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Mehler K, Oberthuer A, Keller T, et al. Survival Among Infants Born at 22 or 23 Weeks’ Gestation Following Active Prenatal and Postnatal Care. JAMA Pediatr. 2016;170(7):671–677. doi:10.1001/jamapediatrics.2016.0207
Can active care improve survival without morbidity for infants born at the border of viability?
In this study of 106 infants born at 22 or 23 weeks of gestation, 86 infants (81%) received active care. Of the infants who received active care, 22 (26%) survived without severe complications.
These results should be considered for individualized parental approaches and decision making.
Rates of survival for infants born at the border of viability are still low and vary considerably among neonatal intensive care units.
To determine whether higher survival rates and better short-term outcomes for infants born at 22 or 23 weeks’ gestation may be achieved by active prenatal and postnatal care.
Design, Setting, and Participants
Retrospective study of 106 infants born at 22 or 23 weeks of gestation at a level III neonatal intensive care unit at the University of Cologne Medical Centre in Cologne, Germany, between January 1, 2010, and December 31, 2014. Data analysis was performed in June 2015.
Active prenatal and postnatal care.
Main Outcomes and Measures
Survival until hospital discharge and survival without neonatal or short-term severe complications (defined as high-grade intraventricular hemorrhage, surgery for abdominal complications, bronchopulmonary dysplasia, or retinopathy of prematurity).
Of 106 liveborn infants (45 born at 22 weeks and 61 born at 23 weeks and 6 days), 20 (19%) received palliative care (17 born at 22 weeks and 3 born at 23 weeks), and 86 (81%) received active care (28 born at 22 weeks and 58 born at 23 weeks). Of the 86 infants who received active care (mean [SD] maternal age, 32  years), 58 (67%) survived until hospital discharge (17 born at 22 weeks and 41 born at 23 weeks). Twenty-two infants survived without severe complications, with 1 infant born at 22 weeks excluded because of missing data (6 of 27 [22%] born at 22 weeks, and 16 of 58 [28%] born at 23 weeks). Survival was predicted by the Apgar score after 5 minutes (odds ratio, 0.62 [95% CI, 0.46-0.84]) and birth weight (odds ratio, 0.001 [95% CI, 0.00-0.40]).
Conclusions and Relevance
One in 4 infants born at the border of viability and offered active care survived without severe complications. This finding should be considered for individualized parental approaches and decision making. Active follow-up information is required to determine childhood outcomes.
Active resuscitation of infants born at 22 or 23 weeks of gestation is a matter of intense debate. Some neonatal intensive care units (NICUs) are presently changing their policies and offering treatment to these preterm infants born at the border of viability,1 whereas other NICUs are now withholding treatment that they offered 10 years ago.2 This contrast is highlighted by a recent study by Rysavy et al,3 in which interquartile ranges for active treatment of infants born at 22 weeks of gestation were 8% to 100% within 24 hospitals in the United States. Either approach, active care or withholding treatment, may be justified in view of the recommendations of the American Academy of Pediatrics and the American Congress of Obstetricians and Gynecologists, both which advocate that clinicians and families should make individualized decisions about treating extremely preterm infants on the basis of parental preference and the most recent data available regarding survival and morbidity.4,5 Yet, the lack of valid data on short- and long-term outcomes6 and the conflicting results of current reports with largely varying outcomes pose a huge problem to physicians who are counseling parents at 22 to 24 weeks’ gestation. Much of the variation in survival rates reflects national or local policy, or nonactive intervention, thus making the data limited but suitable for family-centered, individualized decisions.
