Nutritional management in newborn babies receiving therapeutic hypothermia: two retrospective observational studies using propensity score matching

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 16/79/03. The contractual start date was in September 2017. The draft report began editorial review in December 2019 and was accepted for publication in June 2020. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Copyright statement

Copyright © 2021 Gale et al. This work was produced by Gale et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2021 Gale et al.

Background

In the UK and other high-income settings, therapeutic hypothermia is standard of care for babies who are born at ≥ 36 weeks’ gestational age and show signs of hypoxic–ischaemic encephalopathy (HIE). 1 Although the administration of therapeutic hypothermia itself is well defined and based on high-quality randomised controlled trials (RCTs),2 the optimal nutritional management of babies receiving this therapy is not. There are two primary components of nutritional management: (1) enteral nutrition in the form of milk feeds and (2) intravenous or parenteral nutrition (PN).

During therapeutic hypothermia, babies can have milk feeds introduced incrementally or can have milk feeds withheld (this is the enteral component of nutritional support). Babies who receive therapeutic hypothermia in high-income countries will be commenced on intravenous fluid shortly after admission. This is because they are often unable to effectively co-ordinate sucking and swallowing, regulate fluid balance or maintain glucose metabolism. This intravenous fluid may be an intravenous dextrose solution (with electrolytes, such as sodium and potassium, as required) or PN, which contains protein, fat, carbohydrate, minerals and vitamins (this is the parenteral component of nutritional support).

The lack of high-quality evidence to inform nutritional practice during therapeutic hypothermia leads to variation in the provision of both enteral and parenteral components of nutrition. A recent UK survey of nutrition practices during therapeutic hypothermia reported that only 31% of responding units have feeding guidelines for these babies, 59% of neonatal units report routinely starting enteral feeding and 29% of neonatal units report routinely administering PN during therapeutic hypothermia. 3 International practice is also mixed. In some settings withholding enteral feeds during therapeutic hypothermia is almost universal,4 whereas in other settings starting and incrementing milk feeds is routine practice. 5

A key reason for withholding enteral feeds during therapeutic hypothermia is the premise that this may reduce the risk of necrotising enterocolitis (NEC). 6 NEC is seen in term and near-term babies with HIE; however, its incidence is poorly reported. NEC was reported in only 3 of the 11 RCTs that evaluated therapeutic hypothermia in HIE and only one case was documented. 7–9 Furthermore, there is no evidence that withholding or delaying milk feeds is useful in preventing NEC, even among very preterm babies at high risk of the disease. 10,11 Conversely, there is some limited evidence that enteral feeding of babies with HIE during hypothermia may be associated with lower biochemical markers of systemic inflammation,4 and the wider benefits of maternal breast milk feeding in term babies are well described. 12

In relation to PN support, intravenous dextrose provides sufficient hydration and energy to prevent hypoglycaemia, but does not provide the protein and fat necessary for tissue growth. It is not known how a short period of undernutrition may impact growth or the secondary and tertiary recovery phases that follow brain injury. 3,13,14 Parenteral nutrition is nutritionally superior but leads to higher rates of infection and other adverse outcomes in RCTs in paediatric and adult intensive care settings. 15,16 Moreover, PN is expensive17 and should, therefore, be used only when likely to be beneficial.

To address this paucity of high-quality evidence we aimed to identify optimal enteral and PN strategies for term and near-term babies receiving therapeutic hypothermia. As key outcomes such as NEC are rarely reported in this population, a RCT with power sufficient to analyse such outcomes is not feasible. We therefore undertook an observational study using routinely recorded data and applying propensity score matching to form groups for comparison with near-identical distributions of background variables.

Aims and objectives

Study design

This was a retrospective, population-based, cohort study that used existing data held in the National Neonatal Research Database (NNRD) and applied propensity score methodology.

Setting

The study used data from all designations of NHS neonatal units (i.e. special care baby units, local neonatal units and neonatal intensive care units) in England, Scotland and Wales. 18 Data were extracted for babies born between 1 January 2010 and 31 December 2017 who were admitted to neonatal units contributing to the NNRD, with follow-up data recorded until neonatal unit discharge.

Data source

The NNRD holds de-identified routinely recorded clinical data from all babies admitted to participating NHS neonatal units in England, Scotland and Wales. All NHS neonatal units in England and Wales have contributed data to the NNRD since 2012. The majority of NHS neonatal units in Scotland have contributed data to the NNRD since 2015, with all NHS units contributing as of 2019. Contributing neonatal units are known as the UK Neonatal Collaborative (UKNC). Data are extracted from point-of-care neonatal electronic health records that are completed by health professionals during routine clinical care. A defined data extract, the Neonatal Data Set, of approximately 450 data items19 is transmitted quarterly to the Neonatal Data Analysis Unit at Imperial College London and Chelsea and Westminster Hospital NHS Foundation Trust, where data are checked for internal inconsistencies and duplicates. Data items include demographic and admission items (e.g. maternal conditions, gestation and birthweight), daily items (e.g. respiratory support and feeding information), discharge items (e.g. feeding and weight at discharge) and ad hoc items (entered if and when they occur, e.g. suspected infection, ultrasound scan findings and abdominal radiographic findings). A formal comparison of NNRD data with case record forms from a multicentre RCT showed high levels of data agreement. 20

Access to the full NNRD database population is restricted to authorised users at the Neonatal Data Analysis Unit. A patient-level data set was extracted from the NNRD for the purpose of this analysis. Data linkage with any other database was not performed for this study.

Participants

Babies were eligible for inclusion in the study if they met the following criteria:

• were born and admitted to a NHS neonatal unit between 1 January 2010 and 31 December 2017

• received care at a neonatal unit in England, Scotland and Wales that was part of the UKNC and, therefore, contributing data to the NNRD

• had a recorded gestational age of ≥ 36⁺⁰ weeks^+days at birth

• were recorded as receiving therapeutic hypothermia for 3 consecutive days during their neonatal unit stay or died during the period of therapeutic hypothermia.

Details of data extraction procedures are provided in Appendix 1, Tables 22–24.

Data imputation

Babies who had missing data for receipt of cooling on the second day of cooling, but who were recorded as having received cooling on both the first and the last day and who did not die during cooling, had data for the second day of cooling imputed. No other data imputation was performed.

Variables

The variables used in the analysis are described in this section and are grouped as intervention, background and outcome variables. A detailed description of the data extraction procedure and any transformations or recoding applied to variables during the analysis are provided in Appendix 1, Tables 22–24.

Bias

This was an observational study. The primary source of bias was deemed to be confounding owing to systemic differences in the clinical characteristics between babies receiving different nutritional interventions. For instance, babies with hypotension who receive inotropes may be more likely to have feeds withheld as well as having poorer outcomes. To overcome this bias, matching using propensity scores was implemented to form groups of babies with different enteral and parenteral nutritional interventions during therapeutic hypothermia, but who were balanced in terms of all measured background variables. The process of matching is described in detail in Statistical methods. This approach cannot overcome bias related to systemic differences in unmeasured confounding factors.

Study size

It was estimated that approximately 7200 babies would meet the study inclusion criteria. Pilot data extracted from the NNRD showed that in 2015 a total of 809 babies met the study inclusion criteria, of whom 37% (301/809) received enteral feeds and 29% (238/809) received PN during hypothermia. Using these rates, a sample size of 7200 babies receiving therapeutic hypothermia would be able to detect (two-sided significance 5%, power 90%) a difference of 0.7% in NEC with 2000 matched pairs (assuming that the rate of NEC is negligible in the reference treatment) and a difference of 2% in BSI with 1500 pairs (assuming rates of 1% and 3%). The difference of 0.7% for the rates of NEC (and similar figures for other outcomes) is selected for illustration and does not represent any imperative or objective in the study design.

Statistical methods

Alternative methods for matching on the propensity score and background variables

We refer to the statistical methods detailed thus far as the preliminary method of analysis. We explored the robustness of results to alternative matching methods at three stages of the matching process (see Figure 1). In the preliminary analysis, babies in the intervention group were matched on a 1 : 1 basis to those in the control group. Inverse probability weighting (IPW) is an alternative to matching. In IPW a matched cohort is formed by applying to the babies the reciprocal of the probability of receiving the treatment that was actually received. The weights assigned to babies who received and did not receive enteral feeds and the estimated average effect of being enterally fed and not fed are as follows.

Enterally fed weight:

⁽¹⁾ W i = 1 P S i .

Estimated average effect of receiving enteral feeds:

⁽²⁾ µ F = 1 N ∑ i = 1 N W i T i Y i .

Not enterally fed weight:

⁽³⁾ W i = 1 ( 1 − P S i ) .

Estimated average effect of not being enterally fed:

⁽⁴⁾ µ NF = 1 N ∑ i = 1 N W i ( 1 − T i ) Y i ,

where PS_i is the fitted propensity for baby i, T_i is a binary indicator of the treatment received (T_i = 1 indicates that a baby received enteral feeds) and Y_i is the outcome for subject i. Treatment effects are calculated by the method appropriate for the type of outcome variable (continuous or binary). The standard errors are estimated by the weighted versions of the formulae for random samples.

