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Growth Patterns by Gestational Age in Preterm Infants Developing Morbidity

Journal: BMJ Open

Manuscript ID bmjopen-2016-012872

Article Type: Research

Date Submitted by the Author: 30-May-2016

Complete List of Authors: Klevebro, Susanna; Karolinska Institutet, CLINTEC; Sachsska Barnsjukhuset, Lundgren, Pia; Sahlgrenska Academy at University of Gothenburg, Institute of Neuroscience and Physiology Hammar, Ulf; Karolinska Institutet, Institute of Environmental Medicine, Unit of Biostatistics Smith, Lois; Children\'s Hospital Boston, Department of Ophthalmology Bottai, Matteo; Karolinska Institutet, Institute of Environmental Medicine, Unit of Biostatistics Dommelof, Magnus; Umeå University, Department of Clinical Sciences lovqvist, Chatarina; Sahlgrenska Academy, Ophthalmology Hallberg, Boubou; Karolinska Hospital and Karolinska Institutet, Neonatology & CLINTEC Hellstrom, Ann; Sahlgrenska Academy, Ophthalmology

<b>Primary Subject Heading</b>:

Paediatrics

Secondary Subject Heading: Paediatrics

Keywords: NEONATOLOGY, Neonatal intensive & critical care < INTENSIVE & CRITICAL CARE, PERINATOLOGY, Paediatric ophthalmology < OPHTHALMOLOGY

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Growth Patterns by Gestational Age in Preterm Infants

Developing Morbidity

S. Klevebro1,2

, P. Lundgren3, U. Hammar

4, L. E. Smith

5, M. Bottai

4, M. Domellöf

6,

C. Löfqvist3, B. Hallberg

1,7, A. Hellström

3

Affiliations: 1

Clinical Sciences, Intervention, and Technology, Karolinska Institutet,

Stockholm, Sweden; 2Sachs' Children and Youth Hospital, South General Hospital,

Stockholm, Sweden; 3Department of Ophthalmology, Institute of Neuroscience and

Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; 4Unit of

Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;

5Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School,

Boston, MA, USA; 6Department of Clinical Sciences, Paediatrics, Umeå University, Umeå,

Sweden; 7Department of Neonatology, Karolinska University Hospital, Stockholm, Sweden

Address correspondence to: Susanna Klevebro, [email protected], +46 8 616 4631,

Sachs' Children and Youth Hospital, South General Hospital, Sjukhusbacken 10, 118 83

Stockholm, Sweden

Keywords: Preterm, Growth, Morbidity, Retinopathy of Prematurity, Bronchopulmonary

Dysplasia

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List of Abbreviations

AGA: appropriate for gestational age

BPD: bronchopulmonary dysplasia

BW: birth weight

BWSDS: birth weight standard deviation score

GA: gestational age

IGF-I: insulin-like growth factor I

IVH: intraventricular hemorrhage

NEC: necrotizing enterocolitis

PMA: postmenstrual age

PNA: postnatal age

ROP: retinopathy of prematurity

SGA: small for gestational age

SDS: standard deviation score

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ABSTRACT

Objectives: To examine differences in growth patterns in preterm infants developing major

morbidities including retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD),

necrotizing enterocolitis (NEC), and intraventricular haemorrhage (IVH).

Study Design: Cohort study of 2521 infants born at a gestational age (GA) of 23 to 30 weeks

from eleven level III neonatal intensive care units in USA and Canada, and three Swedish

population based cohorts.

Outcomes: Birth weight and postnatal weight gain were examined relative to birth GA and

ROP, BPD, NEC, and IVH development.

Results: Among infants with a birth GA of 25 to 30 weeks, birth weight standard deviation

score and postnatal weight were lower in those developing ROP and BPD. Infants developing

ROP showed lower growth rates during postnatal weeks 7 to 9 in the 23 to 24 weeks GA

group, during weeks 4 to 6 in the 25 to 26 weeks GA group, and during weeks 1 to 5 in the 27

to 30 weeks GA group. Infants with BPD born at 27 to 30 weeks GA showed lower growth

rates during postnatal weeks 3 to 5. Infants with NEC had lower growth rates after postnatal

week 6 in all GA groups, with no significant differences in birth weight standard deviation

score. IVH was not associated with pre- or postnatal growth.

Conclusions: Postnatal growth is a disease marker, emphasizing the importance of

monitoring growth and of understanding the association between morbidities and specific

growth patterns in relation to postmenstrual weeks.

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ARTICLE SUMMARY

Strengths and Limitations of This Study

• Large cohort study of detailed growth patterns in extremely and very preterm infants.

• A high number of infants in the earliest gestational ages enabling investigation of

differences in growth patterns depending on gestational age at birth.

• Advanced growth models comparing growth patterns generated in collaboration with a

team of statisticians.

• This study does not provide an answer to how the presently described associations are

mediated.

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INTRODUCTION

It is an important challenge in the care of preterm infants to reduce the incidence of neonatal

and long-term morbidity.[1,2] It is suggested that growth during the neonatal period should

mimic intrauterine growth rates to enable normal organ development.[3] This goal is rarely

achieved in extremely preterm infants.[4,5]

Prenatal factors influence intrauterine maturation and growth, and intrauterine growth

restriction (IUGR) increases the risks of abnormal organ development and disease.[6]

Retinopathy of prematurity (ROP), is caused by abnormal postnatal retinal neurovascular

development. Previous research has shown that ROP development is related to growth factor

levels,[7] and that low gestational age (GA) associated with very immature retina as a starting

point for postnatal growth is the strongest risk factor for ROP development.[8] SGA is a risk

factor dependent on GA at birth.[9] Postnatal growth restriction has been used as a marker for

ROP risk, and is an important component of new surveillance systems developed to refine

ROP screening.[10-16] Bronchopulmonary dysplasia (BPD) results from abnormal postnatal

development of pulmonary tissue. It has been suggested that the biological processes that lead

to ROP development also play important roles in BPD development.[17] BPD risk is also

reportedly related to intrauterine growth restriction.[6,18,19] Necrotizing enterocolitis (NEC)

has been associated with IUGR and SGA whereas intraventricular haemorrhage (IVH) has

not.[6,20,21]

The present study aimed to determine if growth is a biomarker for disease and describe how

birth weight and postnatal growth vary with the development of ROP, BPD, NEC, and IVH in

extremely preterm infants.

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PATIENTS AND METHODS

This study used data from five cohorts of preterm infants from Canada, the USA, and Sweden

(Figure 1). The Boston cohort included all infants born before 32 weeks GA and qualified for

ROP screening at Brigham and Women’s Hospital between 2005 and 2008.[12] The North

American cohort originated from a multicentre study conducted between 2006 and 2009 at ten

level III neonatal intensive care units within the USA and Canada. This study aimed to

validate the WINROP® screening method.[13] EXPRESS is a population-based study

including all infants born before 27 weeks GA between 2004 and 2007 in Sweden.[14] The

Gothenburg cohort comprised infants born before 32 weeks GA and screened for ROP in

Gothenburg between 2011 and 2012.[15] Our present study also included a previously

unpublished population-based cohort of infants born before 27 weeks GA in Stockholm

between 2008 and 2011.

Our present study included infants born at a GA of between 23+0 and 30+6 weeks without

severe malformations, who survived to a postmenstrual age (PMA) of 40 weeks, and for

whom data were available regarding birth weight (BW), maximum ROP stage, and/or BPD.

Exclusion criteria were hydrocephalous, which gave rise to non-physiological growth

patterns, and more than two registered weight measurements that were considered to be

unrealistic outliers based on age and relation to adjacent measurements. Data were collected

as described in previous studies.[12-15] Data for infants in the Stockholm cohort were

collected from hospital records. GA at birth was based on ultrasound dating, or on the date of

last menstrual period if no ultrasound had been performed.

Prenatal growth was evaluated as BW compared to the expected weight based on GA and

gender. Comparisons were performed using a Swedish foetal growth reference constructed

based on intrauterine ultrasound measurements,[22] which is considered to reflect undisturbed

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intrauterine growth. For comparison, the descriptive figure for growth also included reference

lines from the Olsen growth chart, which is based on American live-born singletons.[23]

Weight measurements were recorded weekly on average, with documentation of the exact

date of every measurement. SGA was defined as BW below two standard deviation scores

according to the intrauterine growth reference.[22] ROP screening was performed following

routine protocol, with classification according to the international system.[24] BPD was

defined as need for oxygen at a PMA of 36 weeks.[25] NEC was defined as Bell stage 2b or

greater.[26] IVH registration included any grade of intraventricular haemorrhage.

Statistics

All statistical analyses were performed using Stata/IC 13.1 software (StataCorp LP, College

Station, Texas, USA). Data outliers were examined with the use of population- and individual

residuals in the model, and excluded if deemed unrealistic. Level of significance was set at

5%. Descriptive analysis included quantile regression growth models. Differences in BW and

birth weight standard deviation score (BWSDS) were estimated using a linear regression

model with robust standard errors. We applied a mixed effects model including restricted

cubic splines (knots at 2, 4, 6, and 10 weeks), with random slope and intercept, to evaluate

growth as weight and growth rate over time.[27,28] Growth rates were calculated using the

exponential model suggested by Patel et al.[29] In the mixed effects model, we included

growth rates using all weights, and calculated the mean between-group differences in weight

and growth rate. To describe the overall growth rate in the entire cohort, we calculated the

rate from birth weight to weight at 36 weeks PMA. If no measurement at 36 weeks PMA was

available, we used the closest value up to 2 weeks prior.

All analyses were initially stratified by gestational week at birth. For the final analyses,

subjects were divided into three groups by GA: 23 to 24 weeks, 25 to 26 weeks, and 27 to 30

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weeks. The GA groups were selected based on the results of the one-week analysis. Postnatal

growth results are presented from birth until 36 weeks PMA. All analyses were adjusted for

exact gestational age in days, gender, and centre. When analysing differences in weight over

time and growth rate in cases of ROP and BPD, we included further adjustment for NEC and

BWSDS. Analyses were also tested for interaction regarding BWSDS and morbidity and

country and morbidity respectively. No significant association on differences in growth rate

were found and the interaction terms were not included in the final model. Selected

adjustments were based on previously known influences, as well as statistical procedures

including backward selection.