While a review on outcome data from 1995 to 2007 reported survival rates without severe neurodevelopmental impairment of just 2% of infants born at 22 weeks of gestation,7 the more recent report from the US Neonatal Research Network showed improving survival rates without (or with minimal) neurodevelopmental impairment for 9% of infants born at 22 weeks’ gestation and 16% of infants born at 23 weeks’ gestation.3 Similarly, a study from the Japanese Neonatal Research Network showed survival rates without neurodevelopmental impairment of 12% for infants born at 22 weeks’ gestation and 20% for infants born at 23 weeks’ gestation.6 In contrast to these encouraging data, 2 large population-based cohort studies (the EPICure study in England8 and the EPIPAGE-2 [Etude Epidémiologique sur les Petits Ages Gestationnels 2] study in France9) recently reported rates of survival of only 0% and 2%, respectively, for infants born at 22 weeks of gestation, but active treatment was offered only to a minimal fraction of liveborn infants in both countries. Still, comparing the outcome data on extremely immature infants who receive active care is difficult because studies differ widely in terms of patient cohorts, patterns of prenatal care, and gestational ages included.10
In our level 3 NICU, we offer active care to infants from 22 weeks of gestation at parental request after intensive counseling. Our approach comprises several measures aimed at assisting preterm infants in their transition to extrauterine life without invasive mechanical ventilation.11 Short- and long-term follow-up data on infants treated using our approach from 2001 to 2007 was recently published, and the results were encouraging.11,12 The aim of this retrospective study was to analyze the neonatal outcomes of infants born at 22 or 23 weeks of gestation in the past 5 years (2010-2014) using an active prenatal and postnatal approach and to compare these data with the literature.
Our study included data collected retrospectively from our database. We included all infants born at 22 or 23 weeks of gestation in the Department of Gynecology and Obstetrics, University of Cologne Medical Centre, Cologne, Germany, from January 1, 2010, to December 31, 2014. We included liveborn and stillborn infants but excluded terminations of pregnancy and infants born at another hospital and transferred to the University of Cologne Medical Centre after birth, and we referred to our department at a later point for a specific treatment (eg, ligation of patent duct or laser therapy for retinopathy). Gestational age was determined based on the last menstrual period of the mother, with confirmation and correction determined by a first-trimester ultrasonographic examination. Parents were routinely informed about mortality and morbidity rates by an experienced neonatologist, who also took the individual situations into account. If the parents decided on palliative care, then the attendance of a neonatologist at birth was provided at the parents’ request. The local ethics committee (University of Cologne, Germany) approved of the study, and parents provided written informed consent for the retrospective use of the data.
If parents decided on active care for their infant, then a bundle of procedures to optimize prenatal and postnatal management was initiated. The key points of our approach are summarized in the Box. The primary aim of our protocol is the avoidance of invasive positive-pressure ventilation in the first 72 hours of life. This is achieved by the strict use of continuous positive airway pressure (CPAP) to establish spontaneous breathing in the delivery room and a less invasive surfactant application (LISA) via the use of a thin endotracheal catheter during CPAP-assisted spontaneous breathing. Infants are eligible for LISA if they are breathing, if their heart rate is greater than 120 beats per minute, and if their oxygen saturation is greater than 85%. Therefore, eligibility for LISA is actually also a test of the infant’s condition after initial stabilization.
Use of prenatal steroids after parental counseling from 22 weeks of gestation
Cesarean delivery with local anesthesia as preferred mode of delivery
Delayed cord clamping
Comfort positioning (lateral) of the infant
Establishment of spontaneous breathing via a stepwise increase in positive end-expiratory pressure
Less invasive surfactant application
This LISA approach is described in detail elsewhere.11 In addition, after parental counseling, we use prenatal steroids from 22 weeks of gestation on, we perform delayed cord clamping, and we position the infant in the lateral (comfort) position. We found cesarean delivery during local anesthesia to be the preferred mode of delivery, even after taking into account the higher rate of maternal complications compared with vaginal delivery.
In the case of severe neonatal complications (eg, severe grade 4 intraventricular hemorrhage or multiple neonatal adverse events putting the infants at a high risk for severe developmental delay), parents were offered to switch to palliative care. Prenatal steroid use was defined as the administration of at least 1 dose of betamethasone sodium phosphate or dexamethasone sodium phosphate for the mother. Bronchopulmonary dysplasia was defined as the need for CPAP, ventilation, or oxygen at 36 weeks according to Walsh et al.13 Intraventricular hemorrhage was reported according to the classification of Papile et al.14 Retinopathy of prematurity was graded in accordance with the International Classification of Prematurity.15
The primary outcome was survival until hospital discharge. The secondary outcome was survival until hospital discharge without severe complications, which was defined as survival without intraventricular hemorrhage greater than grade 2, bronchopulmonary dysplasia, surgery for necrotizing enterocolitis or focal intestinal perforation, or laser therapy or intravitreal anti–vascular endothelial growth factor treatment for retinopathy of prematurity.
