Original Article
The Limit of Viability -- Neonatal Outcome of Infants Born at 22 to 25 Weeks' Gestation
N Engl J Med 1993; 329:1597-1601November 25, 1993
- Abstract
Background
With improved survival of preterm infants, questions have been raised about the limit of viability. To provide better information and counseling for parents of infants about to be delivered after 22 to 25 weeks' gestation, we evaluated the mortality and neonatal morbidity of preterm infants born at these gestational ages.
Methods
We studied retrospectively all 142 infants born at 22 to 25 weeks' gestation (as judged by best obstetrical estimate) from May 1988 through September 1991 in a single hospital. Mortality in the first six months, including stillbirths, and neonatal morbidity (i.e., the presence of intracranial pathologic conditions, chronic lung disease, and retinopathy of prematurity) were analyzed.
Results
Fifty-six infants (39 percent) survived for six months. Survival improved with increasing gestational age; none of 29 infants born at 22 weeks' gestation survived, as compared with 6 of 40 (15 percent) born at 23 weeks, 19 of 34 (56 percent) born at 24 weeks, and 31 of 39 (79 percent) born at 25 weeks. There were seven stillbirths at 22 weeks' gestation and four stillbirths at 23 weeks. The more immature the infant, the higher the incidence of neonatal complications as determined by the number of days of mechanical ventilation, the length of the hospital stay, and the presence of retinopathy of prematurity, periventricular or intraventricular hemorrhage, or periventricular leukomalacia. Only 2 percent of infants born at 23 weeks' gestation survived without severe abnormalities on cranial ultrasonography, as compared with 21 percent of those born at 24 weeks and 69 percent of those born at 25 weeks.
Conclusions
We believe that aggressive resuscitation of infants born at 25 weeks' gestation is indicated, but not of those born at 22 weeks. Whether the occasional child who is born at 23 or 24 weeks' gestation and does well justifies the considerable mortality and morbidity of the majority is a question that should be discussed by parents, health care providers, and society.
Media in This Article
Figure 1
Survival of Infants Born at 22 to 25 Weeks' Gestation, According to Gestational Age.Figure 2
Six-Month Outcomes in Infants Born at 22 to 25 Weeks' Gestation.Article Activity
- Article
Improved obstetric and neonatal interventions and aggressive techniques of resuscitation have gradually improved the survival of preterm infants and lowered the limit of viability1-10. Although the prophylactic administration of surfactant has further improved the survival of extremely-low-birth-weight infants, its effect on morbidity is unclear,11-14 and the quality of life of the survivors remains a concern.
These developments have created a new difficulty in counseling obstetricians and the parents of infants about to be born at the limit of viability. Options for delivery and resuscitation need to be weighed against the infant's chance of survival and normal life. Current efforts to resuscitate extremely preterm infants aggressively and administer surfactant to them in the delivery room raise the question, What is the limit of viability?
Most studies of mortality and outcome in preterm infants are based on birth weight,1-4,7-10 an objective, reliable criterion. Data based on birth weight are very useful in discussing the treatment and follow-up care of preterm infants with parents and colleagues in a neonatal intensive care unit. Clinical and ultrasonographic estimates of fetal weight are often inaccurate, however, making it difficult to translate data based on birth weight into information that will be helpful in prenatal counseling with parents.
In this study we sought to obtain more accurate information on both survival and neonatal morbidity in preterm infants born at the limit of viability who routinely received surfactant in our institution. We chose infants born at 22 to 25 weeks' gestation in order to include those born 1 week before and 1 week after the limit of viability suggested in the current literature (23 or 24 weeks)1-10. We evaluated all infants born at each week of gestational age, including those stillborn, determining gestational age on the basis of the best obstetrical estimate. Because the incidence of major handicap (cerebral palsy or mental retardation) is 50 to 100 percent in preterm infants with severe grade 3 or 4 intraventricular hemorrhage or periventricular leukomalacia,15-21 we focused on the combination of these neonatal morbid conditions as a primary outcome measure, referring to it as severe abnormality on cranial ultrasonography.