Ethical Statement

The Swedish studies were approved by regional ethical review boards (Lund 2004-42; Sthlm

2007-1613312 and 2013-26532; Gbg 2013-051-13). The North American studies were

approved by institutional review boards at all participating centres.

RESULTS

This study included a total of 2521 infants (Figure 1), with a mean of 14.3 weight

measurements per infant (median, 11; IQR, 9 to 16). The last weight measurement was

registered at a mean PMA of 37+6 weeks (median, 37+5 weeks; IQR, 36+0 to 39+5 weeks).

The infants’ gestational ages were evenly distributed between the early group (23 to 26

weeks; 52%) and later group (27 to 30 weeks; 48%) (Table 1). The later GA group showed a

lower median BWSDS. Infants born at GA 23 to 26 weeks showed significant postnatal

growth restriction, reflected by a reduced mean weight standard deviation score from birth to

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36 weeks PMA, with the most pronounced difference among the more immature infants.

Figure 2 and Table 1 illustrate the growth data. Median weekly growth rates were highest at a

PMA of 30 weeks in infants born at GA 23 to 26 weeks, and at a PMA of 31 to 34 weeks

among infants born at GA 28 to 30 weeks, corresponding to the fifth week of life.

Morbidity

Table 1 displays the numbers and frequencies of ROP, BPD, NEC, and IVH by gestational

week. Differences in BWSDS, postnatal weight, and growth rate are shown in Figure 3 and

Figure 4, as well as in the Appendix.

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Table 1. Infant

Characteristics, Growth, and

Morbidity by Gestational Age

at Birth.

#North America (USA and

Canada).

Mdn denotes median, w weeks,

IQR interquartile range (25th

to

75th

percentile), and Trt

treatment for ROP.

++Overall growth rate from birth

to 36 weeks postmenstrual age

calculated for 2344 infants.

*Information regarding ROP

was missing for one infant born

at a gestational age of 24 weeks,

and one infant at 25 weeks.

Information regarding BPD was

missing from two infants born at

a gestational age of 24 weeks,

two infants at 25 weeks, and five

infants born at 26 weeks.

Infant Characteristics, Growth, and Morbidity

Gestational Age at Birth (weeks)

23 24 25 26 27 28 29 30 All

n % n % n % n % n % n % n % n % N %

Infants 117 4.6 314 12.5 399 15.8 482 19.1 249 9.9 296 11.7 323 12.8 341 13.5 2521 100

Female

Sex 58 49.6 137 43.6 190 47.6 229 47.5 119 47.8 139 47.0 134 41.5 162 47.5 1168 46.3

Country NA# 53 45.3 168 53.5 190 47.6 227 47.1 237 95.2 277 93.6 299 92.6 319 93.5 1770 70.2

Sweden 64 54.7 146 46.5 209 52.4 255 52.9 12 4.8 19 6.4 24 7.4 22 6.4 751 29.8

SGA 5 4.3 38 12.1 81 20.3 115 23.9 77 30.9 110 37.2 107 33.1 114 33.4 647 25.7

Mdn IQR Mdn IQR Mdn IQR Mdn IQR Mdn IQR Mdn IQR Mdn IQR Mdn IQR Mdn IQR

BW (g) 595 550-

655 675

610-

735 770

693-

858 890

776-

995 989

865-

1080 1071

921-

1211 1287

1100-

1420 1415

1195-

1550 915

731-

1153

BWSDS (SDS) −0.4 −1.0-

0.4 −0.6

−1.4-

0.0 −1.0

−1.7-

−0.1 −1.0

−2.0-

−0.2 −1.3

−2.3-

−0.6 −1.6

−2.6-

−0.8 −1.3

−2.3-

−0.4 −1.4

−2.5-

−0.6 −1.1

−2.0-

−0.3

Weight at 36 w

PMA (g) 2072

1847-

2263 2123

1932-

2319 2126

1881-

2377 2190

1905-

2415 2244

1922-

2501 2179

1958-

2500 2320

1973-

2582 2206

1902-

2506 2157

1909-

2391

WSDS at 36 w

PMA (SDS) −2.3

−2.9-

−1.8 −2.2

−2.8-

−1.6 −2.2

−2.9-

−1.4 −2.0

−2.9-

−1.2 −1.6

−2.7-

−0.8 −1.9

−2.5-

−0.9 −1.5

−2.6-

−0.7 −1.8

−2.9-

−0.9 −1.9

−2.7-

−1.2

Growth rate ++

(g/kg/d) 13.7

12.6-

15.2 13.8

12.6-

15.2 13.8

12.7-

15.4 13.8

12.3-

15.4 13.7

12.3-

15.2 13.3

11.6-

14.9 12.4

11.0-

14.2 11.8

9.8-

13.9 13.3

11.8-

15.0

MAX rate

(g/kg/d) 18.9

11.5-

23.6 18.3

12.2-

23.8 19.7

13.1-

25.6 20.3

13.4-

25.6 21.7

17.8-

25.1 20.5

16.9-

23.8 20.4

16.6-

23.7 19.0

15.7-

22.7 17.7

11.3-

22.7

PMA @MAX 30 30 30 30 31 32 33 34 31

n % n % n % n % n % n % n % n % N %

ROP*

No 9 7.7 17 5.4 69 17.3 166 34.4 99 39.8 185 62.5 236 73.1 304 89.1 1085 43.0

ROP 1-2 40 34.2 131 41.9 215 54.0 236 49.0 127 51.0 98 33.1 84 26.0 34 10.0 965 38.3

ROP ≥ 3 68 58.1 165 52.7 114 28.6 80 16.6 23 9.2 13 4.4 3 0.9 3 0.9 471 18.7

Trt 51 43.6 109 34.9 65 16.3 39 8.1 16 6.4 5 1.7 3 0.9 0 0.0 288 11.4

BPD* 104 88.9 247 79.2 289 72.8 308 64.6 124 49.8 108 36.5 58 18.0 30 8.8 1268 50.5

NEC 9 7.7 47 15.0 33 8.3 42 8.7 25 10.0 32 10.8 27 8.4 15 4.4 230 9.1

All IVH 60 51.3 144 45.9 141 35.3 118 24.5 65 26.1 56 18.9 64 19.8 44 12.9 692 27.4

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ROP and Growth

Infants developing ROP of any grade showed lower growth rates compared to infants not

developing ROP. This difference was noted in the 7th

to 9th

weeks of life among infants born

at GA 23 to 24 weeks, and in the 4th

to 6th

weeks of life in those born at GA 25 to 26 weeks.

Infants born at GA 27 to 30 weeks had lower growth rates during their first five weeks of life,

shifting to higher growth rates starting at the 7th

week of life. Among infants born at GA 25 to

30 weeks, BWSDS was lower in infants developing ROP. Differences at birth were greater

among infants born at later GA (Appendix Figure S2, Table S1).

BPD and Growth

Among those born at GA 27 to 30 weeks, infants with BPD had lower growth rates in the 4th

to 5th

week of life compared to infants without BPD, followed by higher growth rates from the

7th

week of life. Among those born at GA 23 to 24 weeks, infants developing BPD showed

significantly lower weight during the 8th

to 12th

week of life compared to those without BPD,

while these groups did not significantly differ in growth rate. Among those born at GA 25 to

30 weeks, BWSDS was lower in infants developing BPD. These differences were greater

among infants born at later GA, and weight continued to be lower from birth to PMA 36

weeks (Appendix Figure S3, Table S2).

NEC and Growth

Among infants born at all GAs, those with NEC showed lower growth rates from the 6th

to 7th

week of life and during the rest of the studied neonatal period compared to infants without

NEC. Infants born at all GAs with and without NEC did not significantly differ in BWSDS

(Appendix Figure S4, Table S3).

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IVH and Growth

Analysis of infants with any IVH compared to with no IVH revealed no associations with pre-

or postnatal growth (Appendix Figure S5).

SGA and Postnatal Growth

Compared to infants born at a weight appropriate for their gestational age, those born SGA

continued to show lower weights until 36 weeks PMA. For the first three weeks of life, SGA

infants showed higher growth rates than appropriate for gestational age infants (Appendix

Figure S1A, B).

DISCUSSION

This study demonstrates that postnatal growth is a marker for disease, and highlight specific

postmenstrual weeks with greater differences in growth rates between morbidities, potentially

implicating important windows of vulnerability partly depending on GA. Knowledge of the

postnatal growth patterns of very preterm infants can improve our understanding of the

pathophysiology of complications. Our present results showed similar patterns of pre- and

postnatal growth restriction between infants developing ROP and BPD. Infants born at a GA

of 25 to 30 weeks who developed ROP and BPD were smaller at birth. Infants born at all GAs

who developed ROP had reduced growth rates. Among those born at GA 23 to 26 weeks, this

reduction was most pronounced around the postnatal weeks corresponding to the 31st

postmenstrual week. Those born at GA 27 to 30 weeks and developing ROP and BPD showed

an initially reduced growth rate, which shifted to higher growth rates in later weeks. Infants

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developing NEC and IVH showed a different pattern of pre- and postnatal growth restriction,

indicating a different pathophysiology.

To our knowledge, this is the largest detailed study of postnatal weight development among

low gestational age infants, including a large proportion of extremely preterm infants.

