Resuscitation Decisions for Extremely Premature Infants: A UK NICU Experience

Abstract

Background:

Improvements in extreme preterm infant outcomes have led to an increasing recognition of the importance of antenatal optimization and delivery room (DR) management strategies for these infants.

Methods:

Retrospective cohort evaluation of every infant born at 22⁺⁰ to 25⁺⁶ weeks gestation in St Mary’s tertiary NICU between 2008 and 2018. Aiming to evaluate utilization of chest compressions and resuscitation medications during DR-resuscitation of extremely premature infants.

Results:

This study found that 90% of infants 22⁺⁰ to 22⁺⁶ weeks did not receive antenatal steroids. Whereas, for infants born between 23⁺⁰ and 23⁺⁶ weeks gestation, 75% did receive antenatal steroids. This difference is significant (P value = .00006).

This study shows there is a predisposition to not provide DR-chest compressions (DR-CC) and/or adrenaline (DR-CC+/−A) to extremely preterm For infants that received DR-CC, there was no statistically significant increase in death and no clear association with poorer long-term outcomes in survivors.

Conclusions:

Marked differences in provision of perinatal care were found dependent on gestational age. If infants are inadequately prepared for delivery and resuscitative measures are not fully utilized, it cannot be clear whether subsequently increased rates of death in the lower gestational age groups are solely due to gestational age or are influenced by the lack of preparative management.

Keywords

Neonates resuscitation prematurity delivery room care ethics

Introduction

Background

The extent of resuscitation for extremely preterm births is a complex area clinically and ethically, with scope for generating significant moral distress for parents and health-care professionals.1 Significant variation exists across neonatal networks and individual countries in their approaches to antenatal interventions and counselling, delivery room (DR) management, and survival outcomes for these extremely premature infants.2-4 In the United Kingdom, guidelines have recently been reviewed and updated by major working groups (BAPM Framework, 2019)7 to reflect the increasing survival and improving long-term outcomes of extremely preterm infants, emphasizing a holistic infant assessment, rather than a singular focus on gestational age alone.

Whilst advances in neonatal care have significantly improved the outcomes in preterm infants, the extent of resuscitation for extremely preterm births remains a complex area attracting much debate and potential ethical conflict.1, 5 Previous limited evidence did not support the use of chest compressions during resuscitation for infants born at gestational ages less than 26 weeks.6 However, this statement is predicated on research done over 20 years ago. Advances in perinatal care have meant that infants delivered at the edges of viability can now survive, and increasingly, are surviving with good short- and long-term outcomes.7 Previous literature, however, including the Nuffield Council on Bioethics guidance,8, 9 has stated that infants born at less than 25 weeks gestation are at high risk of having a poor outcome, and that “the healthcare team should make it clear that statistics indicate that most babies born below 25 weeks of gestation will die.” The Nuffield Council statement goes on to comment that for infants born between 22⁺⁰ and 22⁺⁶ weeks, standard practice should be to not resuscitate the infant.8

These studies place significant weight on using the infant’s gestational age as a guide for prognostication. However, there is emerging focus on a wider assessment of the infant in determining the appropriateness of resuscitation and instigation of intensive care.10 ,11

At the moment of delivery, it remains difficult for clinicians’ to be able to accurately prognosticate the ultimate outcome for any individual infant.12 Even in cases where there has been sufficient time and discussion with parents prior to the delivery, there is a necessary importance placed on the infant’s condition and response at birth to help guide resuscitative decisions. With advances in neonatal care and improving outcomes, there has been a shift away from relying solely on gestational age to guide instigation and extent of resuscitation. Given that the border of viability has been steadily decreasing to lower and lower gestational ages over the last 10 years, this study hypothesized that approaches to extensive resuscitation may have changed to utilizing chest compressions and/or adrenaline in extremely premature infants during DR resuscitation. However, the study instigators acknowledged that conversely there may be an attitudinal persistence that significant resuscitation involving chest compressions and adrenaline at these extremely premature gestations would lead to a poor outcome and therefore, these measures may not be utilized. As Wilkinson et al. acknowledge, “Management of the delivery of an extremely preterm baby is one of the most challenging aspects of perinatal medicine.”10

Objective

To evaluate the extent that chest compressions and resuscitation medications are utilized during DR resuscitation of extremely premature infants.