In the preliminary analysis, propensity score deciles were formed within each background group so that thresholds between deciles varied across the 12 principal background groups. We implemented two alternatives. First, we formed propensity groups prior to forming background groups so that thresholds were common to all the background groups. Second, we ignored background groups altogether and matched only on the propensity groups. In addition to forming propensity groups by splitting into deciles, we also implemented an adaptive method proposed by Imbens and Rubin. 28 Propensities were repeatedly split by the within-group median propensities of provisional propensity groups until the subjects in each group were well balanced on (i.e. had similar means of) the propensities. This method is called adaptive splitting.

In summary, in addition to the preliminary analysis (Figure 1, analysis A) we conducted 11 further analyses (see Figure 1, analyses B–L), implementing alternative methods of propensity and background matching in the primary analysis and all three sensitivity analyses.

FIGURE 1.

Alternative methods of matching on the propensity scores and principal background groups. The preliminary method of analysis is shaded in purple.

Background

Involvement of parents, patients and the public in research can be defined as research being carried out ‘with’ parents, patients and the public, rather than ‘to’ or ‘for’ them. 29 High-quality parent, patient and public involvement in research is considered best practice and is associated with tangible benefits, including higher enrolment in clinical trials. 30 Parents and parent representatives were involved in this study at all stages from conception through to dissemination.

Aim

To gain meaningful parent perspectives into the design, analysis, interpretation and dissemination of this study.

Objectives

Methods

The study was planned and designed by a multiprofessional investigator group that included a parent who had experienced having a baby who received therapeutic hypothermia (author ES). The investigator group also included a representative (author LC) from the national charity Bliss (a charity for babies born prematurely or who are sick) (London, UK) to represent parents more widely and to support ES in contributing to the study. ES and LC contributed to the design, planning, analysis, interpretation and dissemination stages of the study.

A further parent who had experienced having a baby who received therapeutic hypothermia was recruited to join the Study Steering Committee as an independent member through social media channels of the national charity Bliss [i.e. Facebook (URL: www.facebook.com; Facebook, Inc., Menlo Park, CA, USA); Twitter, (URL: www.twitter.com; Twitter, Inc., San Francisco, CA, USA); and Instagram, (URL: www.instagram.com; Instagram, Inc., Menlo Park, CA, USA).

The parent co-investigator, parent Study Steering Committee member and parent representatives were strongly encouraged to actively contribute to discussions, investigator group and steering group meetings.

Parents were informed about the study through the website of the national charity Bliss (Figure 2). Parents were informed that data about their babies were collected by neonatal staff and were added to the NNRD to improve neonatal care through research, using posters and leaflets on all NHS neonatal units [URL: www.imperial.ac.uk/neonatal-data-analysis-unit/about-us/for-parents-and-carers/ (accessed 24 July 2020)].

FIGURE 2.

Bliss webpage informing parents about the study. URL: www.bliss.org.uk/research-campaigns/research/current-research (accessed 29 October 2019). Reproduced with permission from Bliss.

Reproduced with permission from Bliss

Results

Parents influenced the study design and, specifically, the choice of outcomes in several ways. The primary outcome for the enteral nutrition comparison is NEC and the primary outcome for the PN comparison is late-onset infection. Prevention of these outcomes was identified as the third and second most important treatment uncertainties, respectively, by parents, patients and professionals in a James Lind Alliance Priority Setting Partnership related to neonatal care. 31,32

A parent (ES) and a parent representative (Bliss) identified that ‘breastfeeding’ as a binary outcome was not sufficient to capture the different aspects of breastfeeding that may be important to parents of babies who are receiving therapeutic hypothermia. The following outcomes were included in the study as a direct result of this:

• First maternal breast milk feed, defined as the first day when a baby is recorded as receiving maternal breast milk by any route, including suckling at the breast, by bottle or by nasogastric tube.

• Onset of breastfeeding, defined as the first day when a baby is recorded as suckling at the breast. This does not include maternal breast milk given by bottle or nasogastric tube.

• Breastfeeding at discharge, defined as any breastfeeding (i.e. suckling at the breast) at discharge.

Both a parent and a parent representative were actively involved in study oversight and were present at all Study Steering Committee meetings.

A parent and a parent representative contributed to the analysis of study results and drafting of study publications, including this report.

Planned dissemination

Parent-centred plain English summaries of key study results are being co-designed by parents, parent representatives and the study statistician (DJ) to facilitate dissemination of the study results to parents. These will be made freely available online through the Bliss [URL: www.bliss.org.uk (accessed 24 July 2020)] and NNRD [URL: www.imperial.ac.uk/neonatal-data-analysis-unit/ (accessed 24 July 2020)] websites and will be publicised through the Bliss and study team social media channels.

Discussion

Parents and parent representatives were actively involved in this study from its outset. Meaningful parent involvement was achieved, and this translated into the inclusion of outcomes relevant to parents. These outcomes included different aspects of breastmilk feeding, such as first administration of breast milk and first feed at the breast, recognising the different value and importance of these events to parents. Parent and parent representative involvement has also been essential for development of effective plain English research summaries. This study uses data held in the NNRD. Parents have been extensively involved in the development of the NNRD and have expressed strong support for sharing health data for research. 33

The strengths of the study include involvement of a parent who had experienced having a baby who received therapeutic hypothermia from study inception with parallel involvement of a parent representative charity to provide further parent representation and support for the parent co-investigator (ES). This enabled the parent co-investigator (ES) to gain experience and expertise in study design and to contribute meaningfully. Having the same parent co-investigator throughout the study also provided continuity in relation to the parent perspective and input.

The limitations include the challenge of involving parents in a retrospective observational study in which the choice of study outcomes was limited by available data. A further limitation is that we did not involve ex-neonatal patients who experienced therapeutic hypothermia in the neonatal period. This was challenging because of the neonatal patient population and because the treatment of interest, therapeutic hypothermia, became standard of care only 10 years ago.

Parent involvement in this study led to beneficial changes in the design of the study and in the outcomes analysed.

Participants

A total of 703,911 babies were recorded as having been admitted to a NHS neonatal unit in England, Scotland or Wales between 1 January 2010 and 31 December 2017. Of these babies, 6033 were ≥ 36 weeks’ gestational age and recorded as being treated with therapeutic hypothermia for HIE for 6 days or as having died during treatment. After exclusion of babies with missing data for sex or missing feeding data on all days when they were recorded as receiving therapeutic hypothermia, the enteral nutrition and PN cohorts comprised 5847 and 6010 babies, respectively (Figure 3).

FIGURE 3.

Participant flow through study for the primary analysis.

In the primary analysis, propensity score matching created matched cohorts of 3236 babies (i.e. 1618 pairs) for the enteral feeding analysis and 2480 babies (i.e. 1240 pairs) for the PN analysis. These cohorts were smaller than the sample sizes estimated in the protocol of 2000 matched pairs for the enteral nutrition analysis and 1500 matched pairs for the PN analysis.

Descriptive analyses: original study cohort

Enteral feeding analyses

Primary analysis

Background variables in unmatched and matched cohorts

Tables 8 and 9 (see also Appendix 4, Tables 28–31) present the background characteristics of babies recorded as having received enteral feeds during therapeutic hypothermia and babies for whom enteral feeds were recorded as being withheld, before and after matching. There are clear differences between unmatched cohorts of babies who received and babies who did not receive enteral feeds. Higher proportions of babies were delivered by caesarean section and to mothers living in the most deprived LSOAs in the withheld enteral feeds group. Babies who did not receive enteral feeds during therapeutic hypothermia also received more intensive medical care at resuscitation and on the first day of their life. After matching, differences in baseline characteristics between babies who received enteral feeds and babies from whom enteral feeds were withheld were markedly reduced (see Tables 8 and 9), as intended.

TABLE 8 - Background variables, by enteral feeding intervention groups, for unmatched and matched cohorts

Data are collected via a check box indicating presence of condition. Therefore, it is not possible to distinguish between missing data and presence of no condition.

Note

The results were averaged over 25 matched replications.

Variable	Cohort
	Unmatched		Matched
	No enteral feeds	Enterally fed	No enteral feeds	Enterally fed
Total number of babies	3975	1872	1618	1618
Male
n	2173	1055	903	903
%	54.7	56.4	55.8	55.8
Multiple birth
n	116	61	48	54
%	2.9	3.3	3.0	3.3
Gestational age at birth (weeks)
Mean	39.3	39.5	39.5	39.5
SD	1.6	1.5	1.5	1.5
Birthweight (g)
Mean	3358	3395	3403	3386
SD	621	636	625	633
Caesarean delivery
n	1921	738	649	638
%	50.6	41.2	41.9	41.1
Maternal age (years)
Median	30	31	31	31
Lower quartile	26	27	26.9	26.5
Upper quartile	34	35	35	35
Maternal suspected chorioamnionitis
n	406	240	202	187
%	12.6	15.2	15.2	13.7
Smoking in pregnancy
n	524	191	159	169
%	15.4	11.7	11.3	12
Missing, n	566	244	207	205
%	16.6	15	14.7	14.5
Ethnicity (maternal) (%)
White	65.4	63.3	74.5	74.9
Asian and mixed	10.0	10.7	12.5	12.2
Black and mixed	7	6.4	7.0	7.5
Other and missing	17.6	19.6	6.0	5.5
Maternal diabetesa
n	171	75	66	60
%	4.3	4.0	4.1	3.7
Deprivation score (LSOA) (%)
In deciles 1 or 2 (most deprived)	29.4	21.0	23.1	21.6
Primiparousa
n	2107	991	857	844
%	53	52.9	53	52.2

TABLE 9 - Neonatal clinical characteristics, by enteral feeding intervention groups, for unmatched and matched cohorts

Data are collected via a check box indicating presence of condition. Therefore, it is not possible to distinguish between missing data and presence of no condition.