Stratification by GA rather than birth weight enables consideration of the increased morbidity

risks associated with greater degree of immaturity. The wide range of methods used to

evaluate postnatal growth in previous studies makes it difficult to compare results among

studies. In 1999, Ehrenkranz et al.[4] described the postnatal growth pattern of infants

developing morbidity, reporting a mean growth rate (from regaining BW to discharge, death,

or reaching 2 kg) of 14 to 16 g/kg/d, increasing with increasing GA. Horbar et al.[30] reported

growth rates calculated using the two point exponential model from birth to discharge. The

mean growth rates from 2013 in GA 24 to 26 weeks were 13.0 g/kg/d (95% CI 13.0 to 13.1).

Martin et al.[31] reported a relationship between lower BWSDS and higher growth rates

during the first weeks of life that was similar to the association observed in our cohort.

However, Martin et al.[31] did not use an exponential growth model to calculate growth rates,

resulting in higher rates compared to those found in our study. Our presently used exponential

model has been evaluated and deemed most appropriate for calculating growth rates of

preterm infants.[29] Fortes-Filho et al.[32] described a relationship between severe ROP and

proportion of birth weight gained at 6 weeks of age. Their results are consistent with our

findings in infants born at a GA of 25 to 30 weeks. Nyp et al.[33] evaluated growth rate (in

g/kg from BW to 36 weeks PMA) among 140 infants born before 28 weeks of GA, and found

no association with BPD. In our substantially larger cohort, we detected associations between

BPD and postnatal growth that related to specific postnatal weeks.

Limitations of our present study include a lack of information regarding some perinatal

background data. Notably, our material included no information regarding sepsis. Ehrenkranz

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et al.[4] demonstrated that infants with sepsis have growth pattern similar to those of infants

with BPD. Moreover, the use of BWSDS to classify foetal growth restriction could lead to

misclassification of infants who are genetically small for gestational age without foetal

growth restriction. Additionally, this study included only infants who survived to 40 weeks

PMA, which could affect the description of postnatal growth within the entire cohort but not

our main outcomes. The combined dataset included no information regarding time of NEC.

The fact that surgically managed NEC has been previously associated with substantial growth

delay,[34] and the growth patterns demonstrated in our present results suggest that the NEC

disease process precedes growth restriction. IVH—which usually occurs early postnatally—

does not appear to be strongly related to postnatal growth.

From this study it is not possible to determine how the presently described associations are

mediated. Analysis of the relationship between nutrition and ROP in the EXPRESS cohort

revealed that low energy intake during the first four weeks of life was related to increased

frequency of severe ROP, after adjustment for several morbidities.[35] The specific weeks

showing significant differences in growth rate corresponded to a PMA of around 31 weeks in

infants born at a GA of 23 to 26 weeks, implicating an especially important period of growth

in extremely preterm infants. This is the period of maximum growth rate, and represents the

transition from growth failure to catch-up growth among infants born at these GAs. Hansen-

Pupp et al.[36] described increased insulin-like growth factor I (IGF-I) concentrations at PMA

30 weeks, coinciding with the initiation of catch-up growth. Moreover, ROP severity is

correlated to IGF-I serum concentrations and duration of low IGF-I concentrations.[7,37] The

reduced growth rates at a PMA of around 30 weeks could be biologically related to initiation

of phase two of ROP development, which has been demonstrated to correlate to an increase of

the initially low levels of IGF-I.[7] Lower IGF-I levels in the first postnatal weeks are also

associated with BPD among very preterm infants.[17] It is reasonable to postulate that factors

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that control somatic growth also influence retina and lung development. ROP is both a

vascular and neurological disease. Poor neurodevelopment has been related to poor postnatal

growth,[38,39] and postnatal IGF-I concentrations have been associated with brain volume at

term.[40] Future clinical trials should further investigate this time period, and continue to

analyse interactions between growth factors, nutrition, weight gain, and morbidities, including

neurodevelopmental outcomes. Our present results highlight postnatal growth as a marker for

disease, emphasizing the importance of monitoring growth and nutrition in the neonatal

intensive care unit.

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FUNDING

This study is supported by grants provided by Swedish Research Council (DNR# 2011-2432)

and Gothenburg County Council (ALFGBG-426531). S Klevebro was supported by the

Stockholm County Council (combined clinical residency and PhD training program) and has

received grants from Lilla Barnets Fond, Stiftelsen Samariten and Föreningen Mjölkdroppen.

L Smith was supported by NIH EY024864, EY017017, EY022275, P01 HD18655, Lowy

Medical Research Institute, European Commission FP7 project 305485 PREVENT-ROP.

COMPETING INTERESTS

The authors have no competing interests relevant to this article to disclose.

DATA SHARING STATEMENT

No additional data available.

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CONTRIBUTOR STATEMENT

Dr Klevebro collected data from the Stockholm cohort, carried out the analyses, drafted the

initial manuscript, revised the manuscript, and approved the final manuscript as submitted.

Dr Lundgren and Assoc Prof Löfqvist coordinated the data collection, contributed to the

design of the study, reviewed the manuscript, and approved the final manuscript as submitted.

Mr Hammar and Prof Bottai merged the datasets, participated in selection of statistical

methods, carried out the initial analyses, and approved the final manuscript as submitted.

Prof Smith and Prof Domellöf coordinated and supervised data collection from the American

cohorts and Swedish national cohort respectively, reviewed the manuscript, and approved the

final manuscript as submitted.

Dr Hallberg contributed to the design of the study, critically reviewed the manuscript, and

approved the final manuscript as submitted.

Prof Hellström conceptualized and designed the study, supervised data collection, reviewed

the manuscript, and approved the final manuscript as submitted.

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REFERENCES

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dysplasia. Acta paediatrica (Oslo, Norway : 1992). 2015;104:259-63 doi: 10.1111/apa.12888


20. Garite TJ, Clark R, Thorp JA. Intrauterine growth restriction increases

morbidity and mortality among premature neonates. Am J Obstet Gynecol. 2004;191:481-7

doi: 10.1016/j.ajog.2004.01.036 [published Online.

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23. Olsen IE, Groveman SA, Lawson ML, et al. New intrauterine growth curves

based on United States data. Pediatrics. 2010;125:e214-24 doi: 10.1542/peds.2009-0913


24. The International Classification of Retinopathy of Prematurity revisited.



25. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care

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26. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging

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1989;8:551-61 Online.

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29. Patel AL, Engstrom JL, Meier PP, et al. Accuracy of methods for calculating

postnatal growth velocity for extremely low birth weight infants. Pediatrics. 2005;116:1466-

73 doi: 10.1542/peds.2004-1699 [published Online.

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Postnatal Growth Failure in Infants 501 to 1500 Grams: 2000-2013. Pediatrics.

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31. Martin CR, Brown YF, Ehrenkranz RA, et al. Nutritional practices and growth

velocity in the first month of life in extremely premature infants. Pediatrics. 2009;124:649-57

doi: 10.1542/peds.2008-3258 [published Online.

32. Fortes Filho JB, Bonomo PP, Maia M, et al. Weight gain measured at 6 weeks

after birth as a predictor for severe retinopathy of prematurity: study with 317 very low birth

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33. Nyp MF, Taylor JB, Norberg M, et al. Impaired growth at birth and

bronchopulmonary dysplasia classification: beyond small for gestational age. American

journal of perinatology. 2015;32:75-82 doi: 10.1055/s-0034-1376181 [published Online.

34. Hintz SR, Kendrick DE, Stoll BJ, et al. Neurodevelopmental and growth

outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics.

2005;115:696-703 doi: 10.1542/peds.2004-0569 [published Online.

35. Stoltz Sjostrom E, Lundgren P, Ohlund I, et al. Low energy intake during the

first 4 weeks of life increases the risk for severe retinopathy of prematurity in extremely

preterm infants. Archives of disease in childhood Fetal and neonatal edition. 2015; doi:

10.1136/archdischild-2014-306816 [published Online First: 2015/02/14].

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factor I and nutrition during phases of postnatal growth in very preterm infants. Pediatric

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2006/04/06].

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39. Franz AR, Pohlandt F, Bode H, et al. Intrauterine, early neonatal, and

postdischarge growth and neurodevelopmental outcome at 5.4 years in extremely preterm

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insulin-like growth factor-I and low brain volumes in very preterm infants. The Journal of

clinical endocrinology and metabolism. 2011;96:1129-35 doi: 10.1210/jc.2010-2440


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Figure 1. Flowchart of Included Cohorts.

GA denotes gestational age, w weeks, PMA postmenstrual age, HC hydrocephalus, and

FEVR familial exudative vitreoretinopathy.

Table 1. Infant Characteristics, Growth, and Morbidity by Gestational Age at Birth.

#North America (USA and Canada).

Mdn denotes median, w weeks, IQR interquartile range (25th

to 75th


treatment for ROP.

++Overall growth rate from birth to 36 weeks postmenstrual age calculated for 2344 infants.

*Information regarding ROP was missing for one infant born at a gestational age of 24 weeks,

and one infant at 25 weeks. Information regarding BPD was missing from two infants born at

a gestational age of 24 weeks, two infants at 25 weeks, and five infants born at 26 weeks.

Figure 2. Postnatal Weight Development and Growth Rate According to Gestational

Age, Illustrated by the 25th, 50

th, and 75

th Percentiles.

Panel A shows postnatal weight development in grams. Panel B shows postnatal growth rate

in grams/kilograms/day. Growth references 50th

percentiles from Marsal[22] and Olsen[23].

Pink denotes female, and blue male.

Figure 3. Difference in Birth Weight Standard Deviation Score (BWSDS) According to

Gestational Age Group, Between Infants With and Without Respective Morbidities.

Data are shown as mean and 95% confidence interval for each diagnose. All analyses are

adjusted for exact gestational age at birth, gender, and centre.

Figure 4. Difference in Weight and in Growth Rate Over Time According to Gestational

Age Group, Between Infants With and Without Respective Morbidities.

Panel A shows the difference in weight in grams. Panel B shows the difference in growth rate

in grams/kilogram/day. Time is represented by postnatal age (PNA) in weeks. Data are shown

as mean and 95% confidence interval for each diagnose. All analyses are adjusted for exact

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gestational age at birth, gender, and centre. Analyses of differences regarding ROP and BPD

are also adjusted for NEC and in growth rate analyses for birth weight standard deviation

score (BWSDS).