Methods

A retrospective cohort study was undertaken collecting data for every infant born at 22⁺⁰ to 25⁺⁶ weeks gestation in St Mary’s tertiary neonatal intensive care unit (NICU) between 2008 and 2018. This study focused on whether extensive life support practices were implemented. Therefore, for the purpose of this study, extent of resuscitation was defined into 3 categories: no CC (chest compressions), chest compressions alone (DR-CC), or chest compressions and adrenaline (DR-CCA). The unit policy regarding extreme preterm resuscitation (22⁺⁰-24⁺⁶ weeks gestation) was for a process of shared decision-making between parents and the senior neonatal clinician to determine an individualized approach (comfort care or active intervention).

All infants delivered at 22⁺⁰ to 25⁺⁶ weeks gestation were included in the study provided they had been born at St Mary’s tertiary NICU. Infants with congenital abnormalities born at 22⁺⁰ to 25⁺⁶ weeks gestation were included. Infants born at other centers and transferred into St Mary’s for ongoing care were excluded.

Data were collected on gestational age, birth weight, gender, antenatal steroid, and magnesium sulphate provision, condition at birth, and life support interventions provided at birth. Data were also collected regarding infant outcome (survival to discharge, death in delivery suite, or death on the neonatal unit) and, for survivors to discharge, whether the infant was discharged on home oxygen, with intraventricular hemorrhage (IVH) and grade, and presence and grade of retinopathy of prematurity (ROP). These outcome measures were chosen due to their potential impact on infant development and impact on family life. Data were collected from the patient notes, including the online admission and discharge summary database (BadgerNet) and the neonatal delivery assessment card. This process captured all infants within the specified gestational range that were admitted to the NICU.

In order to ensure data were gathered for infants who did not survive delivery, the death and stillbirth registers were reviewed. Data for these infants were gathered from the maternal notes and neonatal delivery card and/or notes.

Statistical Analysis

This is a pragmatic cohort study to investigate the extent that full resuscitation practices were implemented in extremely preterm infants. Therefore, this cohort study was not powered to detect statistically significant differences in outcomes following extensive resuscitation. Statistical analysis was confined to comparative percentage analysis and for nonparametric variables (eg, antenatal steroid provision) the chi-squared test for independence was applied.

Ethics Approval

This was a retrospective review and all data collected were anonymized. The authors sought input from the Trust Research Department regarding the need for ethical clearance for such a retrospective evaluation and were advised that this was not warranted.

Results

Patient Demographics

The study search strategy identified 286 infants born at St Mary’s at 22⁺⁰ to 25⁺⁶ weeks gestation between 2008 and 2018. As gestational age decreased, the number of infants delivered in each subgroup decreased. This likely reflects that in the United Kingdom, pregnancy loss up to 23⁺⁶ weeks gestation is medically defined as miscarriage and therefore, deliveries at this gestation with no signs of life at birth would not have been identified for this study via the stillbirth register.

Delivery Room Chest Compressions With/Without Adrenaline (DR-CC+/−A)

From the study cohort, there were 25 infants who received DR-CC, including 2 infants who received DR-CC with adrenaline. No infant born at 22⁺⁰ to 22⁺⁶ weeks received DR-CC+/−A. For gestations beyond 23⁺⁰ weeks, there were increasing numbers of infants receiving DR-CC with increasing gestational age (see Table 1).

Table 1.

Infant Demographics.

Gestation (Weeks)	22⁺⁰-22⁺⁶	23⁺⁰-23⁺⁶	24⁺⁰-24⁺⁶	25⁺⁰-25⁺⁶
No of infants	37	73	82	93
Average BW (g)	474	566	673	752
Lowest BW (g)	370	370	436	428
Highest BW (g)	693	730	873	1000
Complete AN steroids	0	33	52	60
Partial AN steroids	5	22	18	26
No AN steroids	27	16	11	5
MgSO₄− given	3	15	19	28
DR-CC	0	3	12	8
DR-CCA	0	1	0	1
Survived to discharge	4	33	62	79
Delivery room death	24	7	0	1
Died in NICU	9	33	20	11
Home oxygen	3	21	44	36
IVH G3 (Uni/Bi)	0	7 (3/4)	6 (3/3)	6 (1/5)
IVH G4 (Uni/Bi)	1 (1/0)	1 (0/1)	7 (4/3)	6 (3/3)
ROP 2+	4	20	40	29

Note: AN, antenatal; Bi, bilateral; BW, birth weight; DR-CC, delivery room chest compressions; DR-CCA, delivery room chest compressions and adrenaline; IVH, intraventricular hemorrhage; MgSO₄−, magnesium sulphate; ROP, retinopathy of prematurity; Uni, unilateral.