Note

The results were averaged over 25 matched replications.

Variable	Cohort
	Unmatched		Matched
	No enteral feeds	Enterally fed	No enteral feeds	Enterally fed
Total number of babies	3975	1872	1618	1618
Cord blood gas pH: arterial
> 7.0, n	1240	613	536	536
%	44.1	45.4	46	46
6.9–7.0, n	661	318	262	262
%	23.5	23.5	22.5	22.5
< 6.9, n	913	420	368	368
%	32.4	31.1	31.6	31.6
Missing, n	1161	521	452	452
%	29.2	27.8	27.9	27.9
Apgar score at 1 minute
0 or 1, n	1886	778	720	687
%	47.4	41.6	44.5	42.5
2–4, n	1311	731	604	632
%	33.0	39.0	37.3	39.1
5–7, n	304	154	130	129
%	7.6	8.2	8	7.9
8–10, n	135	76	60	61
%	3.4	4.1	3.7	3.8
Missing, n	339	133	104	109
%	8.5	7.1	6.4	6.8
Apgar score at 5 minutes
0 or 1, n	695	223	231	198
%	17.5	11.9	14.3	12.2
2–4, n	1476	736	650	648
%	37.1	39.3	40.2	40
5–7, n	1140	623	490	537
%	28.7	33.3	30.3	33.2
8–10, n	324	166	147	132
%	8.2	8.9	9.1	8.2
Missing, n	340	124	100	103
%	8.6	6.6	6.2	6.4
Received chest compressions at resuscitationa
n	1555	608	560	532
%	39.1	32.5	34.6	32.9
Received resuscitation drugsa
n	683	209	191	183
%	17.2	11.2	11.8	11.3
Intubated at resuscitationa
n	2619	1126	1020	995
%	65.9	60.1	63	61.5
Time to first spontaneous breath
> 5 minutes, n	2369	1128	985	985
%	59.6	60.3	60.9	60.9
Missing, n	1011	452	383	387
%	25.4	24.1	23.7	23.9
Temperature (°C)
Mean	35.9	36.0	36	35.9
SD	1.3	1.2	1.2	1.2
Transfusion of any blood products on day of admission
n	641	196	180	172
%	16.1	10.5	11.1	10.6
Mechanical ventilation on day of admission
n	3176	1335	1196	1189
%	83.1	73.4	77.6	75.3
Inhaled nitric oxide on day of admission
n	201	57	56	51
%	5.3	3.2	3.7	3.3
Treatment with inotropes on day of admission
n	1099	320	295	288
%	29.0	17.9	19.3	18.5
Early-onset infection (in the first 3 days, defined using NNAP’s definition)
n	44	11	16	11
%	1.1	0.6	1.0	0.7
Admission from postnatal ward
n	30	14	14	11
%	0.8	0.7	0.9	0.7
Postnatal transfer to another neonatal unit within the first 48 hours
n	1908	913	790	796
%	48.0	48.8	48.8	49.2

Quality of the match for enteral feeding analysis

Figure 4 presents histograms of the estimated propensity scores from the final enteral feeding propensity model by intervention (i.e. received enteral feeds) and control (i.e. no enteral feeds) groups. There is good overlap of the propensity scores in the intervention and control groups and so many matched pairs can be formed. Data from 574 babies (9.8% of total sample) were discarded because of extreme propensities.

FIGURE 4.

Histograms of estimated propensity scores for primary enteral feeding analysis. Thick vertical dashed lines indicate trimming thresholds for extreme propensities, thin vertical dashed lines indicate propensity deciles for babies retained for the analysis. (a) Round 1, no enteral feeds; (b) round 1, received enteral feeds; (c) round 2, no enteral feeds; and (d) round 2, received enteral feeds.

Figure 5 presents the balance plot for the background variables included in the final enteral nutrition comparison propensity model. The dashed black line indicates perfect balance between the enteral nutrition for a specific background variable. The shaded area indicates the acceptable limits of imbalance for any variable, equivalent to an imbalance of ≤ 0.01 in absolute value. The imbalance for a specific background variable in the unmatched cohort is depicted by the bold dash, and the light dash indicates the opposite of this imbalance (imbalance multiplied by –1), which represents the same extent of imbalance. The imbalance in the matched cohort is marked by the black disc. The balances for the background variables are summarised by the mean of their absolute values. Prior to matching the mean balance is 0.064 and the balances are between –0.248 and 0.188. The mean balance for the matched data set is 0.0090 and the balances are between –0.037 and 0.029. The mean balances are displayed in Figure 5.

FIGURE 5.

Balance plot for primary analysis of the effect of enteral feeding (1 : 1 matching within propensity score deciles). The dashed black line indicates perfect balance for a specific background variable. The shaded area indicates the acceptable limits of imbalance for any variable, equivalent to an imbalance of ≤ 0.1 in absolute value. The imbalance for a specific background variable in the unmatched cohort is depicted by the bold dash and the light dash indicates the opposite of this imbalance (imbalance multiplied by –1), which represents the same extent of imbalance. The imbalance in the matched cohort is marked by the black disc. Mean balances are displayed in the bottom right of the figure. AdmitBG, admission glucose; AdmitBP, admission blood pressure; AdmitHR, admission heart rate; AdmitOS, oxygen saturation on admission; AdmitTempCe, admission temperature; AdmitTime, admission time; BloodTrans, blood transfusion on day 1; Bweight, birthweight; ChestCompr, chest compressions at resuscitation; CordBaseExcess, umbilical cord base excess; CordpHArt, umbilical cord arterial pH; CsinLabour, in-labour caesarean; FetusAtDelivC, presentation of fetus at delivery; GAweeks, gestational age in weeks; InstrDeliv, instrumental delivery; IntrPartAntiB, intrapartum antibiotics; LSOAdec, LSOA decile; MaternalDis, maternal obstetric condition; Ms, data for this item were missing; MulipleBrt, multiple birth set; OnsetLabour, spontaneous/induced labour; PostNTransfer, postnatal transfer; ProbMedic, maternal medical condition in pregnancy; prp, propensity; RespiSupprt, received respiratory support on day of admission; ResusDrugs, received drugs during resuscitation; SmokePreg, maternal smoking in pregnancy; SpontRespTime, time to first breath.

The balance plot (see Figure 5) demonstrates that several variables in the unmatched cohort exhibited large imbalances between the babies who were provided enteral feeds and the babies from whom enteral feeds were withheld. For example, unacceptable levels of imbalance (imbalance of > 0.1 in absolute value) between the two groups existed in the proportion of babies receiving respiratory support (see Figure 5, RespiSupprt) and the proportion of babies receiving blood transfusions (see Figure 5, BloodTrans). However, after the process of matching all background variables showed acceptable levels of imbalance and in the vast majority of cases the balance was much improved when compared with the unmatched cohort.

Results for outcomes in enteral feeding matched comparisons

The outcomes in babies who were enterally fed during therapeutic hypothermia and in babies who were not fed are presented in Table 10, in unmatched and matched cohorts. Tables 11 and 12 present the results for binary and continuous outcome variables, respectively. The results for dichotomised outcome variables can be found in Appendix 5, Table 32.

TABLE 10 - Outcome variables, by enteral feeding intervention groups, for unmatched and matched cohorts

Note

The results were averaged over 25 matched replications.