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334x221mm (72 x 72 DPI)

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254x340mm (72 x 72 DPI)

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Appendix - Table of Contents

2. Figure S1A and S1B (Growth of Small for Gestational Age Infants)

3. Figure S2 and Table S1 (Growth of Infants With Any ROP vs. No ROP)

4. Figure S3 and Table S2 (Growth of Infants With BPD vs. No BPD)

5. Figure S4 and Table S3 (Growth of Infants With NEC vs. No NEC)

6. Figure S5 (Growth of Infants With Any IVH vs. No IVH)

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Figure S1. Postnatal Weight Development and Postnatal Growth Rate in Infants Born Small for

Gestational Age (SGA) and Appropriate for Gestational Age (AGA) According to Gestational Age.

Panel A shows postnatal weight development in grams. Panel B shows postnatal growth rate in

grams/kilograms/day. Data are shown as mean and 95% confidence interval.

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Figure S2. Postnatal Weight Development According to Gestational Age at Birth in Infants With and

Without Retinopathy of Prematurity (ROP).

Postnatal weight development is shown in grams. Data are shown as mean and 95% confidence interval.

Gestational Age at birth (weeks)

week of life

23-24 25-26 27-30

diff (g/kg/d)

p diff (g/kg/d)

p diff (g/kg/d)

p

1 2.0 0.36 2.7 <0.001 -0.9 0.04

2 1.5 0.33 1.0 0.08 -1.0 <0.001

3 1.0 0.43 -0.7 0.10 -1.2 <0.001

4 0.4 0.77 -2.3 <0.001 -1.2 <0.001

5 -0.3 0.85 -2.9 <0.001 -0.9 0.007

6 -1.2 0.31 -2.1 <0.001 0.0 0.99

7 -2.1 0.04 -0.8 0.07 0.9 0.003

8 -2.4 0.03 0.0 0.96 1.3 <0.001

9 -2.3 0.04 0.3 0.50

10 -1.9 0.06 0.3 0.51

11 -1.4 0.11

12 -0.8 0.27

Table S1. Difference in Growth Rate Over Time According to Gestational Age Group, Between Infants

With and Without Retinopathy of Prematurity (ROP).

Growth rate is reported in grams/kilogram/day. Data are shown as mean and 95% confidence interval. Analyses

are adjusted for exact gestational age at birth, gender, center, necrotizing enterocolitis (NEC), and birth weight

standard deviation score (BWSDS).

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Without Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is defined as requiring O2 at 36 weeks postmenstrual age (PMA). Postnatal weight

development is shown in grams. Data are shown as mean and 95% confidence interval.


week of life

23-24 25-26 27-30

diff (g/kg/d)

p diff (g/kg/d)

p diff (g/kg/d)

p

1 1.6 0.23 2.7 0.45 0.9 0.04

2 1.0 0.31 1.0 0.84 0.2 0.62

3 0.3 0.66 -0.7 0.41 -0.6 0.03

4 -0.3 0.73 -2.3 0.12 -1.3 <0.001

5 -0.7 0.43 -2.9 0.09 -1.3 <0.001

6 -0.9 0.22 -2.1 0.16 -0.3 0.25

7 -0.9 0.16 -0.8 0.73 0.9 0.01

8 -0.8 0.24 0.0 0.70 1.5 <0.001

9 -0.7 0.31 0.3 0.46

10 -0.6 0.35 0.3 0.35

11 -0.5 0.38

12 -0.4 0.48


With and Without Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is defined as requiring O2 at 36 weeks postmenstrual age (PMA). Growth rate is

reported in grams/kilogram/day. Data are shown as mean and 95% confidence interval. Analyses are adjusted for exact

gestational age at birth, gender, center, necrotizing enterocolitis (NEC), and birth weight standard deviation score (BWSDS).

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Without Necrotizing Enterocolitis (NEC).



week of life

23-24 25-26 27-30

diff (g/kg/d)

p diff (g/kg/d)

p diff (g/kg/d)

p

1 1.7 0.28 0.5 0.71 0.2 0.80

2 1.6 0.14 -0.1 0.92 -0.2 0.75

3 1.6 0.08 -0.7 0.39 -0.5 0.23

4 1.4 0.18 -1.3 0.19 -0.8 0.11

5 0.8 0.51 -1.8 0.09 -1.1 0.06

6 -0.6 0.51 -2.2 0.008 -1.1 0.01

7 -2.1 0.008 -2.4 <0.001 -1.1 0.02

8 -2.9 <0.001 -2.5 0.003 -1.3 0.03

9 -3.1 <0.001 -2.3 0.005

10 -2.9 <0.001 -2.1 0.005

11 -2.5 <0.001

12 -2.1 0.001


With and Without Necrotizing Enterocolitis (NEC).

Growth rate is shown in grams/kilograms/day. Data are shown as mean and 95% confidence interval. Analyses

are adjusted for exact gestational age at birth, gender and center.

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Figure S5. Postnatal Weight Development by Gestational Age at Birth in Infants With and Without

Intraventricular Hemorrhage (IVH).


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STROBE Statement—checklist of items that should be included in reports of observational studies

Item

No Recommendation

Title and abstract

Page 3

1 (a) Indicate the study’s design with a commonly used term in the title or the

abstract

(b) Provide in the abstract an informative and balanced summary of what was done

and what was found

Introduction

Background/rationale

Page5

2 Explain the scientific background and rationale for the investigation being reported

Objectives

Page 5

3 State specific objectives, including any prespecified hypotheses

Methods

Study design

Page 6

4 Present key elements of study design early in the paper

Setting

Page 6

5 Describe the setting, locations, and relevant dates, including periods of recruitment,

exposure, follow-up, and data collection

Participants

Page 6

6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of

selection of participants. Describe methods of follow-up

Case-control study—Give the eligibility criteria, and the sources and methods of

case ascertainment and control selection. Give the rationale for the choice of cases

and controls

Cross-sectional study—Give the eligibility criteria, and the sources and methods of

selection of participants

(b) Cohort study—For matched studies, give matching criteria and number of

exposed and unexposed

Case-control study—For matched studies, give matching criteria and the number of

controls per case

Variables

Page 6-7

7 Clearly define all outcomes, exposures, predictors, potential confounders, and

effect modifiers. Give diagnostic criteria, if applicable

Data sources/

measurement

Page 6-7

8* For each variable of interest, give sources of data and details of methods of

assessment (measurement). Describe comparability of assessment methods if there

is more than one group

Bias

Page 7-8

9 Describe any efforts to address potential sources of bias

Study size

Page 6

10 Explain how the study size was arrived at

Quantitative variables

Page 7-8

11 Explain how quantitative variables were handled in the analyses. If applicable,

describe which groupings were chosen and why

Statistical methods

Page 7-8

12 (a) Describe all statistical methods, including those used to control for confounding

(b) Describe any methods used to examine subgroups and interactions

(c) Explain how missing data were addressed

(d) Cohort study—If applicable, explain how loss to follow-up was addressed

Case-control study—If applicable, explain how matching of cases and controls was

addressed

Cross-sectional study—If applicable, describe analytical methods taking account of

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sampling strategy

(e) Describe any sensitivity analyses

Results

Participants

Page 8 and Fig1

13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible,

examined for eligibility, confirmed eligible, included in the study, completing follow-up,

and analysed

(b) Give reasons for non-participation at each stage

(c) Consider use of a flow diagram

Descriptive data

Page 8

Table 1

Fig 2

14* (a) Give characteristics of study participants (eg demographic, clinical, social) and

information on exposures and potential confounders

(b) Indicate number of participants with missing data for each variable of interest

(c) Cohort study—Summarise follow-up time (eg, average and total amount)

Outcome data

Page 9-10

Table 1

15* Cohort study—Report numbers of outcome events or summary measures over time

Case-control study—Report numbers in each exposure category, or summary measures of

exposure

Cross-sectional study—Report numbers of outcome events or summary measures

Main results

Page 11-12

Fig 3 and 4

And Appendix

16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their

precision (eg, 95% confidence interval). Make clear which confounders were adjusted for

and why they were included

(b) Report category boundaries when continuous variables were categorized

(c) If relevant, consider translating estimates of relative risk into absolute risk for a

meaningful time period

Other analyses

Page 8 and

Appendix

17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity

analyses

Discussion

Key results

Page 12-13

18 Summarise key results with reference to study objectives

Limitations

Page 13-14

19 Discuss limitations of the study, taking into account sources of potential bias or imprecision.

Discuss both direction and magnitude of any potential bias

Interpretation

Page 14-15

20 Give a cautious overall interpretation of results considering objectives, limitations,

multiplicity of analyses, results from similar studies, and other relevant evidence

Generalisability

Page 15

21 Discuss the generalisability (external validity) of the study results

Other information

Funding

Page 16

22 Give the source of funding and the role of the funders for the present study and, if

applicable, for the original study on which the present article is based

*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and

unexposed groups in cohort and cross-sectional studies.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and

published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely

available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at

http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is

available at www.strobe-statement.org.

