of Viability Factors Affecting Outcome of ELBW infants at 47.5 Months of Age (1986-2000) Hoekstra et al; Pediatrics 2004; 113:e1-e6

Problems with predicting long-term outcome The Limits of Viability: How Small Is Too Small? Problems with predicting long-term outcome Adverse medium-term neurodevelopmental outcomes in ELBW infants correlate with severe brain injury, CLD, NEC, steroid use for CLD, male gender (Vohr et al, 1999) However, long-term neurodevelopmental outcomes do not correlate well with these predictors and maternal education and home environment are more important than all other factors except severe brain injury

Outcome of ELBW Infants - NICHD American Experience The Limits of Viability: How Small Is Too Small? Outcome of ELBW Infants - NICHD American Experience Patient population of 1126 infants (BW = 501 - 800 g) Females have a survival advantage of 90 g SGA neonates had a survival advantage of 57 g Antenatal steroids confer a survival advantage of 67 g Tyson et al JAMA 1996; 276:1645

Odds of Survival between 23 and 246/7 weeks The Limits of Viability: How Small Is Too Small? Odds of Survival between 23 and 246/7 weeks Chance of survival improves by 2% a day during 23 to 26 weeks gestational age Overall, 50% survive and 50% of the survivors are handicapped (the “50 - 50” rule)

The Limits of Viability: How Small Is Too Small? The Gray Zone: 23 - 24 6/7 weeks gestation and 500 - 600 grams Recent survival data (especially on non-compromised ELBW neonates) Lower incidence of severe ROP, CLD and/or severe head ultrasound abnormalities Overall “intact” survival has increased from <10% to > 40% Outcome still very uncertain for individual patient especially at 23 weeks gestational age

Three approaches to care The Limits of Viability Decision Making at The Threshold of Infant Viability Three approaches to care Wait Until Certainty Approach Treatment begins on every infant thought to have any chance of survival, wait until all information is in before deciding whether continuing care is the right decision (eg: USA) Statistical Approach Determine categories of patients in which treatment may be limited or withheld (eg: Sweden) Individualized Approach (eg: UK) Ststistical approach - neonatology in Sweden eg all infants <24 weeks, <500 gm Clin Perinatol, 1996

The Limits of Viability: Decision-Tree Unreasonable Mandatory Gray Zone 23-24 6/7 wks and 500-600 g <23 wks 25 wks Comfort Care Only Full Critical Care Parents indicate definite wishes for non-active intervention (importance of counseling regarding impact of initial condition/perinatal stress on outcome) Requires much discussion, probably on multiple occasions in order to work well; if desire active intervention in gray zone, need to discuss limits if poor response; if desire non-active intervention, may want to discuss situations that might warrant active intervention. Parents need to understand situation chnages rapidly with time and increased age Parents desire active intervention or defer to medical judgement Follow parents wishes, unless evidence parents not working in best interest of the baby Extent of active intervention based on condition and response

Decision-Making at the Threshold of Infant Viability  500g* or < 23wk Gray Zone 23 - 246/7 wk and 500 - 599g  600g or  25wks No resuscitation Initiate comfort care measures Initiate resuscitation Clinical course will dictate management Heart rate Present >40-50 Bag/Intubate Low or Absent HR = 60 - 100/min HR > 100/min Give surfactant; insert lines; check ABG; start fluids Can’t intubate or poor response (HR < 60/min for 5mins) Consider brief CPR, drugs and bolus fluids x1 good response Poor response At end say: For all these infants, in the gray zone, if parents request no intervention, that should be honored. Otherwise an investigational approach is used, allowing the infant to receive active vs comfort care intervention based on clinical presentation and response to intervention Transfer to NICU Discontinue interventions & initiate comfort care measures Parents desire active management carry on, set limits NICU Care Ongoing evaluation Poor clinical status * The occasional infant <500g BW (usually IUGR), who is vigorous at birth may warrant active intervention

Decision-Making at the Threshold of Infant Viability The algorithm assumes appropriate antenatal counseling Gestational age should be determined antenatally Birth weight must be obtained at the time of delivery At each stage of resuscitation, the prognosis for reasonable outcome should be reevaluated Parental wishes regarding extent of intervention in the gray zone should be honored until parents except their baby’s fate At end say: For all these infants, in the gray zone, if parents request no intervention, that should be honored, providing they are acting in best interest of baby. Otherwise an investigational approach is used, allowing the infant to receive active vs comfort care intervention based on clinical presentation and response to intervention

Decision-Making at the Threshold of Infant Viability Relative weighting of parental, clinician and societal views of active intervention with increasing gestational age Relative Weighting 22 23 24 25 26 27 28 Gestational Age at Birth Parents Clinicians Society

Limits of Viability Questions?