Variable	Cohort
	Unmatched		Matched
	No enteral feeds	Enterally fed	No enteral feeds	Enterally fed
Total number of babies	3975	1872	1618	1618
Severe NEC
n	< 5	< 5	< 5	< 5
NEC (pragmatic definition)
n	54	11	18	9
%	1.4	0.6	1.1	0.6
Late-onset infection (NNAP definition)
n	25	5	8	< 5
%	0.6	0.3	0.5
Late-onset infection (pragmatic definition)
n	1193	321	460	271
%	30.0	17.1	28.4	16.8
Survival at discharge
n	3498	1794	1465	1552
%	88.1	95.9	90.6	96.0
Hypoglycaemia
n	846	316	293	269
%	21.3	16.9	18.1	16.6
Breastfeeding at discharge
n	1690	1029	752	883
%	42.5	55.0	46.5	54.6
Onset of breastfeeding (days)
Median	7	6	7	6
Lower quartile	6	5	6	5
Upper quartile	10	8	9.4	8
Missing, n	1735	544	626	477
%	43.6	29.1	38.7	29.5
≤ 28 days, n	2211	1320	982	1133
%	55.6	70.5	60.7	70.0
Time to first mother’s milk (days)
Median	5	3	5	3
Lower quartile	5	2	5	2
Upper quartile	6	4	6	4
Missing, n	832	221	294	197
%	20.9	11.8	18.2	12.2
≤ 28 days, n	3140	1650	1324	1420
%	79.0	88.1	81.8	87.8
Received PN
n	1689	683	674	596
%	42.5	36.5	41.6	36.8
Duration of PN (days)
Median	3	3	3	3
Lower quartile	2	2	2	2
Upper quartile	5	3	5	3
Had a central venous line
n	3832	1637	1546	1417
%	96.4	87.4	95.5	87.6
Days of central venous line in situ
Median	5	4	5	4
Lower quartile	4	3	4	3
Upper quartile	7	5	6	5
Weight z-score at discharge
Median	–0.7	–0.6	–0.6	–0.7
Lower quartile	–1.5	–1.3	–1.4	–1.4
Upper quartile	0.1	0.2	0.2	0.1
Missing, n	2	9	4	8
%	0.1	0.5	0.1	0.3
Length of stay (days)
Median	11	10	11	10
Lower quartile	8	7	8	7
Upper quartile	17	13	16	13
> 14 days, n	1351	392	484	344
%	34.0	21.0	29.9	21.3

TABLE 11 - Analysis of binary outcome variables for babies provided with enteral feeds vs. babies for whom enteral feeds were withheld

n/a, not analysed.

Note

Results averaged over the 25 replications of the matching procedure.

Variable	Intervention, % (95% CI)		Rate difference, % (95% CI)	OR estimate (95% CI)	p-value
	No enteral feeds rate	Enterally fed rate
Total number of babies	1618	1618
Severe NEC	n/a	n/a	n/a	n/a	n/a
NEC (pragmatic definition)	1.1 (0.7 to 1.4)	0.5 (0.2 to 0.9)	–0.5 (–1.0 to –0.1)	0.50 (0.22 to 1.12)	0.03
Late-onset infection (NNAP definition)	0.5 (0.2 to 0.7)	0.3 (0.04 to 0.4)	–0.2 (–0.5 to 0.1)	0.55 (0.17 to 1.80)	0.19
Late-onset infection (pragmatic definition)	28.4 (26.7 to 30.0)	16.7 (15.0 to 184)	–11.6 (–14.0 to –9.3)	0.51 (0.43 to 0.60)	< 0.001
Hypoglycaemia	18.1 (16.7 to 19.5)	16.6 (15.0 to 18.3)	–1.5 (–3.7 to 0.6)	0.90 (0.75 to 1.08)	0.17
Survival at discharge	90.8 (89.7 to 91.8)	96.0 (95.0 to 96.8)	5.2 (3.9 to 6.6)	2.42 (1.80 to 3.26)	< 0.001
Breastfeeding at discharge	46.7 (44.8 to 48.5)	54.6 (52.4 to 56.8)	8.0 (5.1 to 10.8)	1.38 (1.20 to 1.58)	< 0.001

TABLE 12 - Analysis of continuous outcome variables for babies provided with enteral feeds vs. babies for whom enteral feeds were withheld

Note

Results averaged over the 25 replications of the matching procedure.

Variable	Intervention		Difference (95% CI)	p-value
	No enteral feeds	Enterally fed
Total number of babies	1618	1618
Length of stay (days) (95% CI)	14.8 (14.2 to 15.5)	12.7 (12.0 to 13.3)	–2.2 (–3.0 to –1.2)	< 0.001
First day suckling at breast (95% CI)	8.7 (8.4 to 9.0)	7.3 (6.9 to 7.7)	–1.4 (–1.9 to –0.9)	< 0.001
First day of maternal milk 95% CI)	5.4 (5.4 to 5.5)	3.3 (3.2 to 3.4)	–2.1 (–2.2 to –2.0)	< 0.001
Duration of PN (days) (95% CI)	3.7 (3.5 to 3.8)	3.0 (2.7 to 3.4)	–0.7 (–1.1 to –0.2)	0.02
Duration of central venous line in situ (days) (95% CI)	5.5 (5.3 to 5.7)	4.3 (4.1 to 4.5)	–1.2 (–1.5 to –0.9)	< 0.001
Weight z-score (95% CI)	–0.60 (–0.65 to –0.55)	–0.54 (–0.59 to –0.48)	0.06 (–0.01 to 0.13)	0.11

The incidence of severe NEC was so low that cases were potentially identifiable and, therefore, counts of < 5 were used in Tables 10 and 11. Owing to the small numbers of cases in both babies who were fed and babies from whom feeds were withheld, no further analyses were undertaken for severe NEC. Although it was rare in both groups, following matching the incidence of pragmatically defined NEC was lower in babies fed than in babies not fed during therapeutic hypothermia (0.5% and 1.1%, respectively; p = 0.03) (see Tables 10 and 11).

Late-onset infection, as defined using the NNAP definition, was rare and, after matching the incidence, was similar between babies fed and babies not fed during therapeutic hypothermia. We found no evidence (p = 0.19) of a difference in the rates of NNAP-defined late-onset infection between babies who received enteral feeds and babies from whom enteral feeds were withheld. However, when defined using the more pragmatic definition, there was strong evidence (p < 0.001) that the risk of late-onset infection was lower in babies who were provided with enteral feeds. Babies who were provided with enteral feeds were estimated to have approximately half the odds of having pragmatically defined late-onset infection than babies from whom enteral feeds were withheld (OR 0.51, 95% CI 0.43 to 0.60) (see Table 11).

We found strong evidence (p < 0.001) of a higher survival rate in babies who were fed during therapeutic hypothermia in the matched comparison, in addition to higher rates of breastfeeding at discharge (p < 0.001) (see Tables 10 and 11). In matched comparisons, babies who received enteral feeds during therapeutic hypothermia had a mean length of stay of 2.2 days (95% CI 1.2 to 3.0 days) shorter than those babies who were not fed (p < 0.001) and a mean duration of central line placement in situ that was 1.2 days (95% CI 0.9 to 1.5 days) shorter than those who were not fed (p < 0.001) (see Table 12). Similar patterns were observed in matched comparisons for the dichotomised versions of the continuous outcomes. The odds of a baby staying in the neonatal unit for > 14 days was reduced by an estimated 37% in babies fed compared with those from whom enteral feeds were withheld (OR 0.63, 95% CI 0.54 to 0.74; p < 0.001) (see Appendix 5, Table 32).

Patterns of enteral feeding

Details of the types of milk that babies received during therapeutic hypothermia and up to day 7, in both matched and unmatched cohorts, are shown in Figure 6. In both cohorts, the most common enteral feed type was mother’s breast milk. There were a substantial number of missing data on the type of milk provided to babies on the first day of life.

FIGURE 6.

Type of enteral feeds provided up to 7 days of life for babies treated with therapeutic hypothermia, in (a) unmatched and (b) matched cohorts, as a proportion of babies who received enteral feeds.

In the unmatched cohort the median time to first enteral feed was 5 days after birth, with the probability of being enterally fed reaching 80% at 6 days after birth.

The highest rates of enteral feeding were in the North West London ODN and South East Coast ODN (89% and 59% of babies treated with therapeutic hypothermia, respectively). The lowest rates of enteral feeding during therapeutic hypothermia were in West Midlands (12%), East Midlands (13%) and Wales (13%) (Table 14).

TABLE 14 - Provision of enteral feeding during therapeutic hypothermia by neonatal ODN

Note

Seventeen babies were treated at units that could not be assigned to a relevant ODN and a further 181 babies were missing information on enteral feeding status.

ODN	Provision of enteral feeds
	No		Yes
	n	%	n	%
East Midlands	313	86.9	47	13.1
East of England	369	68.0	174	32.0
North Central and East London	324	72.5	123	27.5
North West	521	81.8	116	18.2
North West London	25	11.0	203	89.0
Northern	157	69.5	69	30.5
South East Coast	228	41.0	328	59.0
South West	314	62.6	188	37.5
South London	253	66.1	130	33.9
Thames Valley and Wessex	361	63.9	204	36.1
West Midlands	492	88.0	67	12.0
Yorkshire and the Humber	290	70.7	120	29.3
Isle of Man	< 5		< 5
Scotland	121	63.0	71	37.0
Wales	194	86.6	30	13.4
Total	3962	67.9	1870	32.1

Parenteral nutrition analysis

Primary analysis

Background variables in unmatched and matched cohorts

Tables 15 and 16 (see also Appendix 8, Tables 34–37) present the background characteristics of babies recorded as having received PN during therapeutic hypothermia and those babies who were not recorded as receiving PN, before and after matching. Prior to matching, the characteristics of babies who received PN were similar to those who did not receive PN, although the latter tended to have higher proportions of mothers from areas of deprivation. After matching, differences in baseline characteristics between babies who received PN and babies who did not receive PN were reduced (see Tables 15 and 16).