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Cohort Study of Growth Patterns by Gestational Age in Preterm Infants Developing Morbidity

Journal: BMJ Open

Manuscript ID bmjopen-2016-012872.R1

Article Type: Research

Date Submitted by the Author: 12-Sep-2016

Complete List of Authors: Klevebro, Susanna; Karolinska Institutet, CLINTEC; Sachsska Barnsjukhuset, Lundgren, Pia; Sahlgrenska Academy at University of Gothenburg, Institute of Neuroscience and Physiology Hammar, Ulf; Karolinska Institutet, Institute of Environmental Medicine, Unit of Biostatistics Smith, Lois; Children\'s Hospital Boston, Department of Ophthalmology Bottai, Matteo; Karolinska Institutet, Institute of Environmental Medicine, Unit of Biostatistics Dommelof, Magnus; Umeå University, Department of Clinical Sciences lovqvist, Chatarina; Sahlgrenska Academy, Ophthalmology Hallberg, Boubou; Karolinska Hospital and Karolinska Institutet, Neonatology & CLINTEC Hellstrom, Ann; Sahlgrenska Academy, Ophthalmology

<b>Primary Subject Heading</b>:

Paediatrics

Secondary Subject Heading: Paediatrics

Keywords: NEONATOLOGY, Neonatal intensive & critical care < INTENSIVE & CRITICAL CARE, PERINATOLOGY, Paediatric ophthalmology < OPHTHALMOLOGY


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Cohort Study of Growth Patterns by Gestational Age in Preterm Infants

Developing Morbidity

S. Klevebro1,2

, P. Lundgren3, U. Hammar

4, L. E. Smith

5, M. Bottai

4, M. Domellöf

6,

C. Löfqvist3, B. Hallberg

1,7, A. Hellström

3

Affiliations: 1

Clinical Sciences, Intervention, and Technology, Karolinska Institutet,

Stockholm, Sweden; 2Sachs' Children and Youth Hospital, South General Hospital,

Stockholm, Sweden; 3Department of Ophthalmology, Institute of Neuroscience and

Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; 4Unit of

Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;

5Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School,

Boston, MA, USA; 6Department of Clinical Sciences, Paediatrics, Umeå University, Umeå,

Sweden; 7Department of Neonatology, Karolinska University Hospital, Stockholm, Sweden

Address correspondence to: Susanna Klevebro, [email protected], +46 8 616 4631,

Sachs' Children and Youth Hospital, South General Hospital, Sjukhusbacken 10, 118 83

Stockholm, Sweden

Keywords: Preterm, Growth, Morbidity, Retinopathy of Prematurity, Bronchopulmonary

Dysplasia

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List of Abbreviations

AGA: appropriate for gestational age

BPD: bronchopulmonary dysplasia

BW: birth weight

BWSDS: birth weight standard deviation score

GA: gestational age

IGF-I: insulin-like growth factor I

IVH: intraventricular hemorrhage

NEC: necrotizing enterocolitis

PMA: postmenstrual age

PNA: postnatal age

ROP: retinopathy of prematurity

SGA: small for gestational age

SDS: standard deviation score

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ABSTRACT

Objectives: To examine differences in growth patterns in preterm infants developing major

morbidities including retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD),

necrotizing enterocolitis (NEC), and intraventricular haemorrhage (IVH).

Study Design: Cohort study of 2521 infants born at a gestational age (GA) of 23 to 30 weeks

from eleven level III neonatal intensive care units in USA and Canada, and three Swedish

population based cohorts.

Outcomes: Birth weight and postnatal weight gain were examined relative to birth GA and

ROP, BPD, NEC, and IVH development.

Results: Among infants with a birth GA of 25 to 30 weeks, birth weight standard deviation

score and postnatal weight were lower in those developing ROP and BPD. Infants developing

ROP showed lower growth rates during postnatal weeks 7 to 9 in the 23 to 24 weeks GA

group, during weeks 4 to 6 in the 25 to 26 weeks GA group, and during weeks 1 to 5 in the 27

to 30 weeks GA group. Infants with BPD born at 27 to 30 weeks GA showed lower growth

rates during postnatal weeks 3 to 5. Infants with NEC had lower growth rates after postnatal

week 6 in all GA groups, with no significant differences in birth weight standard deviation

score. IVH was not associated with pre- or postnatal growth.

Conclusions: In this cohort study of extremely preterm infants we found that the postnatal

growth pattern was associated with morbidities such as ROP, BPD, NEC and IVH as well as

with gestational age at birth.

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ARTICLE SUMMARY

Strengths and Limitations of This Study

• Large cohort study of detailed growth patterns in extremely and very preterm infants.

• A high number of infants in the earliest gestational ages enabling investigation of

differences in growth patterns depending on gestational age at birth.

• Advanced growth models comparing growth patterns generated in collaboration with a

team of statisticians.

• This study does not provide an answer to how the presently described associations are

mediated.

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INTRODUCTION

It is an important challenge in the care of preterm infants is to reduce the incidence of

neonatal and long-term morbidity.[1,2] It is suggested that growth during the neonatal period

should mimic intrauterine growth rates to enable normal organ development, but the optimal

growth pattern for preterm infants is not known.[3] Intrauterine growth rates during the entire

neonatal period are rarely achieved in extremely preterm infants.[4,5]

Prenatal factors influence intrauterine maturation and growth, and intrauterine growth

restriction (IUGR) increases the risks of abnormal organ development and disease.[6]

Retinopathy of prematurity (ROP), is caused by abnormal postnatal retinal neurovascular

development. Previous research has shown that ROP development is related to growth factor

levels,[7] and that low gestational age (GA), associated with very immature retina as a

starting point for postnatal growth, is the strongest risk factor for ROP development.[8] SGA

is a risk factor dependent on GA at birth.[9] Postnatal growth restriction has been used as a

marker for ROP risk, and is an important component of new surveillance systems developed

to refine ROP screening.[10-16] Bronchopulmonary dysplasia (BPD) results from abnormal

postnatal development of pulmonary tissue. It has been suggested that the biological

processes that lead to ROP development also play important roles in BPD development.[17]

BPD risk is also reportedly related to intrauterine growth restriction.[6,18,19] Necrotizing

enterocolitis (NEC) has been associated with IUGR and SGA whereas intraventricular

haemorrhage (IVH) has not.[6,20,21]

The present study aimed to describe how GA, birth weight and postnatal growth vary with the

development of ROP, BPD, NEC, and IVH in extremely preterm infants.

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PATIENTS AND METHODS

This study used data from five cohorts of preterm infants from Canada, the USA, and Sweden

(Figure 1). The Boston cohort included all infants born before 32 weeks GA and qualified for

ROP screening at Brigham and Women’s Hospital between 2005 and 2008.[12] The North

American cohort originated from a multicentre study conducted between 2006 and 2009 at ten

level III neonatal intensive care units within the USA and Canada. This study aimed to

validate the WINROP® screening method.[13] EXPRESS is a population-based study

including all infants born before 27 weeks GA between 2004 and 2007 in Sweden.[14] The

Gothenburg cohort comprised infants born before 32 weeks GA and screened for ROP in

Gothenburg between 2011 and 2012.[15] Our present study also included a previously

unpublished population-based cohort of infants born before 27 weeks GA in Stockholm

between 2008 and 2011.

Our present study included infants born at a GA of between 23+0 and 30+6 weeks without

severe malformations, who survived to a postmenstrual age (PMA) of 40 weeks, and for

whom data were available regarding birth weight (BW), maximum ROP stage, and/or BPD.

Exclusion criteria were hydrocephalus, which gave rise to non-physiological growth patterns,

and more than two registered weight measurements that were considered to be unrealistic

outliers based on age and relation to adjacent measurements. Data were collected as described

in previous studies.[12-15] Data for infants in the Stockholm cohort were collected from

hospital records. GA at birth was based on ultrasound dating, or on the date of last menstrual

period if no ultrasound had been performed.

Prenatal growth was evaluated as BW compared to the expected weight based on GA and

gender. Comparisons were performed using a Swedish foetal growth reference constructed

based on intrauterine ultrasound measurements,[22] which is considered to reflect undisturbed

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intrauterine growth. For comparison, the descriptive figure for growth also included reference

lines from the Olsen growth chart, which is based on American live-born singletons.[23]

Weight measurements were recorded weekly on average, with documentation of the exact

date of every measurement. SGA was defined as BW below two standard deviation scores

according to the intrauterine growth reference.[22] ROP screening was performed following

routine protocol, with classification according to the international system.[24] BPD was

defined as need for oxygen at a PMA of 36 weeks.[25] NEC was defined as Bell stage 2b or

greater.[26] IVH registration included any grade of intraventricular haemorrhage.

Statistics

All statistical analyses were performed using Stata/IC 13.1 software (StataCorp LP, College

Station, Texas, USA). Data outliers were examined with the use of population- and individual

residuals in the model, and excluded if deemed unrealistic. Level of significance was set at

5%. Descriptive analyses included quantile regression growth models. Differences in BW and

birth weight standard deviation score (BWSDS) were estimated using a linear regression

model with robust standard errors. We applied a mixed effects model including restricted

cubic splines (knots at 2, 4, 6, and 10 weeks), with random slope and intercept, to evaluate

growth as weight and growth rate over time.[27,28] Growth rates were calculated using the

exponential model suggested by Patel et al.[29] In the mixed effects model, we included

growth rates using all weights, and calculated the mean between-group differences in weight

and growth rate. To describe the overall growth rate in the entire cohort, we calculated the

rate from birth weight to weight at 36 weeks PMA. If no measurement at 36 weeks PMA was

available, we used the closest value up to 2 weeks prior.

All analyses were initially stratified by gestational week at birth. For the final analyses,

subjects were divided into three groups by GA: 23 to 24 weeks, 25 to 26 weeks, and 27 to 30

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weeks. The GA groups were selected based on the results of the one-week analysis. Postnatal

growth results are presented from birth until 36 weeks PMA. All analyses were adjusted for

exact gestational age in days, gender, and centre. Date of birth was also tested and eliminated

as a confounder and therefore not included in the final model. When analysing differences in

weight over time and growth rate in cases of ROP and BPD, we included further adjustment

for NEC and BWSDS. Analyses were also tested for interaction regarding BWSDS and

morbidity and country and morbidity respectively. No significant association on differences in

growth rate were found and the interaction terms were not included in the final model.

Selected adjustments were based on previously known influences, as well as statistical

procedures including backward selection.