Neurodevelopmental testing at 24 months’ corrected age is mandatory in Germany for all preterm infants weighing less than 1500 g, and either the Bayley Scales of Infant Development16 or the Bayley Scales of Infant and Toddler Development17 is used for testing. Because the scores of both Bayley editions cannot be equated, we chose to use the developmental quotient (DQ) to evaluate developmental delay. The DQ was calculated by dividing developmental age by chronological age (corrected for prematurity) and multiplying by 100. A DQ between 85 and 100 indicated normal development, a DQ between 70 and 85 indicated minor developmental delay, and a DQ of less than 70 indicated severe developmental delay.
Statistical analysis was performed using IBM SPSS Statistics 23 for Windows (SPSS Inc). Variables are described as median (IQR), mean (SD), or absolute and relative frequency. Differences between groups were compared by use of the t test for normally distributed data, the Mann-Whitney U test for other metric data, or the exact Fisher test for categories. In addition, for outcomes, 95% CIs were calculated. Binary logistic regression analyses were performed to determine factors influencing survival. Initially, we included in the regression model all significant factors from univariate analysis and added variables known to be important predictors for survival. The final model was reached by backward selection, including factors with P < .05. Adjusted odds ratios (with 95% CIs) for the final regression model were calculated. A 2-sided P < .05 was defined as statistically significant. All analyses were regarded as explorative, and P values were not adjusted for multiple testing.
Our study included 45 infants born at 22 weeks of gestation and 61 infants born at 23 weeks of gestation. Two additional infants born at 22 weeks were stillborn, presenting with an Apgar score of 0 at 1 minute. Palliative care was initiated for 17 of 45 infants born at 22 weeks (38%) and for 3 of 61 infants born at 23 weeks (5%), of whom 2 presented with a birth weight of less than 200 g. Infants who received palliative care were slightly more immature (mean [SD] age, 22 weeks and 3  days) than infants who received active prenatal and postnatal care (mean [SD] age, 22 weeks and 4  days) (P = .02). There were no significant differences in mean (SD) maternal age (31  vs 31  years), mean (SD) birth weight (450  vs 468  g), and percentage of multiple births (47% [8 of 17] vs 46% [13 of 28]) between infants who received palliative care and those who received active care. Infants who received active care were more likely than infants who received palliative care to have had an assisted pregnancy (eg, in vitro fertilization or artificial insemination; 36% [10 of 28] vs 6% [1 of 17]; P = .03). As expected infants who received palliative care received fewer prenatal steroids compared with infants who received active care (29% [5 of 17] vs 93% [26 of 28]; P < .001). Steroid treatment was not continued or initiated after the parents decided on palliative care. Taken together, active care was offered to 28 of 45 infants born at 22 weeks of gestation (62%) and 58 of 61 infants born at 23 weeks of gestation (95%) (Figure). All infants who received active care were admitted to the NICU, and none died in the delivery room.
In total, 58 of 86 infants (67%) who received active prenatal and postnatal care survived until hospital discharge. The survival rate was 61% (17 of 28) for infants born at 22 weeks of gestation and 71% (41 of 58) for infants born at 23 weeks of gestation. Deaths occurred mainly because of either respiratory failure (12 of 25 infants [48%]) or multiorgan failure (6 of 25 infants [24%]). Moreover, 4 infants who received active care at birth received palliative care later on because of severe complications (high-grade intraventricular hemorrhage) following parental counseling.