TABLE 15 - Background variables, by parenteral nutrition intervention groups, for unmatched and matched cohorts

Data are collected via a checkbox indicating presence of condition. Therefore, it is not possible to distinguish between missing data and presence of no condition.

Note

The results were averaged over 25 matched replications.

Variable	Cohort
	Unmatched		Matched
	No PN	PN	No PN	PN
Total number of babies	4535	1475	1240	1240
Male
n	2507	810	652	664
%	55.3	54.9	52.6	53.5
Multiple birth
n	121	58	42	45
%	2.7	3.9	3.4	3.6
Gestational age at birth (weeks)
Mean	39.4	39.29	39.4	39.4
SD	1.55	1.6	1.6	1.6
Birthweight (g)
Mean	3385	3321	3330	3328
SD	621	631	609	628
Caesarean delivery
n	2066	667	545	549
%	47.7	47.1	45.9	46.1
Maternal age (years)
Median	30	31	30	31
Lower quartile	26	26	26	26
Upper quartile	35	34	34	34
Maternal suspected chorioamnionitis
n	479	175	147	150
%	12.8	14.5	14.5	14.6
Smoking in pregnancy
n	520	211	175	176
%	13.3	16.9	16.6	16.8
Ethnicity (maternal) (%)
White	65.7	61.4	80.8	79.9
Asian and mixed	11.2	6.8	7.9	7.5
Black and mixed	7.5	4.3	4.3	5
Other and missing	15.5	27.5	6.9	7.6
Maternal diabetesa
n	191	65	49	53
%	4.2	4.4	4.0	4.3
Deprivation score (LSOA) (%)
In deciles 1 or 2 (most deprived)	27.9	22.3	23.9	21.7
Primiparousa
n	2425	778	669	671
%	53.5	52.7	54	54.1

TABLE 16 - Neonatal clinical characteristics, by parenteral nutrition intervention groups, for unmatched and matched cohorts

Data are collected via a checkbox indicating presence of condition. Therefore, it is not possible to distinguish between missing data and presence of no condition.

Note

The results were averaged over 25 matched replications.

Variable	Cohort
	Unmatched		Matched
	No PN	PN	No PN	PN
Total number of babies	4535	1475	1240	1240
Cord blood gas pH: arterial
> 7.0, n	1439	451	396	396
%	44.4	44.0	45.3	45.3
6.9–7.0, n	756	248	198	198
%	23.3	24.2	22.7	22.7
< 6.9, n	1049	326	280	280
%	32.3	31.8	32.0	32.0
Missing, n	1291	450	366	366
%	28.5	30.5	29.5	29.5
Apgar score at 1 minute
0 or 1, n	2062	679	553	562
%	45.5	46.0	44.6	45.3
2–4, n	1601	494	429	415
%	35.3	33.5	34.6	33.5
5–7, n	347	116	99	99
%	7.7	7.9	8	8
8–10, n	165	53	47	49
%	3.6	3.6	3.7	4.0
Missing, n	360	133	113	115
%	7.9	9.0	9.1	9.3
Apgar score at 5 minutes
0 or 1, n	730	218	188	182
%	16.1	14.8	15.1	14.7
2–4, n	1704	563	450	470
%	37.6	38.2	36.2	37.9
5–7, n	1372	433	389	362
%	30.3	29.4	31.3	29.2
8–10, n	374	130	107	116
%	8.2	8.8	8.6	9.4
Missing, n	355	131	107	109
%	7.8	8.9	8.6	8.8
Received chest compressions at resuscitationa
n	1705	523	431	427
%	37.6	35.5	34.8	34.4
Received resuscitation drugsa
n	719	206	176	172
%	15.9	14.0	14.2	13.9
Intubated at resuscitationa
n	2925	935	784	783
%	64.5	63.4	63.2	63.1
Time to first spontaneous breath
6 (> 5 minutes) , n	2701	896	757	758
%	59.6	60.7	61	61.1
Missing, n	1160	344	283	284
%	25.6	23.3	22.8	22.9
Time to admission (minutes)
Median	30	30	30	29
Lower quartile	20	20	21	20
Upper quartile	44	45	45	44
Temperature (°C)
Mean	35.9	35.9	35.9	35.9
SD	1.3	1.2	1.3	1.2
Transfusion of any blood products on day of admission
n	648	214	195	187
%	14.3	14.5	15.8	15.1
Mechanical ventilation on day of admission
n	3508	1122	951	956
%	80.2	79.5	79.6	80.2
Inhaled nitric oxide on day of admission
n	197	70	50	58
%	4.5	5.0	4.2	4.9
Treatment with inotropes on day of admission
n	1126	335	295	287
%	26.0	23.9	25.0	24.2
Early-onset infection (in the first 3 days, defined using NNAP definition)
n	37	18	9	14
%	0.8	1.2	0.7	1.1
Admission from postnatal ward
n	32	12	11	11
%	0.7	0.8	0.9	0.9
Postnatal transfer to another neonatal unit within the first 48 hours
n	2219	640	546	549
%	48.9	43.4	44.0	44.2

Quality of the match of parenteral nutrition analysis

Figure 7 presents the estimated propensity scores from the primary PN comparison propensity model by intervention (i.e. received PN) and control (i.e. did not receive PN) groups. The fitted propensities for the two treatment groups have good overlap. Data from 687 babies (11.4% of unmatched sample) were discarded because of extreme propensities.

FIGURE 7.

Histograms of estimated propensity scores for primary parenteral nutrition analysis. Thick vertical dashed lines indicate trimming thresholds for extreme propensities and thin vertical dashed lines indicate propensity deciles for babies retained for analysis. (a) Round 1, no parental nutrition; (b) round 1, received parental nutrition; (c) round 2, no parental nutrition; and (d) round 2, received parental nutrition.

Figure 8 presents the balance plot for the background variables included in the primary propensity model for the PN comparison. As previously, the dashed black line indicates perfect balance between the PN analysis groups for each specific background variable. The shaded area indicates the acceptable limits of imbalance for the variables, from –0.1 to 0.1. The imbalance for a specific background variable in the unmatched cohort is marked by a bold dash and the light dash indicates this imbalance by –1 to facilitate comparison to imbalance in the matched cohort, which itself is marked by the black disc. The balances for the background variables are summarised by the mean of their absolute values. Prior to matching, the mean balance is 0.061 and the balances are in the range from –0.215 to 0.563. The mean balance for the matched data set is 0.010 and the balances are between –0.025 and 0.051. The mean balances are displayed in Figure 8.

FIGURE 8.

Balance plot for primary analysis of the effect of parenteral nutrition (1 : 1 matching within propensity score deciles). The dashed black line indicates perfect balance for a specific background variable. The shaded area indicates the acceptable limits of imbalance for any variable, equivalent to an imbalance of ≤ 0.1 in absolute value. The imbalance for a specific background variable in the unmatched cohort is depicted by the bold dash and the light dash indicates the opposite of this imbalance (multiplied by –1), which represents the same extent of imbalance. The imbalance in the matched cohort is marked by the black disc. Mean balances are displayed in the bottom right of the figure. AdmitBG, admission glucose; AdmitBP, admission blood pressure; AdmitHR, admission heart rate; AdmitOS, oxygen saturation on admission; AdmitTempCe, admission temperature; AdmitTime, admission time; BloodTrans, blood transfusion on day 1; Bweight, birthweight; ChestCompr, chest compressions at resuscitation; CordBaseExcess, umbilical cord base excess; CordpHArt, umbilical cord arterial pH; CsinLabour, in-labour caesarean; FetusAtDelivC, presentation of fetus at delivery; GAweeks, gestational age in weeks; InstrDeliv, instrumental delivery; IntrPartAntiB, intrapartum antibiotics; LSOAdec, LSOA decile; MaternalDis, maternal obstetric condition; Ms, data for this item were missing; MulipleBrt, multiple birth set; OnsetLabour, spontaneous/induced labour; PostNTransfer, postnatal transfer; ProbMedic, maternal medical condition in pregnancy; prp, propensity; RespiSupprt, received respiratory support on day of admission; ResusDrugs, received drugs during resuscitation; SmokePreg, maternal smoking in pregnancy; SpontRespTime, time to first breath.

The balance plot shows that several variables in the unmatched cohort exhibited large imbalances between the two treatment groups. For example, unacceptable levels of imbalance (i.e. an imbalance of > 0.1 in absolute value) were present for ethnicity other or not given, and missing deprivation score. After matching, all background variables showed acceptable levels of imbalance. Several variables, including sex and proportion of babies delivered by caesarean section, demonstrated slightly greater imbalances after matching. The balance plot confirms that these imbalances are not substantial and that all variables included in the propensity model have acceptable levels of imbalance after matching.

Results for outcomes in parenteral nutrition matched comparisons

Outcomes for babies who received PN during therapeutic hypothermia and babies who did not are presented in Table 17, in unmatched and matched cohorts. Tables 18 and 19 present the results for binary and continuous outcome variables. The results for dichotomised outcome variables can be found in Appendix 9, Table 38.