Ethical Statement

The Swedish studies were approved by regional ethical review boards (Lund 2004-42;

Stockholm 2007-1613312 and 2013-26532; Gothenburg 2013-051-13). The North American

studies were approved by institutional review boards at all participating centres (Brigham and

Women’s Hospital, Boston, Massachusetts; Beaumont Hospital/Associated Retinal

Consultants, Oakland University William Beaumont School of Medicine, Royal Oak,

Michigan; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,

Massachusetts; Emory University Hospital Midtown, Emory University School of Medicine,

Atlanta, Georgia; Morristown Medical Center at Atlantic Health, Atlantic Neonatal Research

Institute, Morristown, New Jersey; Mount Sinai Hospital, University of Toronto Faculty of

Medicine, Toronto, ON, Canada; Nationwide Children's Hospital, Ohio State University

College of Medicine, Columbus; New York-Presbyterian Morgan Stanley Children's Hospital,

Columbia University College of Physicians and Surgeons, New York, New York; North

Carolina Children's Hospital, University of North Carolina School of Medicine, Chapel Hill;

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UMass Memorial Medical Center, UMass Medical School, Worcester, Massachusetts;

Wilford Hall Medical Center, Uniformed Services University of the Health Sciences,

Lackland Air Force Base, Texas).

RESULTS

This study included a total of 2521 infants (Figure 1), with a mean of 14.3 weight

measurements per infant (median, 11; IQR, 9 to 16). The last weight measurement was

registered at a mean PMA of 37+6 weeks (median, 37+5 weeks; IQR, 36+0 to 39+5 weeks).

Baseline characteristics are demonstrated in table 1. The infants’ gestational ages were evenly

distributed between the early group (23 to 26 weeks; 52%) and later group (27 to 30 weeks;

48%). The later GA group showed a lower median BWSDS. Infants born at GA 23 to 26

weeks showed significant postnatal growth restriction, reflected by a reduced mean weight

standard deviation score from birth to 36 weeks PMA, with the most pronounced difference

among the more immature infants. Figure 2 and Table 1 illustrate the growth data. Median

weekly growth rates were highest at a PMA of 30 weeks in infants born at GA 23 to 26

weeks, and at a PMA of 31 to 34 weeks among infants born at GA 28 to 30 weeks,

corresponding to the fifth week of life.

Morbidity

Table 1 displays the numbers and frequencies of ROP, BPD, NEC, and IVH by gestational

week. Differences in BWSDS, postnatal weight, and growth rate are shown in Figure 3 and

Figure 4, as well as in the Appendix.

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Table 1. Infant

Characteristics, Growth, and

Morbidity by Gestational Age

at Birth. #North America (USA and

Canada).

Mdn denotes median, w weeks,

IQR interquartile range (25th

to

75th


treatment for ROP.

++Overall growth rate from birth

to 36 weeks postmenstrual age

calculated for 2344 infants.

*Information regarding ROP

was missing for one infant born

at a gestational age of 24 weeks,

and one infant at 25 weeks.

Information regarding BPD was

missing from two infants born at

a gestational age of 24 weeks,

two infants at 25 weeks, and five

infants born at 26 weeks.

Infant Characteristics, Growth, and Morbidity

Gestational Age at Birth (weeks)

23 24 25 26 27 28 29 30 All

n % n % n % n % n % n % n % n % N %

Infants 117 4.6 314 12.5 399 15.8 482 19.1 249 9.9 296 11.7 323 12.8 341 13.5 2521 100

Female

Sex 58 49.6 137 43.6 190 47.6 229 47.5 119 47.8 139 47.0 134 41.5 162 47.5 1168 46.3

Country NA# 53 45.3 168 53.5 190 47.6 227 47.1 237 95.2 277 93.6 299 92.6 319 93.5 1770 70.2

Sweden 64 54.7 146 46.5 209 52.4 255 52.9 12 4.8 19 6.4 24 7.4 22 6.4 751 29.8

SGA 5 4.3 38 12.1 81 20.3 115 23.9 77 30.9 110 37.2 107 33.1 114 33.4 647 25.7

Mdn IQR Mdn IQR Mdn IQR Mdn IQR Mdn IQR Mdn IQR Mdn IQR Mdn IQR Mdn IQR

BW (g) 595 550-

655 675

610-

735 770

693-

858 890

776-

995 989

865-

1080 1071

921-

1211 1287

1100-

1420 1415

1195-

1550 915

731-

1153

BWSDS (SDS) −0.4 −1.0-

0.4 −0.6

−1.4-

0.0 −1.0

−1.7-

−0.1 −1.0

−2.0-

−0.2 −1.3

−2.3-

−0.6 −1.6

−2.6-

−0.8 −1.3

−2.3-

−0.4 −1.4

−2.5-

−0.6 −1.1

−2.0-

−0.3

Weight at 36 w

PMA (g) 2072

1847-

2263 2123

1932-

2319 2126

1881-

2377 2190

1905-

2415 2244

1922-

2501 2179

1958-

2500 2320

1973-

2582 2206

1902-

2506 2157

1909-

2391

WSDS at 36 w

PMA (SDS) −2.3

−2.9-

−1.8 −2.2

−2.8-

−1.6 −2.2

−2.9-

−1.4 −2.0

−2.9-

−1.2 −1.6

−2.7-

−0.8 −1.9

−2.5-

−0.9 −1.5

−2.6-

−0.7 −1.8

−2.9-

−0.9 −1.9

−2.7-

−1.2

Growth rate ++

(g/kg/d) 13.7

12.6-

15.2 13.8

12.6-

15.2 13.8

12.7-

15.4 13.8

12.3-

15.4 13.7

12.3-

15.2 13.3

11.6-

14.9 12.4

11.0-

14.2 11.8

9.8-

13.9 13.3

11.8-

15.0

MAX rate

(g/kg/d) 18.9

11.5-

23.6 18.3

12.2-

23.8 19.7

13.1-

25.6 20.3

13.4-

25.6 21.7

17.8-

25.1 20.5

16.9-

23.8 20.4

16.6-

23.7 19.0

15.7-

22.7 17.7

11.3-

22.7

PMA @MAX 30 30 30 30 31 32 33 34 31

n % n % n % n % n % n % n % n % N %

ROP*

No 9 7.7 17 5.4 69 17.3 166 34.4 99 39.8 185 62.5 236 73.1 304 89.1 1085 43.0

ROP 1-2 40 34.2 131 41.9 215 54.0 236 49.0 127 51.0 98 33.1 84 26.0 34 10.0 965 38.3

ROP ≥ 3 68 58.1 165 52.7 114 28.6 80 16.6 23 9.2 13 4.4 3 0.9 3 0.9 471 18.7

Trt 51 43.6 109 34.9 65 16.3 39 8.1 16 6.4 5 1.7 3 0.9 0 0.0 288 11.4

BPD* 104 88.9 247 79.2 289 72.8 308 64.6 124 49.8 108 36.5 58 18.0 30 8.8 1268 50.5

NEC 9 7.7 47 15.0 33 8.3 42 8.7 25 10.0 32 10.8 27 8.4 15 4.4 230 9.1

All IVH 60 51.3 144 45.9 141 35.3 118 24.5 65 26.1 56 18.9 64 19.8 44 12.9 692 27.4

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ROP and Growth

Infants developing ROP of any grade showed lower growth rates compared to infants not

developing ROP. This difference was noted in the 7th

to 9th

weeks of life among infants born

at GA 23 to 24 weeks, and in the 4th

to 6th

weeks of life in those born at GA 25 to 26 weeks.

Infants born at GA 27 to 30 weeks had lower growth rates during their first five weeks of life,

shifting to higher growth rates starting at the 7th

week of life. Among infants born at GA 25 to

30 weeks, BWSDS was lower in infants developing ROP. Differences at birth were greater

among infants born at later GA (Appendix Figure S1, Table S1).

BPD and Growth

Among those born at GA 27 to 30 weeks, infants with BPD had lower growth rates in the 4th

to 5th

week of life compared to infants without BPD, followed by higher growth rates from the

7th

week of life. Among those born at GA 23 to 24 weeks, infants developing BPD showed

significantly lower weight during the 8th

to 12th

week of life compared to those without BPD,

while these groups did not significantly differ in growth rate. Among those born at GA 25 to

30 weeks, BWSDS was lower in infants developing BPD. These differences were greater

among infants born at later GA, and weight continued to be lower from birth to PMA 36

weeks (Appendix Figure S2, Table S2).

NEC and Growth

Among infants born at all GAs, those with NEC showed lower growth rates from the 6th

to 7th

week of life and during the rest of the studied neonatal period compared to infants without

NEC. Infants born at all GAs with and without NEC did not significantly differ in BWSDS

(Appendix Figure S3, Table S3).

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IVH and Growth

Analysis of infants with any IVH compared to with no IVH revealed no associations with pre-

or postnatal growth (Appendix Figure S4).

SGA and Postnatal Growth

Compared to infants born at a weight appropriate for their gestational age, those born SGA

continued to show lower weights until 36 weeks PMA. For the first three weeks of life, SGA

infants showed higher growth rates than appropriate for gestational age infants (Appendix

Figure S5).

DISCUSSION

This study demonstrates differences in postnatal growth patterns in infants developing

morbidities, and highlights specific postmenstrual weeks with greater differences in growth

rates, potentially implicating important windows of vulnerability partly depending on GA.

Our present results showed similar patterns of pre- and postnatal growth restriction between

infants developing ROP and BPD. Infants born at a GA of 25 to 30 weeks who developed

ROP and BPD were smaller at birth. Infants born at all GAs who developed ROP had reduced

growth rates. Among those born at GA 23 to 26 weeks, this reduction was most pronounced

around the postnatal weeks corresponding to the 31st postmenstrual week. Those born at GA

27 to 30 weeks and developing ROP and BPD showed an initially reduced growth rate, which

shifted to higher growth rates in later weeks. Infants developing NEC and IVH showed a

different pattern of pre- and postnatal growth restriction, indicating a different

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pathophysiology. The frequency of especially ROP and BPD is high among the most

immature infants; 76% of the infants in GA 23 to 24 weeks developed both ROP and BPD,

which is important to bear in mind comparing the growth patterns between morbidities

(Appendix Table S4).