Survival to discharge initially appeared improved for infants who had not received DR-CC+/−A at birth. However, this difference was not statistically significant (P value .22). Additionally, whilst this study was not powered to detect statistically significant differences in outcome measures, from the data that is available, there is no indication that there are increased rates of IVH ≥3, ROP ≥2, or need for home oxygen for those infants who received DR-CC and survived to discharge (Figure 1). Therefore, for infants in this study who have responded well to extensive resuscitation, there is no clear evidence of increased risk in their longer-term outcomes.

Figure 1.

Comparative outcome measures for infants who received no DR-CC and those that received DR-CC+/−A. For long-term outcome measures (Home O2/ROP/IVH), these were calculated using number of survivors to discharge as the denominator.

For the 2 infants who received DR-CC+A (Table 2), resuscitation was unsuccessful and both died in the DR. In the case of infant A, this was a 23+3 week female infant with a birth weight of 500 g who received a full course of antenatal steroids prior to delivery. There were concerns regarding chorioamnionitis at delivery. By contrast, infant B was delivered at 25+6 weeks gestation and a birth weight of 770 g. He had received no antenatal steroids or magnesium sulphate prior to delivery and there was a history of positive maternal colonization with group B streptococcus. Both infants received full DR resuscitation with chest compressions and adrenaline. In both cases, this was unsuccessful and the infants died at delivery.

Table 2.

Details for Infants Who Received DR-CCA.

Infants who received DR-CCA
Number of infants	2 Infant A Infant B	23+3 25+6	550 grams 770 grams	Singleton Singleton	Full steroids No steroids	No MgSO4- No MgSO4-	Female Male	Chorioamnionitis GBS +ve
Died in Delivery Room	2
Died on NICU	0
Survived to Discharge	0

Applying the BAPM Framework, whilst infant B benefitted from being more mature at 25+6 weeks gestation and being born in a tertiary unit, there were multiple other unfavorable risk factors (male, singleton, and lack of antenatal steroids) which modified his survival chances. Conversely, infant A at 23+3 weeks gestation could have been viewed as an inappropriate candidate for extensive resuscitation given her gestational age. However, infant A possessed many favorable modifiers such as being female, singleton, being born in a tertiary unit, and having received a full course of antenatal steroids, which would have improved her survival chances compared to other infants born at her gestational age. Where there are favorable modifiers, gestational age alone should not constitute the sole reason to not attempt full resuscitation.13

Resuscitative Approaches for Infants Born at 22⁺⁰ to 23⁺⁶ Weeks Gestation

There were no 22⁺⁰ to 22⁺⁶ week infants in this cohort that received DR-CC+/−A. For infants born at 23⁺⁰ to 23⁺⁶ weeks, there were 4 infants who received DR-CC+/−A. There may be an expectation that the outcomes would be poor for these infants. Data from this study support this, showing that, albeit with limited infant numbers, a mere 25% of infants born at 23 weeks gestation who received DR-CC+/−A survived to discharge. To compare, for infants born 23⁺⁰ to 23⁺⁶ weeks who did not receive DR-CC, the survival to discharge rate was 47%.

There were 4 infants born at 23⁺⁰ to 23⁺⁶ weeks who received DR-CC+/−A. All 4 infants had birth weights between 550 and 650 g. All 4 infants received antenatal steroids prior to delivery (2 infants had a full course of antenatal steroids; 2 infants had a partial course). Three of these infants were born at 23⁺⁶ weeks. The fourth infant was born at 23⁺³ weeks and died in delivery suite after receiving DR-CCA (infant A in Table 2). Of the remaining 3 infants, 2 died following admission to NICU and 1 survived to discharge. For the surviving infant, she received chest compressions for 12 min at delivery, survived through her NICU admission, and was discharged on home oxygen, with ROP stage 2 and no IVH.

The lack of provision of DR-CC+−A for infants between 22+0 and 22+6 weeks may indicate a reluctance by attending staff to instigate this resuscitative measure at this gestation. This may be due to the expectation that if an infant at this gestation—which may be referred to as the cusp of viability—requires DR-CC that there will be a poor outcome. However, infants born at these extremes of gestational age can also pose mechanical challenges in providing adequate airway support. Many may receive intermittent positive pressure ventilation prior to intubation and it may be problematic to provide an adequate mask seal at this gestation, which could lead to a delay or deterioration in heart rate. In addition, the gestational age can only ever be a guide.14 Infants may well be more, or less, mature than anticipated.

As stated, within the study dataset, there were no infants between 22+0 and 22+6 weeks that received DR-CC, despite there being a range of birth weights within this gestational age range. Of the 38 infants identified by this study born at gestational age of 22+0 to 22+6 weeks, there were 5 infants who had a birth weight above 500 g (500-693 g) who died in delivery suite without receiving DR-CC but had been intubated and received surfactant (Table 3).