TABLE 17 - Outcome variables, by parenteral nutrition intervention groups, for unmatched and matched cohorts

Note

The results were averaged over 25 matched replications.

Variable	Cohort
	Unmatched		Matched
	No PN	PN	No PN	PN
Total number of babies	4538	1476	1240	1240
Late-onset infection (NNAP definition)
n	16	14	< 5	11
%	0.4	0.9		0.9
Late-onset infection (pragmatic definition)
n	1175	383	313	323
%	25.9	26.0	25.3	26.1
Severe NEC
n	6	< 5	7	< 5
%	0.1		0.6
NEC (pragmatic definition)
n	52	16	17	13
%	1.1	1.1	1.4	1.1
Survival at discharge
n	4056	1374	1116	1154
%	89.5	93.2	90.0	93.1
Hypoglycaemia
n	946	258	235	212
%	20.9	17.5	18.9	17.1
Breastfeeding at discharge
n	2110	670	582	575
%	46.5	45.4	47.0	46.4
Onset of breastfeeding (days)
Median	7	7	7	7
Lower quartile	6	6	6	6
Upper quartile	9	9	9	9
Missing, n	1774	576	488	474
%	39.1	39.1	39.3	38.2
≤ 28 days, n	2735	888	744	757
%	60.3	60.2	60.0	61.0
Time to first mother’s milk (days)
Median	5	5	5	5
Lower quartile	4	3	4	3
Upper quartile	6	5	6	5
Missing, n	868	223	235	182
%	19.1	15.1	18.9	14.7
≤ 28 days, n	3665	1250	1005	1057
%	80.8	84.7	81.1	85.2
Had a central venous line
n	4184	1441	1145	1213
%	92.3	97.7	92.3	97.9
Days of central venous line in situ
Median	5	5	5	5
Lower quartile	3	4	3	4
Upper quartile	6	7	6	7
Weight z-score at discharge
Median	–0.6	–0.7	–0.7	–0.6
Lower quartile	–1.4	–1.4	–1.4	–1.4
Upper quartile	0.2	0.1	0.1	0.2
Missing, n	9	2	8	4
%	0.2	0.1	0.2	0.2
Length of stay (days)
Median	11	10	10	11
Lower quartile	8	7	8	8
Upper quartile	17	13	16	16
> 14 days, n	1338	466	361	382
%	29.5	31.6	29.1	30.8

TABLE 18 - Analysis of binary outcome variables for babies provided with parenteral nutrition vs. babies from whom parenteral nutrition was withheld

n/a, not analysed.

This p-value is common to the OR and to the difference in rates. Overlap of the CI cannot be taken for significance because it involves two intervals, both with a 5% margin.

Note

The data were for results averaged over 25 matched replications.

Variable	Intervention, % (95% CI)		Rate difference, % (95% CI)	OR estimate (95% CI)	p-value
	No PN rate	PN rate
Total number of babies	1240	1240
Late-onset infection (NNAP definition)	0.3 (0.1 to 0.5)	0.9 (0.4 to 1.4)	0.6 (0.1 to 1.2)	3.04 (0.95 to 9.76)	0.03a
Late-onset infection (pragmatic definition)	25.3 (23.6 to 27.1)	26.1 (23.8 to 28.3)	0.8 (–2.1 to 3.6)	1.04 (0.87 to 1.25)	0.61
Severe NEC	n/a	n/a	n/a	n/a	n/a
NEC (pragmatic definition)	1.4 (0.9 to 1.9)	1.1 (0.6 to 1.6)	–0.3 (–1.0 to 0.4)	0.77 (0.38 to 1.58)	0.39
Hypoglycaemia	19.0 (17.5 to 20.6)	17.0 (15.1 to 18.9)	–2.1 (–4.5 to 0.4)	0.87 (0.71 to 1.07)	0.10
Survival at discharge	89.9 (88.7 to 91.1)	93.2 (91.8 to 94.5)	3.1 (1.5 to 4.7)	1.50 (1.17 to 2.01)	< 0.001
Breastfeeding at discharge	47.0 (45.1 to 48.9)	46.4 (43.9 to 48.9)	–0.6 (–3.8 to 2.6)	0.98 (0.83 to 1.14)	0.71

TABLE 19 - Analysis of continuous outcome variables for babies provided with parenteral nutrition vs. babies from whom parenteral nutrition was withheld

Note

The data were for results averaged over 25 matched replications.

Variable	Intervention		Difference (95% CI)	p-value
	No PN	PN
Total number of babies	1240	1240
Length of stay (days) (95% CI)	14.1 (13.6 to 14.7)	15.0 (14.1 to 15.8)	0.8 (–0.2 to 1.8)	0.12
Onset of breastfeeding (days) (95% CI)	8.4 (8.0 to 8.7)	8.6 (8.0 to 9.1)	0.2 (–0.5 to 0.8)	0.56
First maternal milk (days) (95% CI)	4.9 (4.8 to 4.9)	4.6 (4.5 to 4.8)	–0.2 (–0.4 to –0.1)	0.01
Duration of central venous line in situ (days) (95% CI)	5.1 (5.0 to 5.3)	6.0 (5.7 to 6.3)	0.9 (0.5 to 1.2)	< 0.001
Weight z-score (95% CI)	–0.66 (–0.71 to –0.61)	–0.65 (–0.71 to –0.58)	0.02 (–0.07 to 0.10)	0.68

Although late-onset infection defined using the NNAP definition was rare, there was some evidence (p = 0.03) of increased late-onset infection in babies who were provided PN compared with babies from whom PN was withheld during therapeutic hypothermia (risk difference 0.6%, 95% CI 0.1% to 1.2%). Late-onset infection defined using the more pragmatic definition was more common, but we found no evidence of a difference (p = 0.61) in incidence between babies who did and did not receive PN during therapeutic hypothermia (see Table 18). Mortality was lower among babies who received PN during therapeutic hypothermia in the matched comparison. There was no evidence of differences between matched groups in the incidence of hypoglycaemia, pragmatically defined NEC or breastfeeding at discharge. The incidence of severe NEC was so low that cases were potentially identifiable and, therefore, counts of < 5 were used and comparative analyses after matching were not undertaken for this comparison.

After matching, length of stay, time to first breastfeed, time to first feed with maternal breast milk and weight at discharge were all similar between babies who received PN during therapeutic hypothermia and those who did not (see Table 19). Although there was a statistically significant difference in time to first feed with maternal breast milk, this difference of 0.2 days (95% CI 0.1 to 0.4 days) was not considered clinically important. Babies who did not receive PN had a shorter duration with a central line in situ, with a mean difference of approximately 1 day (p < 0.001).

Similar patterns were observed in matched comparisons when continuous outcomes were dichotomised. Babies who did not receive PN had a lower rate of any central line insertion than babies who received PN (92.4% vs. 97.9%; p < 0.001) (see Appendix 9, Table 38).

Key results

In this large, UK population-based cohort of term and near-term infants treated with therapeutic hypothermia, we identify widespread variation in nutritional practice, with sizable minorities of babies receiving milk feeds and/or PN during hypothermia. We demonstrate that severe NEC, using a robust and validated definition, is rare in this population, with an incidence of < 1 per 1000 babies. Late-onset, culture-positive BSI is also rare in these infants, occurring in approximately 5 per 1000 infants.

To identify optimal nutritional management we undertook comparative analyses using matched groups that were balanced on multiple potentially confounding background variables and followed a pre-registered protocol. 34 We found that severe NEC, defined using a validated case definition,21 was comparatively rare whether or not babies were fed during therapeutic hypothermia. We used a more pragmatic definition of NEC to identify potential cases that were not fatal and did not require surgery, and, although NEC defined in this way was rare, it was somewhat more common in babies for whom feeds were witheld during therapeutic hypothermia. Introduction of feeds during therapeutic hypothermia was associated with benefit across multiple other outcomes in matched analyses, including earlier initiation of breastfeeding and higher rates at discharge, lower rates of pragmatically defined late-onset infection, shorter lengths of stay and higher survival to neonatal unit discharge. When feeds were introduced they were predominantly maternal breast milk and tended to be started later in the course of therapeutic hypothermia. Based on the consistent benefit associated with introduction of milk feeding during hypothermia, we conclude that initiating milk feeds, preferably with maternal breast milk, during therapeutic hypothermia is safe and may be beneficial.

Matched analyses comparing babies who received PN during therapeutic hypothermia with those who did not found more mixed results. Although culture-positive infection was rare in both groups, it was more common in babies who received PN. Conversely, survival to discharge rates were higher in babies who received PN. Results for other outcomes, such as breastfeeding outcomes and length of stay, were similar between babies who received PN and those who did not, with the exception of central line duration, which was longer in babies who received PN. The apparent survival benefit seen in babies who received PN is contrary to RCT data from neonates being cared for on paediatric intensive care units. 35 This result may reflect residual confounding by indication, favouring babies who received PN.