To our knowledge, this is the largest detailed study of postnatal weight development among

low gestational age infants, including a large proportion of extremely preterm infants.

Stratification by GA rather than birth weight enables consideration of the increased morbidity

risks associated with a greater degree of immaturity. The wide range of methods used to

evaluate postnatal growth in previous studies makes it difficult to compare results among

studies. In 1999, Ehrenkranz et al.[4] described the postnatal growth pattern of infants

developing morbidity, reporting a mean growth rate (from regaining BW to discharge, death,

or reaching 2 kg) of 14 to 16 g/kg/d, increasing with increasing GA. Horbar et al.[30] reported

growth rates calculated using the two point exponential model from birth to discharge. The

mean growth rates from 2013 in GA 24 to 26 weeks were 13.0 g/kg/d (95% CI 13.0 to 13.1).

Martin et al.[31] reported a relationship between lower BWSDS and higher growth rates

during the first weeks of life that was similar to the association observed in our cohort.

However, Martin et al.[31] did not use an exponential growth model to calculate growth rates,

resulting in higher rates compared to those found in our study. Our presently used exponential

model has been evaluated and deemed most appropriate for calculating growth rates of

preterm infants.[29] Fortes-Filho et al.[32] described a relationship between severe ROP and

proportion of birth weight gained at 6 weeks of age. Their results are consistent with our

findings in infants born at a GA of 25 to 30 weeks. Nyp et al.[33] evaluated growth rate (in

g/kg from BW to 36 weeks PMA) among 140 infants born before 28 weeks of GA, and found

no association with BPD. In our substantially larger cohort, we detected associations between

BPD and postnatal growth that related to specific postnatal weeks.

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Limitations of our present study include a lack of information regarding some perinatal

background data preventing any conclusions regarding causality. Notably, our material

included no information regarding sepsis. Ehrenkranz et al.[4] demonstrated that infants with

sepsis have growth pattern similar to those of infants with BPD. Moreover, the use of

BWSDS to classify foetal growth restriction could lead to misclassification of infants who are

genetically small for gestational age without foetal growth restriction. Additionally, this study

included only infants who survived to 40 weeks PMA, which could affect the description of

postnatal growth within the entire cohort but not our main outcomes. The combined dataset

included no information regarding time of NEC. The fact that surgically managed NEC has

been previously associated with substantial growth delay,[34] and the growth patterns

demonstrated in our present results suggest that the NEC disease process precedes growth

restriction. IVH—which usually occurs early postnatally—does not appear to be strongly

related to postnatal growth. Caution is advised interpreting significant results in a study

including multiple comparisons. This study examines growth in four morbidities in three

strata of GA. The time is handled as a continuum, p-values regarding differences in growth

rates are presented week by week in the Appendix.

From this study it is not possible to determine how the presently described associations are

mediated. Analysis of the relationship between nutrition and ROP in the EXPRESS cohort

revealed that low energy intake during the first four weeks of life was related to increased

frequency of severe ROP, after adjustment for several morbidities.[35] Nutrition practices

have most likely been continuously altered during the studied period of time. Including date

of birth in the model did not alter the results, but the need to adjust for center in the final

model demonstrates that center is associated with weight and disease development even

adjusted for GA at birth and BWSDS and could be a reflection of differences in perinatal

care. Both the pattern of initially reduced and later increased growth rates could be of

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importance for processes involved in the development of ROP and BPD. The specific weeks

showing significantly reduced growth rates corresponded to a PMA of around 31 weeks in

infants born at a GA of 23 to 26 weeks, implicating an especially important period of growth

in extremely preterm infants. This is the period of maximum growth rate, and represents the

transition from growth failure to catch-up growth among infants born at these GAs. Hansen-

Pupp et al.[36] described increased insulin-like growth factor I (IGF-I) concentrations at PMA

30 weeks, coinciding with the initiation of catch-up growth. Moreover, ROP severity is

correlated to IGF-I serum concentrations and duration of low IGF-I concentrations.[7,37] The

reduced growth rates at a PMA of around 30 weeks could be biologically related to initiation

of phase two of ROP development, which has been demonstrated to correlate to an increase of

the initially low levels of IGF-I.[7] Lower IGF-I levels in the first postnatal weeks are also

associated with BPD among very preterm infants.[17] It is reasonable to postulate that factors

that control somatic growth also influence retina and lung development. ROP is both a

vascular and neurological disease. Poor neurodevelopment has been related to poor postnatal

growth,[38,39] and postnatal IGF-I concentrations have been associated with brain volume at

term.[40] Neonatal care should aim at optimal growth during the entire neonatal period.

Future clinical trials should further investigate the specific periods of slower growth rates and

catch up growth, and continue to analyse interactions between growth factors, nutrition,

weight gain, and morbidities, including neurodevelopmental outcomes. Our present results

highlight postnatal growth as a marker for disease, emphasizing the importance of monitoring

growth and nutrition in the neonatal intensive care unit.

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FUNDING

This study is supported by grants provided by Swedish Research Council (DNR# 2011-2432)

and Gothenburg County Council (ALFGBG-426531). S Klevebro was supported by the

Stockholm County Council (combined clinical residency and PhD training program) and has

received grants from Lilla Barnets Fond, Stiftelsen Samariten and Föreningen Mjölkdroppen.

L Smith was supported by NIH EY024864, EY017017, EY022275, P01 HD18655, Lowy

Medical Research Institute, European Commission FP7 project 305485 PREVENT-ROP.

COMPETING INTERESTS

The authors have no competing interests relevant to this article to disclose.

DATA SHARING STATEMENT

No additional data available.

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CONTRIBUTOR STATEMENT

Dr. Klevebro collected data from the Stockholm cohort, carried out the analyses, drafted the

initial manuscript, revised the manuscript, and approved the final manuscript as submitted.

Dr. Lundgren and Assoc. Prof. Löfqvist coordinated the data collection, contributed to the

design of the study, reviewed the manuscript, and approved the final manuscript as submitted.

Mr. Hammar and Prof. Bottai merged the datasets, participated in selection of statistical

methods, carried out the initial analyses, and approved the final manuscript as submitted.

Prof. Smith and Prof. Domellöf coordinated and supervised data collection from the American

cohorts and Swedish national cohort respectively, reviewed the manuscript, and approved the

final manuscript as submitted.

Dr. Hallberg contributed to the design of the study, critically reviewed the manuscript, and

approved the final manuscript as submitted.

Prof. Hellström conceptualized and designed the study, supervised data collection, reviewed

the manuscript, and approved the final manuscript as submitted.

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doi: 10.1542/peds.2008-3258 [published Online.

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33. Nyp MF, Taylor JB, Norberg M, et al. Impaired growth at birth and

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first 4 weeks of life increases the risk for severe retinopathy of prematurity in extremely

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39. Franz AR, Pohlandt F, Bode H, et al. Intrauterine, early neonatal, and

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40. Hansen-Pupp I, Hovel H, Hellstrom A, et al. Postnatal decrease in circulating

insulin-like growth factor-I and low brain volumes in very preterm infants. The Journal of

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Figure 1. Flowchart of Included Cohorts.

GA denotes gestational age, w weeks, PMA postmenstrual age, HC hydrocephalus, and

FEVR familial exudative vitreoretinopathy.

Table 1. Infant Characteristics, Growth, and Morbidity by Gestational Age at Birth.

#North America (USA and Canada).

Mdn denotes median, w weeks, IQR interquartile range (25th

to 75th


treatment for ROP.

++Overall growth rate from birth to 36 weeks postmenstrual age calculated for 2344 infants.

*Information regarding ROP was missing for one infant born at a gestational age of 24 weeks,

and one infant at 25 weeks. Information regarding BPD was missing from two infants born at

a gestational age of 24 weeks, two infants at 25 weeks, and five infants born at 26 weeks.

Figure 2. Postnatal Weight Development and Growth Rate According to Gestational

Age, Illustrated by the 25th, 50

th, and 75

th Percentiles.

Panel A shows postnatal weight development in grams. Panel B shows postnatal growth rate

in grams/kilograms/day. Growth references 50th

percentiles from Marsal[22] and Olsen[23].

Pink denotes female, and blue male.

Figure 3. Difference in Birth Weight Standard Deviation Score (BWSDS) According to

Gestational Age Group, Between Infants With and Without Respective Morbidities.

Data are shown as mean and 95% confidence interval for each diagnose. All analyses are

adjusted for exact gestational age at birth, gender, and centre.

Figure 4. Difference in Weight and in Growth Rate Over Time According to Gestational

Age Group, Between Infants With and Without Respective Morbidities.

Panel A shows the difference in weight in grams. Panel B shows the difference in growth rate

in grams/kilogram/day. Time is represented by postnatal age (PNA) in weeks. Data are shown

as mean and 95% confidence interval for each diagnosis. All analyses are adjusted for exact

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gestational age at birth, gender, and centre. Analyses of differences regarding ROP and BPD

are also adjusted for NEC and in growth rate analyses for birth weight standard deviation

score (BWSDS).

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Figure 1. Flowchart of Included Cohorts. GA denotes gestational age, w weeks, PMA postmenstrual age, HC hydrocephalus, and FEVR familial

exudative vitreoretinopathy.

Figure 1 299x198mm (300 x 300 DPI)

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Figure 2. Postnatal Weight Development and Growth Rate According to Gestational Age, Illustrated by the 25th, 50th, and 75th Percentiles.


grams/kilograms/day. Growth references 50th percentiles from Marsal[22] and Olsen[23]. Pink denotes female, and blue male.

Figure 2 299x400mm (300 x 300 DPI)

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Figure 3. Difference in Birth Weight Standard Deviation Score (BWSDS) According to Gestational Age Group, Between Infants With and Without Respective Morbidities.