Perinatal data arranged according to gestational age is presented in Table 1. As expected, infants born at 22 weeks of gestation presented with a significantly lower birth weight (468 vs 537 g) and received significantly less prenatal steroids (complete course: 12 of 28 infants [43%] vs 42 of 57 infants [74%]) than did infants born at 23 weeks of gestation. Interestingly, no significant differences were observed in maternal age, Apgar scores, mode of delivery, and eligibility for LISA between infants born at 22 weeks’ gestation and infants born 23 weeks’ gestation. A premature rupture of membranes for more than 7 days and an assisted pregnancy (eg, in vitro fertilization or artificial insemination) were more often observed for infants born at 22 weeks than for infants born at 23 weeks, without reaching statistical significance.
Furthermore, both survival and survival without severe complications, as well as duration of hospitalization, did not differ significantly between infants born at 22 weeks of gestation and infants born at 23 weeks of gestation (Table 2). To identify factors that possibly influence the probability of survival, we performed a binary logistic regression analysis, including the following significantly different variables: Apgar scores at 1, 5, and 10 minutes and eligibility for LISA. In addition, birth weight and use of prenatal steroids were included as possible relevant factors, which are known as important predictors for survival. We did not include the also-relevant parameters of sex and gestational age because these parameters did not differ between survivors and nonsurvivors (difference in males <1%, in mean age <1 day). In the final regression model, the Apgar score at 5 minutes (odds ratio, 0.62 [95% CI, 0.46-0.84]) and birth weight (odds ratio, 0.001 [95% CI, 0.00-0.40]) were independent significant prognostic factors for survival until hospital discharge, with higher values indicating improved survival.
Of note, 18 infants (7 born at 22 weeks and 11 born at 23 weeks) received active care but were not eligible for LISA. Of these, 7 survived (2 without neonatal adverse events).
Follow-up data on cognitive development (DQ calculated as described in the Methods section) at 2 years’ corrected age was available for 32 infants born during the period from 2010 to 2012. Normal development was observed in 16 of the 32 infants (50%). Of these 16 infants, 10 (63%) had no adverse neonatal event. Of the 16 of 32 infants (50%) with developmental delay, 7 (44%) had minor disabilities, and 9 (56%) had severe disabilities. Of these 16 infants, 11 (69%) had 1 or more neonatal complications. Taken together, 16 of 58 infants who received active care (28%) had severe developmental delay at 2 years’ corrected age.
The border of viability in many developed countries is presently around 24 weeks of gestation, and several guidelines and statements exist that comment on initiating vs withholding treatment to infants born at 22 or 23 weeks of gestation.19,20 Guidelines focusing on decisions regarding gestational age are highly controversial,21 and recommendations tend to move away from arbitrary intervention thresholds to individualized, family-centered decisions. A recent report on ethics in delivery-room care emphasized the impact of self-fulfilling prophecies, meaning that the recommendation not to treat at 22 weeks of gestation inevitably has to lead to low rates of survival. Consequently, reports on big national cohorts in settings where treatment is predominantly withheld for extremely immature infants cannot produce valid data on survival.22
Although we report data from a single center, the number of infants born at 22 or 23 weeks of gestation who received active care and were admitted to an NICU is comparable to the numbers in large national studies such as EPICure,8 EPIPAGE-2,9 the Extremely Preterm Infants in Sweden Study,23 and the National Institute of Child Health and Human Development Neonatal Research Network.24 In addition, although local data have been shown to be subject to variation, survival rates did not change significantly during the years reported (with a minimum survival rate of 60% in 2013 and a maximum survival rate of 81% in 2011).25
In our retrospective analysis, by following an active prenatal and postnatal care approach, we observed that 2 in 3 infants born at the border of viability survived until hospital discharge and that 1 in 4 infants survived without severe neonatal complications. While older studies report survival rates of as low as 0% for infants born at 22 weeks and 6% to 26% for infants born at 23 weeks,26-28 recent data from Japan, Sweden, and the United States show more encouraging results.3,6,23,29 These encouraging results may primarily be attributed to the more active prenatal and postnatal care that these preterm infants have received in recent years. Still, the definition and procedures associated with active care differ widely and make comparisons between studies difficult. In addition, it remains unclear which elements of active care should be combined to improved outcome. Less invasive surfactant application shows a trend to be beneficial for the prevention of bronchopulmonary dysplasia,30-32 but the body of evidence is still small and even smaller regarding the benefit of prenatal steroids or the mode of delivery at the border of viability. Thus, many aspects of our active care approach need to be tested in studies. For example, by preferring cesarean to vaginal delivery, we take a higher risk for maternal complications into account while the benefit for the infant remains unclear. Yet, we think that our data add substance to the assumption that an active prenatal and postnatal care approach might improve outcome and therefore support currently ongoing initiatives favoring active care of extremely premature infants. Active care of infants at the threshold of viability routinely means intubation and mechanical ventilation in the delivery room.23,29 Yet, although the majority of the infants at the border of viability in our study presented with low Apgar scores at 1 minute, spontaneous breathing could be established within the first 10 minutes in 80% of infants using high CPAP levels, making them eligible for LISA. Following this strategy, most infants were eligible for LISA. On the contrary, only 11% of infants intubated and ventilated in the delivery room survived without neonatal complications, suggesting a bias in our retrospective observation in favor of infants with a less severe illness.