Putative benefits from administering PN to infants during therapeutic hypothermia include improved brain growth and repair, potentially leading to improved neurodevelopment. 36 In this study we were unable to examine later neurodevelopmental outcomes because of high incompleteness of such data within currently available routine databases. Therefore, we were unable to evaluate a key potential benefit of administering PN in this group. Conclusions from this study are uncertain in relation to provision of PN during therapeutic hypothermia, and are consistent with both potential benefits and potential harms from this practice. We are unable to identify an optimal approach to PN during therapeutic hypothermia using currently available routinely recorded neonatal data and recommend further prospective interventional research that captures longer-term neurodevelopmental outcomes.

Results in context

This study involved > 6000 infants who received therapeutic hypothermia and reports population-level data from all babies admitted to NHS neonatal care in England, Scotland and Wales (neonatal intensive care such as therapeutic hypothermia is not undertaken at non-NHS units in the UK). To the best of our knowledge, this is the largest and most comprehensive cohort of such babies. For comparison, the most recent Cochrane review2 in this area identified 11 trials and 1505 infants in total. NEC is one of the most feared complications of neonatal care6 and is well described in case studies and single-centre series in babies with HIE. 37,38 There has been a paucity of robust incidence data because studies have hitherto been limited by small size and the use of subjective definitions of NEC. By applying a validated definition of severe NEC with confirmation of cases to large-scale population data,21 we have produced robust incidence rates for rare but important outcomes (e.g. NEC and late-onset infection) in babies receiving therapeutic hypothermia.

Using routinely recorded national data we have accurately described current nutritional practice in the UK for babies receiving therapeutic hypothermia, in contrast to previous studies that have relied on surveys that report intention rather than actual practice. 3 We find that feeding during therapeutic hypothermia occurs less commonly in practice (i.e. 31% of babies) than would be suggested by the most recent survey3 (in which 59% of responding neonatal units reported feeding during hypothermia). Furthermore, and in contrast to surveys of UK practice that suggest that enteral feeding is becoming more common during hypothermia (i.e. 29% of units in 20106 vs. 59% of units in 20163), we found that the proportion of babies for whom enteral feeds were introduced (31%) remained stable over the 8-year period 2010–17. These findings may be explained by incomplete survey coverage or simply reflect the difference between reported and actual practice. We note that the rate of PN administration seen in this study (i.e. 25%) more closely mirrors that seen in the most recent UK survey3 (i.e. 29%).

Our finding that the introduction of enteral feeding during therapeutic hypothermia is safe and may be associated with benefits such as a lower risk of pragmatically defined NEC, earlier initiation of breastfeeding, higher rates of breastfeeding at discharge and shorter lengths of stay is supported by the limited data from previous studies. 4,5 A retrospective case–control study4 of 34 infants in the USA compared minimal enteral nutrition with withholding feeds during therapeutic hypothermia, and found that the duration of PN and hospital stay was shorter in the enteral feeding group. This study did not adjust for illness severity and there were some differences between groups, for example in relation to clinical staging of encephalopathy. 4 This suggests that confounding by indication (whereby infants who are more sick have their feeds withheld) may in part explain these results. Another small retrospective study5 compared 34 babies cared for at a unit in the UK in which feeds are commonly withheld with 51 babies cared for in Sweden where feeds are commonly initiated during hypothermia. 5 In keeping with our data, this study also found that feeding during hypothermia was safe, with no complications noted in either group. In addition, rates of breastfeeding at discharge were higher among babies cared for in Sweden where enteral feeds were started during hypothermia. The degree to which this is explained by cultural and social differences between countries, rather than initiation of treatment, is unclear. Our study adds considerably to the existing literature through the very large population-level nature of the cohort and by application of statistically robust approaches to deal with potential confounding in comparative analyses.

In the UK and other high-income settings, infants who receive therapeutic hypothermia receive some form of intravenous fluid to maintain hydration and blood glucose concentration. This can be in the form of intravenous fluid or PN. We find that the use of PN is associated with a higher incidence of culture-positive BSI, but also with lower mortality prior to neonatal discharge. This latter finding is counter to adult and paediatric intensive care trials that demonstrated clinical benefits from later compared with early initiation of PN. 15,16 Although similar trials have not been undertaken in neonatal intensive care units or among infants receiving therapeutic hypothermia, the paediatric intensive care-based PEPaNIC (Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit) trial15 randomised 209 infants in the neonatal period (< 28 days) to early (i.e. < 24 hours after admission) or late (i.e. > 7 days after admission) commencement of PN. Pre-planned secondary analysis of these infants found lower rates of infection in babies recruited at < 1 week of age and randomised to receive early PN,35 in keeping with our study. This secondary neonatal analysis found similar mortality between early and late PN groups, but mortality was low in both trial arms and, therefore, the trial lacked power to detect a clinically important difference. The PEPaNIC trial15 also found higher rates of hypoglycaemia in neonates randomised to late PN, which is not confirmed in our study. This may be explained by how data are held in the NNRD, whereby diagnoses (such as hypoglycaemia) are not recorded in a way that is attributable to a particular day of stay, but are attributed to an ‘episode’ of care on a particular neonatal unit. As a result, we were unable to determine whether or not hypoglycaemic episodes occurred during the period of therapeutic hypothermia. We were unable to identify further studies that examined the use of PN in babies receiving therapeutic hypothermia. The conflicting findings seen both in this study and when considered with the of the PEPaNIC trial15 indicate that further research is required to identify the role of PN in these babies. We note that supplemental nutrition following brain injury has shown promise in a small pilot trial,36 supporting a potential role of early nutrition in optimising longer-term neurodevelopmental outcomes and highlighting the importance of such outcomes in any future research.

Strengths and limitations

The main aim of this study was to identify optimal approaches to nutrition through comparative analyses of babies fed milk and those not fed milk, and between babies who received PN and babies who did not. Although we did not undertake a randomised trial, we applied multiple approaches to limit bias. We utilised the comprehensive range of background data items held in the Neonatal Data Set19 and available within the NNRD to form matched groups, balanced on all measured potential confounders by matching on key background factors and on propensity score. To prevent outcome switching or data dredging, we followed a detailed pre-registered protocol that specified exposures, background factors and outcomes, and the data items used to define them, as well as the matching process to be applied. 34 The use of routinely recorded data reduced the risk of ascertainment bias, as data collection occurred well in advance of study conception. Furthermore, we applied prespecified sensitivity analyses to examine whether or not data quality and definitions of the nutritional exposures influenced results, and post hoc sensitivity analyses to determine whether or not different approaches to matching influenced the findings. Finally, primary results were robust to sensitivity analyses. By using existing data we were able to include a large number of infants and to examine rare outcomes, such as pragmatically defined NEC and culture-positive BSI. The sample size was several times larger than in all previous randomised trials of therapeutic hypothermia combined. 2 A further strength of this study was the considerably lower level of resources required to undertake it. The study was funded at < 10% of the cost of contemporaneous National Institute for Health Research-funded neonatal clinical trials and reported over a shorter time frame.

The most important limitation of this study stems from the non-randomised design used (i.e. the matching approach applied in this study was able to account for only measured confounders). Although we utilised a wide range of background and day 1 clinical data items to form matched groups, and the statistical measures of balance indicated that acceptable balance had been obtained, we cannot exclude the possibility that clinically relevant factors may have differed by small but clinically relevant degrees between the groups, or that there were important differences in unmeasured factors between the comparator groups. In matched analyses we found higher survival to neonatal unit discharge in babies who were fed during therapeutic hypothermia. This difference in survival is unlikely to be caused by enteral feeding during therapeutic hypothermia and suggests that residual confounding is present in the enteral comparison. This is supported by background data indicating that, although the proportion of babies receiving inotropes on the first day was more balanced after matching, a potentially clinically relevant difference remained (see Table 9). Furthermore, there may be other additional markers of ‘sickness’ that are discernible to clinicians and influence decision-making around enteral feeding, but are not captured in the extensive data items held in the NNRD. Such residual and unmeasured confounding by indication may overestimate the benefit associated with enteral feeding, and results should be interpreted accordingly. However, in the light of the low rate of adverse outcomes seen in both fed and non-fed infants, and the consistent benefit seen across outcomes favouring fed infants, we conclude that initiating milk feeds, preferably with maternal breast milk, during therapeutic hypothermia is safe and may be beneficial.

Similar residual or unmeasured confounding by indication may be present in the comparative analyses of PN. This study found a higher level of survival among babies treated with PN, despite higher levels of culture-positive late-onset BSI, a finding that is counter to randomised trials of early compared with late PN in adults. Such confounding is, again, likely to overestimate the benefit of early PN in this population of infants. Given the more mixed results of the PN analyses, which were consistent with both benefit and harm from early administration of PN, we suggest further randomised evaluations of early PN in this group.