Data are shown as mean and 95% confidence interval for each diagnose. All analyses are adjusted for exact

gestational age at birth, gender, and centre. Figure 3

299x224mm (300 x 300 DPI)

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Figure 4. Difference in Weight and in Growth Rate Over Time According to Gestational Age Group, Between Infants With and Without Respective Morbidities.

Panel A shows the difference in weight in grams. Panel B shows the difference in growth rate in

grams/kilogram/day. Time is represented by postnatal age (PNA) in weeks. Data are shown as mean and 95% confidence interval for each diagnosis. All analyses are adjusted for exact gestational age at birth,

gender, and centre. Analyses of differences regarding ROP and BPD are also adjusted for NEC and in growth rate analyses for birth weight standard deviation score (BWSDS).

Figure 4 299x342mm (300 x 300 DPI)

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Table of Contents

2-3. Figure S1A, S1B and Table S1 (Growth of Infants With Any ROP vs. No ROP)

4-5. Figure S2A, S2B and Table S2 (Growth of Infants With BPD vs. No BPD)

6-7. Figure S3A, S3B and Table S3 (Growth of Infants With NEC vs. No NEC)

8. Figure S4 (Growth of Infants With Any IVH vs. No IVH)

9. Figure S5A and S5B (Growth of Small for Gestational Age Infants)

10. Table S4 (Multiple Morbidities by Gestational Age)

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Without Retinopathy of Prematurity (ROP).

Panel A shows postnatal weight development in grams. Panel B shows development in weight standard

deviation score (SDS) according to Marsal[22]. Data are shown as mean and 95% confidence interval.

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week of life

23-24 25-26 27-30

diff (g/kg/d)

p diff (g/kg/d)

p diff (g/kg/d)

p

1 2.0 0.36 2.7 <0.001 -0.9 0.04

2 1.5 0.33 1.0 0.08 -1.0 <0.001

3 1.0 0.43 -0.7 0.10 -1.2 <0.001

4 0.4 0.77 -2.3 <0.001 -1.2 <0.001

5 -0.3 0.85 -2.9 <0.001 -0.9 0.007

6 -1.2 0.31 -2.1 <0.001 0.0 0.99

7 -2.1 0.04 -0.8 0.07 0.9 0.003

8 -2.4 0.03 0.0 0.96 1.3 <0.001

9 -2.3 0.04 0.3 0.50

10 -1.9 0.06 0.3 0.51

11 -1.4 0.11

12 -0.8 0.27

Table S1. Difference in Growth Rate Over Time According to Gestational Age Group, Between

Infants With and Without Retinopathy of Prematurity (ROP).

Growth rate is reported in grams/kilogram/day. Data are shown as mean and 95% confidence interval.

Analyses are adjusted for exact gestational age at birth, gender, center, necrotizing enterocolitis (NEC), and

birth weight standard deviation score (BWSDS).

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Without Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is defined as requiring O2 at 36 weeks postmenstrual age (PMA).



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week of life

23-24 25-26 27-30

diff (g/kg/d)

p diff (g/kg/d)

p diff (g/kg/d)

p

1 1.6 0.23 2.7 0.45 0.9 0.04

2 1.0 0.31 1.0 0.84 0.2 0.62

3 0.3 0.66 -0.7 0.41 -0.6 0.03

4 -0.3 0.73 -2.3 0.12 -1.3 <0.001

5 -0.7 0.43 -2.9 0.09 -1.3 <0.001

6 -0.9 0.22 -2.1 0.16 -0.3 0.25

7 -0.9 0.16 -0.8 0.73 0.9 0.01

8 -0.8 0.24 0.0 0.70 1.5 <0.001

9 -0.7 0.31 0.3 0.46

10 -0.6 0.35 0.3 0.35

11 -0.5 0.38

12 -0.4 0.48


Infants With and Without Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is defined as requiring O2 at 36 weeks postmenstrual age (PMA).

Growth rate is reported in grams/kilogram/day. Data are shown as mean and 95% confidence interval.

Analyses are adjusted for exact gestational age at birth, gender, center, necrotizing enterocolitis (NEC), and

birth weight standard deviation score (BWSDS).

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Without Necrotizing Enterocolitis (NEC).



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week of life

23-24 25-26 27-30

diff (g/kg/d)

p diff (g/kg/d)

p diff (g/kg/d)

p

1 1.7 0.28 0.5 0.71 0.2 0.80

2 1.6 0.14 -0.1 0.92 -0.2 0.75

3 1.6 0.08 -0.7 0.39 -0.5 0.23

4 1.4 0.18 -1.3 0.19 -0.8 0.11

5 0.8 0.51 -1.8 0.09 -1.1 0.06

6 -0.6 0.51 -2.2 0.008 -1.1 0.01

7 -2.1 0.008 -2.4 <0.001 -1.1 0.02

8 -2.9 <0.001 -2.5 0.003 -1.3 0.03

9 -3.1 <0.001 -2.3 0.005

10 -2.9 <0.001 -2.1 0.005

11 -2.5 <0.001

12 -2.1 0.001


Infants With and Without Necrotizing Enterocolitis (NEC).

Growth rate is shown in grams/kilograms/day. Data are shown as mean and 95% confidence interval.

Analyses are adjusted for exact gestational age at birth, gender and center.

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Figure S4. Postnatal Weight Development by Gestational Age at Birth in Infants With and Without

Intraventricular Hemorrhage (IVH).


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Figure S5. Postnatal Weight Development and Postnatal Growth Rate in Infants Born Small for

Gestational Age (SGA) and Appropriate for Gestational Age (AGA) According to Gestational Age.


grams/kilograms/day. Data are shown as mean and 95% confidence interval.

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23-24 25-26 27-30

No BPD BPD No BPD BPD No BPD BPD

No ROP No NEC 2 23 80 145 618 149

NEC 0 1 5 4 43 14

ROP No NEC 65 282 166 411 205 138

NEC 11 44 26 36 23 19

Table S4. Number of Infants Developing ROP, BPD, NEC and Combinations of these Morbidities by

Gestational Age.

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STROBE Statement—checklist of items that should be included in reports of observational studies

Item

No Recommendation

Title and abstract

Page 3

1 (a) Indicate the study’s design with a commonly used term in the title or the

abstract

(b) Provide in the abstract an informative and balanced summary of what was done

and what was found

Introduction

Background/rationale

Page5

2 Explain the scientific background and rationale for the investigation being reported

Objectives

Page 5

3 State specific objectives, including any prespecified hypotheses

Methods

Study design

Page 6

4 Present key elements of study design early in the paper

Setting

Page 6

5 Describe the setting, locations, and relevant dates, including periods of recruitment,

exposure, follow-up, and data collection

Participants

Page 6

6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of

selection of participants. Describe methods of follow-up

Case-control study—Give the eligibility criteria, and the sources and methods of

case ascertainment and control selection. Give the rationale for the choice of cases

and controls

Cross-sectional study—Give the eligibility criteria, and the sources and methods of

selection of participants

(b) Cohort study—For matched studies, give matching criteria and number of

exposed and unexposed

Case-control study—For matched studies, give matching criteria and the number of

controls per case

Variables

Page 6-7

7 Clearly define all outcomes, exposures, predictors, potential confounders, and

effect modifiers. Give diagnostic criteria, if applicable

Data sources/

measurement

Page 6-7

8* For each variable of interest, give sources of data and details of methods of

assessment (measurement). Describe comparability of assessment methods if there

is more than one group

Bias

Page 7-8

9 Describe any efforts to address potential sources of bias

Study size

Page 6

10 Explain how the study size was arrived at

Quantitative variables

Page 7-8

11 Explain how quantitative variables were handled in the analyses. If applicable,

describe which groupings were chosen and why

Statistical methods

Page 7-8

12 (a) Describe all statistical methods, including those used to control for confounding

(b) Describe any methods used to examine subgroups and interactions

(c) Explain how missing data were addressed

(d) Cohort study—If applicable, explain how loss to follow-up was addressed

Case-control study—If applicable, explain how matching of cases and controls was

addressed

Cross-sectional study—If applicable, describe analytical methods taking account of

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sampling strategy

(e) Describe any sensitivity analyses

Results

Participants

Page 8 and Fig1

13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible,

examined for eligibility, confirmed eligible, included in the study, completing follow-up,

and analysed

(b) Give reasons for non-participation at each stage

(c) Consider use of a flow diagram

Descriptive data

Page 8

Table 1

Fig 2

14* (a) Give characteristics of study participants (eg demographic, clinical, social) and

information on exposures and potential confounders

(b) Indicate number of participants with missing data for each variable of interest

(c) Cohort study—Summarise follow-up time (eg, average and total amount)

Outcome data

Page 9-10

Table 1

15* Cohort study—Report numbers of outcome events or summary measures over time

Case-control study—Report numbers in each exposure category, or summary measures of

exposure

Cross-sectional study—Report numbers of outcome events or summary measures

Main results

Page 11-12

Fig 3 and 4

And Appendix

16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their

precision (eg, 95% confidence interval). Make clear which confounders were adjusted for

and why they were included

(b) Report category boundaries when continuous variables were categorized

(c) If relevant, consider translating estimates of relative risk into absolute risk for a

meaningful time period

Other analyses

Page 8 and

Appendix

17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity

analyses

Discussion

Key results

Page 12-13

18 Summarise key results with reference to study objectives

Limitations

Page 13-14

19 Discuss limitations of the study, taking into account sources of potential bias or imprecision.

Discuss both direction and magnitude of any potential bias

Interpretation

Page 14-15

20 Give a cautious overall interpretation of results considering objectives, limitations,

multiplicity of analyses, results from similar studies, and other relevant evidence

Generalisability

Page 15

21 Discuss the generalisability (external validity) of the study results

Other information

Funding

Page 16

22 Give the source of funding and the role of the funders for the present study and, if

applicable, for the original study on which the present article is based

*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and

unexposed groups in cohort and cross-sectional studies.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and

published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely

available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at

http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is

available at www.strobe-statement.org.

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