Methods
We retrospectively studied all 142 infants born at 22 or 25 weeks' gestation between May 26, 1988, when routine prophylactic administration of calf-lung surfactant extract (Infasurf) was begun, and September 3, 1991, when a new surfactant protocol was instituted at our hospital. Gestational age at delivery was estimated on the basis of the date of the most recent menstrual period, ultrasonography of the fetus, and physical examination of the neonate, because at this age there are no good postnatal measures of gestational age22,23.
During this period, there were no specific protocols in our hospital for the care of fetuses or infants born at the limit of viability. In general, the obstetricians and neonatologists consulted with each other and with the families about the timing and mode of delivery and the care of the infant in the delivery room. Because of the risk to the mother and concern about the infant's survival, the obstetricians tried to avoid performing cesarean section at 22 to 24 weeks' gestation.
A neonatologist attended each delivery whenever possible and determined whether the neonate was viable and how aggressive resuscitation should be. No resuscitation was given if the infant was stillborn. In general, if the infant was initially vigorous, he or she underwent intubation, was given surfactant, and was taken immediately to the neonatal intensive care unit. If the infant had poor respiratory effort or a low heart rate at birth, our general practice was to attempt resuscitation with bag-and-mask ventilation; if there was a response, the infant underwent intubation and was given surfactant. There was no prolonged resuscitation of infants who did not respond.
The mortality rate we used differs from traditional calculations of mortality in that we included stillbirths, so that the results would be applicable to the labor and delivery room as well as to the neonatal intensive care unit. Because we sought the most realistic assessment of mortality, we included deaths occurring up to six months after birth. The survival rate was defined as the number of infants born at a given gestational age who survived six months from birth, divided by the number of infants born at that gestational age, including stillborn infants.
Mortality was determined from a computerized data base in the neonatal intensive care unit, the obstetrical logbook, the pathology logbook, and the follow-up clinic records. Age at death was also recorded. The time of fetal death in utero was generally not discernible, however, because most parents and obstetricians chose not to monitor a fetus if no intervention was planned. Because no infant born at 22 weeks of gestation survived, these data are included only in the mortality data.
Cranial ultrasonography was performed in surviving infants at least three times: 3 to 7 days after birth, at 10 to 14 days, and again at 6 weeks or at the time a term delivery would have occurred. The images were analyzed by ultrasonographers who were unaware, for the most part, of the infants' clinical status. The Papile grading system was used to grade periventricular or intraventricular hemorrhages on a scale from 1 to 424. Periventricular leukomalacia was defined as any cyst formation observed at any time (excluding periventricular echodensities that subsequently disappeared). We defined poor outcome on the basis of the percentage of all infants born at a given gestational age, including those stillborn, who died or in whom severe abnormalities developed that were detected on cranial ultrasonography, either grade 3 or 4 intraventricular hemorrhage or periventricular leukomalacia.
Other indicators of neonatal morbidity included measures of chronic lung disease (i.e., the duration of mechanical ventilation or supplemental oxygen therapy), postmenstrual age (calculated as the infant's gestational age at birth plus the chronologic age) at the discontinuation of oxygen therapy, the length of the hospital stay, and the presence of retinopathy of prematurity. All the surviving infants were examined in the neonatal intensive care unit by an ophthalmologist skilled at diagnosing retinopathy of prematurity. This condition was scored as present if there was active disease (stage 2, 3, or 3+). The administration of cryotherapy treatment to either eye was also recorded.
Mortality, including the incidence of stillbirths, was analyzed in the overall group and according to gestational age. Morbidity was analyzed in surviving infants according to gestational age. The effect of various maternal and perinatal factors and of sex and race on mortality and perinatal outcomes (poor vs. good) was evaluated by logistic-regression analysis. Differences in morbidity between gestational-age groups were investigated with a one-way analysis of variance using the Student-Newman-Keuls comparison.