Other limitations include the smaller than planned numbers of infant pairs that were able to be included in the matched analyses (i.e. 1618 pairs were analysed for the enteral nutrition analysis and 1240 pairs for the PN analysis vs. estimated samples of 2000 matched pairs and 1500 matched pairs, respectively). The planned numbers of pairs were selected for illustration only and did not represent an imperative or objective of the study design. Consequently, the lower than planned achieved number of pairs should not be interpreted as indicating that the study is underpowered. These matched groups were still considerably larger than in previous trials2 and are able to detect small but clinically relevant differences of 1.0% in NEC and 2.5% in the incidence of late-onset infection. As with any study that utilises routinely recorded data, data completeness and accuracy are dependent on the health-care professionals who enter the data and may be variable between sites. The NNRD is formed from data entered as part of a baby’s clinical care record and data are used for multiple purposes, including national audit and determining neonatal unit activity for purposes such as funding and staffing. Furthermore, the data held in the NNRD have been validated against those data recorded in case record forms of a multicentre trial,39 which demonstrated a high degree of data agreement (> 95%) for multiple background and outcome variables,10 including key data items for this study, such as receipt of enteral feeds and presence of central line in situ. This validation study did not examine other key data items used in this study, such as receipt of therapeutic hypothermia, administration of PN or type of enteral feed (for which considerable missing data were found on day 1; see Figure 6), and, therefore, data quality for such items is less well known. For these reasons, we do not consider incomplete and inaccurate data to be a major problem in this study. Given the retrospective nature of this study and the routine nature of data collection, there is no reason for poor data quality to be more common in one comparative arm than another and, therefore, any incompleteness or inaccurate data would be expected to lead to imprecision in all estimates, rather than any systematic bias. We also acknowledge that cases of both severe and pragmatic NEC may have been missed when suspected NEC occurred in infants with severe encephalopathy and a decision to provide palliative care had been made. When NEC was felt to contribute to the infant death then this would have been recorded on the death certificate (and hence in the severe NEC definition) and so the incidence of such missed cases is likely to be very low. Finally, limitations in the data available within the NNRD meant that we were unable to examine the relationship between volume of feeds, including very small-volume or ‘trophic feeds’, and outcomes in this study.

Interpretation

The incremental introduction of enteral feeds in term and near-term babies during therapeutic hypothermia appears safe and may be associated with benefits including higher rates of breastfeeding at discharge and shorter lengths of stay.

Necrotising enterocolitis is rare in term and near-term babies receiving therapeutic hypothermia and may be less common in babies fed during therapeutic hypothermia.

Optimal parenteral nutritional support for babies receiving therapeutic hypothermia could not be established.

Generalisability

This study used data from all babies who were ≥ 36 gestational weeks of age and who were recorded as receiving therapeutic hypothermia in NHS neonatal units, over a contemporary 8-year period. As ongoing neonatal intensive care is not undertaken outside NHS units, this population-level study is highly generalisable to current neonatal care in the UK and other high-income health-care systems. We did not limit the study to infants who met National Institute for Health and Care Excellence guidance for therapeutic hypothermia and, therefore, the analysed population included infants who were treated for mild HIE and other conditions (e.g. postnatal collapse). As such babies are increasingly treated with therapeutic hypothermia in the UK40 and internationally, the results of this study are therefore generalisable to current clinical practice, where ‘therapeutic creep’ is widespread in relation to hypothermia treatment.

We did not include preterm babies earlier than 36 gestational weeks of age in this study because of the specifications laid out by the funder when commissioning this research. More preterm infants have higher rates of feed intolerance than term infants and the results of this study may not be generalisable to these more preterm babies receiving therapeutic hypothermia. A number of infants who received therapeutic hypothermia were not able to be matched (see Figure 3). This occurred because for babies with certain background profile one or the other nutritional management was selected almost exclusively by clinical staff. Consequently, the results of this study are generalisable to the range of infants described by the matched cohorts, rather than the wider population of all infants who received therapeutic hypothermia.

Recommendations/implications for future research

• Optimal PN for babies receiving therapeutic hypothermia is unknown. This should be examined in a RCT comparing early with delayed provision of PN, which should examine both short-term outcomes, such as late-onset infection and neonatal survival, and longer-term outcomes, such as neurodevelopment.

• Future RCTs to examine enteral feeding during therapeutic hypothermia are unlikely to be warranted or feasible. The optimal speed of introduction of enteral feeds or optimal choice of milk when mothers’ milk is not available are not known and may benefit from further research.

• Mechanisms to obtain population-level, long-term outcome data for babies who receive neonatal care generally and babies who are treated with hypothermia specifically, such as data linkage and national routine reporting, should be prioritised.

Contributions of authors

Chris Gale (https://orcid.org/0000-0003-0707-876X) (Reader in Neonatal Medicine and Consultant Neonatologist) conceived, designed and planned the study. He contributed to planning data extraction and analysis, interpretation of results and wrote the first and final draft of the study report.

Dusha Jeyakumaran (https://orcid.org/0000-0002-8209-9694) (Neonatal Research Statistician) contributed to planning data extraction, analysis and interpretation the results, wrote the first draft of the study report and contributed to and approved the final report.

Cheryl Battersby (https://orcid.org/0000-0002-2898-553X) (Senior Clinical Lecturer in Neonatal Medicine and Consultant Neonatologist) conceived, designed and planned the study. She contributed to planning data extraction and analysis, undertook data extraction, interpreted the results, and contributed to and approved the final report.

Kayleigh Ougham (https://orcid.org/0000-0002-6724-1867) (Senior Data Analyst) contributed to the planning of the study and led data extraction. She contributed to and approved the final report.

Shalini Ojha (https://orcid.org/0000-0001-5668-4227) (Clinical Associate Professor in Neonatal Medicine and Consultant Neonatologist) conceived, designed and planned the study. She contributed to the analysis and interpretation of the results. She contributed to and approved the final report.

Lucy Culshaw (https://orcid.org/0000-0002-4542-2659) (Senior Research Engagement Officer at Bliss) contributed to the planning of the study and interpretation of results. She led parent involvement in the study, and contributed to and approved the final report.

Ella Selby (https://orcid.org/0000-0002-1125-7712) (parent with experience of having a baby that needed therapeutic hypothermia) contributed to the planning of the study and interpretation of results. She led parent involvement in the study, and contributed to and approved the final report.

Jon Dorling (https://orcid.org/0000-0002-1691-3221) (Professor of Paediatrics and Division Head of Neonatal-Perinatal Medicine) conceived, designed and planned the study. He contributed to the analysis and interpretation of the results. He contributed to and approved the final report.

Nicholas Longford (https://orcid.org/0000-0003-4129-9726) (Senior Statistician) conceived, designed and planned the study. He led the analysis and undertook matching. He contributed to the interpretation of the results. He contributed to and approved the final report.

Publications

Battersby C, Longford N, Patel M, Selby E, Ojha S, Dorling J, Gale C. Study protocol: optimising newborn nutrition during and after neonatal therapeutic hypothermia in the United Kingdom: observational study of routinely collected data using propensity matching. BMJ Open 2018;8:e026739.

Ojha S, Dorling J, Battersby C, Longford N, Gale C. Optimising nutrition during therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed 2019;104:F230–1.

Gale C, Longford NT, Jeyakumaran D, Ougham K, Battersby C, Ojha S, Dorling J. Feeding during neonatal therapeutic hypothermia, assessed using routinely collected National Neonatal Research Database data: a retrospective, UK population-based cohort study. Lancet Child Adolesc Health 2021;5:408–16.

Gale C, Jeyakumaran D, Longford N, Battersby C, Ojha S, Oughham K, Dorling J. Administration of parenteral nutrition during therapeutic hypothermia: a population level observational study using routinely collected data held in the National Neonatal Research Database. Arch Dis Child Fetal Neonatal Ed 2021. Published online 5 May 2021.

Data-sharing statement

Data are available through the NNRD with relevant approvals. More information is available at URL: www.imperial.ac.uk/neonatal-data-analysis-unit/neonatal-data-analysis-unit/utilising-the-national-neonatal-research-database/. All data requests should be submitted to the corresponding author for consideration.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care.

Clinical Investigator Group members

• Chris Gale (Chairperson), Reader in Neonatal Medicine and Consultant Neonatologist, Imperial College London and Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.

• Nicholas Longford, Senior Statistician, Imperial College London, London, UK.

• Cheryl Battersby, Clinical Senior Lecturer in Neonatal Medicine and Consultant Neonatologist, Imperial College London and Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.

• Jon Dorling, Professor of Neonatal Medicine, IWK Health Centre, Halifax, NS, Canada.

• Shalini Ojha, Clinical Associate Professor in Neonatal Medicine, University of Nottingham, Nottingham, UK.

• Lucy Culshaw, Senior Research Engagement Officer, Bliss, London, UK. (Prior to March 2019 this role was held by Mehali Patel, Research Engagement Officer, Bliss, London, UK.)

• Ella Selby, mother of child who received therapeutic hypothermia as a baby.

Study Steering Group members

• David Odd (Independent chairperson), Senior Clinical Lecturer in Neonatal Medicine and Consultant Neonatologist, University of Bristol and North Bristol NHS Trust, Bristol, UK.

• Louise Linsell (Independent), Senior Medical Statistician, Clinical Trials Unit, National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK.

• James Carpenter (Independent), Professor of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

• Carol Rhodes (Independent), mother of child who received therapeutic hypothermia as a baby.

• Chris Gale (Non-independent), Reader in Neonatal Medicine and Consultant Neonatologist, Imperial College London and Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.