Table 3.

Management and Outcomes for Infants Born >500 g at 22 and 23 Weeks Gestation.

Infants > 500 g	22+0-22+6	23+0-23+6
No of infants	13	64
Average BW (g)	552	585
Lowest BW (g)	500	500
Highest BW (g)	693	730
Complete AN steroids	0	28
Partial AN steroids	3	20
No AN steroids	8	15
MgSO4− given	1	14
DR-CC	0	3
DR-CCA	0	1
Survived to discharge	4	31
Delivery room death	5	5
Died in NICU	4	28
Home oxygen	3	19
IVH G3 (Uni/Bi)	0	7 (3/4)
IVH G4 (Uni/Bi)	1 (0/1)	1 (0/1)
ROP 2+	4	19

For comparison, of the infants born at 23+0 to 23+6 weeks gestation who had a birth weight between 500 and 693 g, there were 62 infants. Four of these infants received DR-CC+/−A. As stated earlier, of these 4 infants, 1 died in delivery suite (DR-CC + adrenaline), 2 subsequently died on NICU secondary to pulmonary hypertension (DR-CC only), and 1 survived to discharge (DR-CC for 12 min). Whilst these outcomes are poor when considered as a group (75% mortality for the group), considering the individual infant who survived to discharge and their family this survival represents encouraging progress in pushing forward outcomes for extremely preterm infants, which are continuing to improve.15

Predelivery Management

Provision of antenatal steroids has significantly improved the outcomes of preterm infants.16,17 However, of note in this study cohort, 90% of infants 22+0 to 22+6 weeks did not receive antenatal steroids (Figure 2). Those that did, received only a partial course of steroids. No infant born between 22+0 and 22+6 weeks received a full course of antenatal steroids. Whereas, for infants born between 23+0 and 23+6 weeks gestation, 75% did receive antenatal steroids (44% full course; 29% partial course). This difference in antenatal steroid provision at these different gestational ages is significant (P value = .00006), and highlights the issue that if infants are not adequately prepared for delivery and then resuscitative measures are not fully utilized, then it cannot be clear whether the subsequent increased rates of death in the 22 week gestation group are solely due to gestational age or are influenced by the lack of preparative management.

Figure 2.

Antenatal Steroid Provision by Gestational Age (Weeks).

The difference demonstrated in this study regarding the extent of resuscitation for 22 week infants compared to 23 week infants despite similar birth weights, suggests that there is physician predisposition to be reliant on the gestational age to guide the provision of antenatal steroids and the extent of DR resuscitation. This approach, of reliance solely on gestational age, is actively discouraged by the recently released BAPM Framework.7 The data from this study support BAPM’s more comprehensive assessment approach to guide DR resuscitation management.

Discussion

Limitations

The retrospective nature of this cohort study is a limitation. However, in this research area, it would seem impractical and unethical to conduct randomized controlled trials. Therefore, learning from retrospective case review is one of a limited range of avenues for development in preterm resuscitation practices.

Due to the retrospective nature of this study, there is reliance on the quality of resuscitation documentation. There was often poor-quality documentation as to the grade of staff member involved in parental discussions and variable documentation regarding details of any predelivery parental discussions regarding their beliefs and stance toward extensive resuscitation for their extremely preterm child.

The study did ensure that all notes applicable to each infant were reviewed, including those for deaths coded as DR deaths or stillbirths. All infants delivered at the tertiary neonatal center were included. Any infants delivered in a district general hospital and transferred to the tertiary center were excluded. This may limit the applicability of the results from this study to infants delivered outside a tertiary unit. Tertiary NICU intervention at these gestations may be perceived as trending toward being more invasive, and it is known that outcomes for extreme preterm infants delivered at tertiary units are improved.18

Conclusions

This study illustrates that provision of DR-CC+/−A is uncommon at delivery of extremely preterm infants. From this study cohort, DR-CC was utilized in a mere 9% of extreme preterm infants, with <1% receiving DR-CC and adrenaline.

From the data available, there is no indication that DR-CC alone is a significant risk factor for death (Table 4). However, where there has been administration of adrenaline alongside DR-CC, then there is an increased risk of death overall.

Table 4.

Delivery Room Chest Compressions With/Without Adrenaline (DR-CC+/−A).