Our study is limited for several reasons. Most important, we report retrospective data from a single center using a highly specific approach of care for extremely premature infants. Thus, although sustained inflation and LISA are becoming increasingly popular in European NICUs, our results are probably not applicable or easily transferrable to other tertiary neonatal centers. Second, we cannot provide neurodevelopmental data for all infants and may therefore overestimate our results. To identify infants at risk for severe developmental delay, we decided on using “survival without severe complications” as the primary outcome criteria because it is a predictive factor for a life without disability.33,34Although a correlation between neonatal adverse events and neurodevelopmental delay can be observed, this correlation has been shown to be imperfect in a study by Manuck et al,34 in which 19% of infants who were discharged without neonatal morbidity had severe neurodevelopmental impairment at 2 years of age. In contrast, more than 40% of the infants with up to 4 neonatal adverse events in this study34 had normal results. In our study, 38% of infants with neonatal complications had normal neurologic examination results compared with 31% of infants with disability and no neonatal adverse events.
In our study, half of the infants who were tested at 2 years’ corrected age showed normal development. On the other hand, almost one-third of the surviving infants were severely impaired. Many of these infants presumably will have a poor quality of life, and the families caring for these infants will be negatively affected in many ways, ranging from socioeconomic issues to emotional distress, anxiety, and depression.
Finally, we make clear that our outcome data refer to infants who received active care and not to all the reported population (including 19% of infants receiving palliative care). Therefore, caution should be exercised in using our data for parental counselling.
In addition, we could not include data from infants born at 24 weeks of gestation because many of these infants were included in a randomized clinical trial on LISA,18 and half of them were randomized for intubation and mechanical ventilation in the delivery room.
In our single-center, retrospective analysis, 1 in 4 infants born at 22 or 23 weeks of gestation who received active care survived the neonatal period without severe complications. Our data may convince clinicians to recommend and parents to decide in favor of active care. Yet, future studies should focus on optimizing delivery-room management strategies for these vulnerable infants in order to identify best practices that improve the outcomes of extremely premature infants.
Accepted for Publication: January 20, 2016.
Published Online: May 23, 2016. doi:10.1001/jamapediatrics.2016.0207
Correction: This article was corrected on July 27, 2020, to fix an error in the Results section of the abstract.
Corresponding Author: Katrin Mehler, MD, Division of Neonatology, Children´s Hospital, University of Cologne, Kerpenerstrasse 62, 50937 Cologne, Germany (email@example.com).
Author Contributions: Drs Mehler and Oberthuer had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Oberthuer and Mehler contributed equally.
Study concept and design: Mehler, Oberthuer, Roth, Kribs.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Mehler, Oberthuer, Keller, Kribs.
Critical revision of the manuscript for important intellectual content: Mehler, Oberthuer, Becker, Valter, Roth, Kribs.
Statistical analysis: Mehler, Oberthuer, Becker.
Administrative, technical, or material support: Oberthuer, Keller, Kribs.
Study supervision: Oberthuer, Roth, Kribs.
Conflict of Interest Disclosures: None reported.
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