Results
Mortality Including Stillbirths
Among the 142 infants born at 22 to 25 weeks' gestation according to the best obstetrical estimate, 80 (56 percent) survived long enough (at least 30 minutes) to be admitted to the neonatal intensive care unit, and 56 (39 percent) survived for at least 6 months. Both mortality and the proportion of infants who died in the delivery room decreased with increasing gestational age (Figure 1Figure 1
Survival of Infants Born at 22 to 25 Weeks' Gestation, According to Gestational Age.). Of 29 infants born at 22 weeks, including 7 stillborn, none survived for 6 months. Survival improved to 15 percent (6 of 40 infants, including 4 stillborn) at 23 weeks' gestation, to 56 percent (19 of 34 infants) at 24 weeks, and to 80 percent (31 of 39 infants) at 25 weeks. There were no stillbirths at 24 or 25 weeks of gestation.Demographic Characteristics
The mean (±SD) birth weight of the stillborn infants was 459 ±81 g (range, 405 to 690). The mean birth weight of the 80 infants admitted to the neonatal intensive care unit was 703 ±121 g. The mean birth weight of the 56 infants who lived six months was 724 ±112 g. More girls lived at least six months (32 of 39, or 82 percent) than did boys (24 of 41, or 59 percent; P = 0.02). Table 1Table 1
Demographic Characteristics of Infants Admitted to the Neonatal Intensive Care Unit. shows the birth weight, sex, race, and maternal socioeconomic status of the 80 infants who were admitted to the neonatal intensive care unit. When the best obstetrical estimates were used, with an extension of the standard curve for intrauterine growth, only three infants were small for their gestational ages; all three were born at 25 weeks' gestation, and two survived for 6 months.Only 23 to 28 percent of the infants admitted to the neonatal intensive care unit in a given gestational-age group were white. Two infants were Hispanic, and one was Asian. For purposes of analysis, these three infants were grouped with the black infants. All three infants born at 22 weeks' gestation who underwent successful resuscitation in the delivery room were black.
Morbidity and Length of Stay
The infants born at each gestational age who survived for six months were compared by an analysis of variance in which the variables were the number of days of mechanical ventilation, the number of days of supplemental oxygen administration, the infant's postmenstrual age at the discontinuation of oxygen, and the length of the hospital stay (Table 2Table 2
Outcomes in Infants Born at 23 to 25 Weeks' Gestation Who Survived for 6 Months.). The only significant differences were those between the infants born at 23 to 24 weeks of gestation and the infants born at 25 weeks.Active retinopathy of prematurity (stage 2, 3, or 3+) occurred in five of the six surviving infants born at 23 weeks' gestation (83 percent), 53 percent of those born at 24 weeks, and 32 percent of those born at 25 weeks (Table 2).
The incidence of periventricular or intraventricular hemorrhage and periventricular leukomalacia decreased with increasing gestational age (Table 2). One of 6 survivors born at 23 weeks of gestation, 5 of 19 infants born at 24 weeks (26 percent), and 20 of 31 infants born at 25 weeks (65 percent) had normal cranial ultrasonograms.
The proportion of infants who died or had severe abnormalities on cranial ultrasonography at each gestational age is shown in Figure 2Figure 2
Six-Month Outcomes in Infants Born at 22 to 25 Weeks' Gestation.. The majority of infants born at 23 or 24 weeks' gestation (98 percent and 79 percent, respectively) had poor outcomes (they either died or had severe intracranial abnormalities). In contrast, less than one third (31 percent) of those born at 25 weeks' gestation had poor outcomes.Relation between Perinatal Variables and Outcome
In a logistic-regression analysis in which mortality was used as the dependent variable, the following perinatal variables were evaluated: birth weight (≤ 600 vs. >600 g), gestational age (≤ 24 weeks vs. >24 weeks), sex, race, mode of delivery (vaginal vs. cesarean), and the presence or absence of antepartum hemorrhage, fetal distress, illicit drug use by the mother, and chorioamnionitis. Only birth weight of 600 g or less (P<0.001) and male sex (P = 0.02) were significantly related to increased mortality. When poor outcome was used as the dependent variable in a similar analysis with the same perinatal variables, only gestational age of 24 weeks or less (P = 0.03) and male sex (P = 0.005) were significantly related to poor outcome.