	Not Received DR-CC+/−A	Received DR-CC+/−A
No of infants	257	25
Average gestation	24+3	24+3
Average BW (g)	647	650
Lowest BW (g)	370	436
Highest BW (g)	1,000	858
Survived to discharge (%)	64	52
Delivery room death (%)	11	8
Died on NICU (%)	25	40
Home oxygen (%)	59	38
IVH G3 (%)	11	8
IVH G4 (%)	8	8
ROP 2+ (%)	52	38

Traditional approaches may dissuade clinicians from providing DR-CC to extreme preterm infants. The data in this study show that outcomes for infants where DR-CC was provided were more positive than anticipated, with 52% surviving to discharge. This is in keeping with the recent paper by Wilkinson et al,13 which concluded that, “in the absence of sufficient evidence to justify a different approach in extremely preterm babies … the [BAPM] Working Group recommends applying newborn resuscitation algorithms as used in more mature babies.”

Whilst this study was not powered to detect statistically significant differences in outcome measures, from the data that is available, there is no indication that there are increased rates of IVH ≥3, ROP ≥2, or need for home oxygen for those infants who received DR-CC and survived to discharge (Figure 1). Therefore, for infants in this study who have responded well to extensive resuscitation, there is no clear evidence of increased risk in their longer-term outcomes.

Infants as Individuals

There are many ways of categorizing infants. These are employed throughout their neonatal stay, categorizing them into gestational age groups, those that have certain diagnoses, are on certain treatments, undergoing certain procedures, or receiving a certain level of care. These categorizations are important to ensure staff can quickly attune to an infant’s clinical case and anticipate the medical issues that the infant is likely to encounter.

However, this categorization is useful only to allow prediction. Categorization should not dictate a specific course of action. An infant born at 22 weeks gestation certainly has an increased likelihood of death and disability, and clinicians attending the birth or providing care for the infant should be cognizant of this. However, being an infant in the 22 week category does not provide clinicians with an assurance of the specific response of that infant to a variety of situations. The infant may follow a predictably unstable course, for example, being born in a compromised condition, or, that individual infant may surprise clinicians by being born in a better condition than expected. The medically necessary categorization of infants still requires individual assessment when implementing a management plan. This is increasingly recognized in neonatal care, particularly in regard to DR management of preterm infants (as reflected in the BAPM Framework on Extreme Preterm Birth7).

Crucially, resuscitation interventions in extremely preterm infants must always be tailored to the individual infant, their response to initial stabilization measures and incorporate parental preferences. A comprehensive holistic assessment is vital, rather than a singular focus on gestational age alone. This holistic assessment must be multidisciplinary, as if active intervention is desired in conjunction with parental views, then management should ensure antenatal optimization with antenatal steroids and magnesium sulphate. Gestational age, whilst an important modifier, should not take centerstage in decision-making. The BAPM Framework places gestational age alongside other risk modifiers (sex/antenatal steroids/location) in order to comprehensively refine individual infant risk. Whilst individualized comprehensive assessments are not a new concept (Tyson, amongst others, encouraged the move to this type of risk assessment over a decade ago19), it has not yet become standard practice in many centers as there remains apprehension about the potential for inflicting harm by intervening at ever decreasing gestations. The central issue with continuing to focus predominantly on gestational age to guide management is that this creates conflict with the ethical principle of justice. If the focus is purely on gestational age, an infant born at 24+0 weeks (male, twin, and no antenatal steroids) may be offered DR-CC+/−A over a 23+4 week infant, even though the 23+4 week infant may have more favorable modifiers (female, singleton, well grown, full course of steroids). As Mercurio and Carter11 summarize, “It is a breach of justice to deny the option of resuscitation to one child yet offer it to another with a worse prognosis.” There are many unanswered questions about the optimal management of infants at the edges of viability. However, in the absence of evidence to the contrary, it would seem prudent to not deny these extremely preterm infants’ access to interventions which have proved to confer benefit to older gestational age infants. Compassionate care does not restrict access to intensive interventions. The concept of parallel planning is critical in these frontier areas of neonatology. Active interventions should be considered for implementation in the initial instance, as practitioners would with more mature infants, with reorientation of care following once there is evidence of lack of response or futility of treatment. As increasing numbers of studies are illustrating, intervention at extremes of prematurity cannot be considered futile.3 ,4

Further studies are required to research and uncover the optimal management of this emerging group of unique infants and to assess and monitor long-term outcomes in this population.

Footnotes

Authors’ Contributions

JP devised and designed the project. JP, MK, RT, and NM collected the data. JP wrote the manuscript. RR supervised the project and edited the manuscript. All authors reviewed the manuscript prior to the submission.

Declaration of Conflicting Interests

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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