Discussion
Our results suggest that the limit of viability in the era of routine use of surfactants is 23 to 24 weeks of gestation. The survival rate reported here is slightly better than the rate before surfactant was routinely used: 15 percent as compared with 3 to 8 percent in infants born at 23 weeks, and 56 percent as compared with 4 to 31 percent in those born at 24 weeks7. Since few studies have included stillbirths in their analysis, this improvement in survival is a conservative estimate. Data from our hospital suggest that survival at the limit of viability has improved since the introduction of surfactant, as compared with historical controls25. However, other changes in obstetrical and neonatal management may have contributed to the improved survival.
Occasional survivors born at 22 weeks' gestation have been reported7. Despite our initial resuscitation of three infants born at 22 weeks' gestation who appeared to be viable (i.e., there was a heart rate and respiratory effort at birth), all died by 4 months of age. The frequency of late deaths was similar to that previously reported. Hack and Fanaroff7 found that aggressive treatment (such as delivery by cesarean section or the use of intubation) of infants with birth weights below 750 g did not change neonatal mortality but only increased the mean age at death from 73 to 880 hours. Although an argument can be made in favor of keeping an infant alive long enough for the parents to say goodbye, deliberately prolonging death beyond a few hours is difficult to justify. Prolonging death means prolonging suffering, not only for the infant, but also for the family and the members of the staff.
In defining a poor outcome as death or the presence of a severe abnormality on cranial ultrasonography, we attempted to provide parents and obstetricians with more informative data than would be gained merely from studying mortality rates for each gestational age. Because the long-term developmental outcome of these infants is not known, we evaluated predictors of outcome (i.e., measures of chronic lung disease, retinopathy of prematurity, and intracranial pathology). As expected, these neonatal conditions were frequent, especially in the most immature infants. The mean duration of mechanical ventilation and the mean length of the hospital stay compared favorably with the data reported by Nwaesei et al.5 in infants born before 27 weeks' gestation, who received 50 days of mechanical ventilation and who stayed 135 days in the hospital.
Because the incidence of major handicapping conditions is high (50 to 100 percent) in infants with severe abnormalities on cranial ultrasonography,15-21 we think our measure of poor outcome was appropriate. If we assume instead that disability would develop in 60 percent of infants with severe ultrasonographic abnormalities, the results would still be discouraging: 93 percent of infants born at 23 weeks of gestation, 67 percent of those born at 24 weeks, and 26 percent of those born at 25 weeks would have poor outcomes.
In decisions about aggressive resuscitation for infants born at 23 or 24 weeks of gestation, how much weight should the possibility of a good outcome carry? During prenatal discussions of cesarean section, resuscitation, and surfactant administration, parents deeply committed to having children frequently hold onto even a small possibility of a good outcome. Parents are important partners in the decision-making process, but these discussions are difficult in the delivery room.
These and other data suggest that we should define a limit of viability, but is it enough to use criteria based on gestational age, birth weight, or both? Should other factors, such as the parents' desires and history of fertility, the method of payment, the infant's sex, the response to resuscitation, and the findings on cranial ultrasonography, also be considered? Concern about limited health care resources necessitates opening discussions about who should receive intensive care and how these decisions should be made.
Supported by the Thomas Wilson Sanitarium for the Children of Baltimore City.
We are indebted to M. Douglas Jones, Jr., M.D., for his support.
Source Information
From the Department of Pediatrics, Johns Hopkins University School of Medicine (M.C.A., P.K.D.), and the Department of Pediatric Nursing, Johns Hopkins Hospital (A.E.D.), both in Baltimore.
Address reprint requests to Dr. Allen at the Johns Hopkins Hospital, CMSC 210, 601 N. Wolfe St., Baltimore, MD 21287-3200.
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