Original Article

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Adverse Impact of Maternal Cigarette Smoking on Preterm Infants: A Population-Based Cohort Study Tetsuya Isayama, MD1,2 Prakesh S. Shah, MD, FRCPC, MSc1,2 Xiang Y. Ye, MSc2 Michael Dunn, MD, FRCPC1 Orlando Da Silva, MD, FRCPC, MSc3 Ruben Alvaro, MD4 Shoo K. Lee, MBBS, FRCPC, PhD1,2 1 Department of Pediatrics, University of Toronto, Toronto,

Ontario, Canada 2 Maternal-Infant Care Research Centre, Mount Sinai Hospital, Toronto, Ontario, Canada 3 Department of Paediatrics, University of Western Ontario, London, Ontario, Canada 4 Department of Pediatrics & Child Health, University of Manitoba, Winnipeg, Manitoba, Canada

Address for correspondence Prakesh S. Shah, MD, FRCPC, MSc, Department of Pediatrics, Mount Sinai Hospital, 600 University Avenue, Room 19-231A, Toronto, Ontario, M5G 1X5 (e-mail: [email protected]).

Abstract

Keywords

► ► ► ► ►

pregnancy smoking preterm infants morbidity cohort study

Objective The aim of the study is to examine the impact of exposure to maternal cigarette smoking on neonatal outcomes of very preterm infants. Study Design A retrospective cohort study examined preterm infants (< 33 weeks gestational age) admitted to the Canadian Neonatal Network centers between 2003 and 2011. Mortality and major morbidities (bronchopulmonary dysplasia, severe intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy) were compared between infants exposed and unexposed to maternal smoking during pregnancy after adjusting for confounders. Results Among 29,051 study infants, 4,053 (14%) were exposed to maternal smoking during pregnancy. Multivariable analysis revealed higher odds of grade 3 or 4 intraventricular hemorrhage or periventricular leukomalacia (adjusted odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.04–1.41) and bronchopulmonary dysplasia (adjusted OR: 1.16, 95% CI: 1.02–1.33) in the smoking group, while mortality, severe retinopathy, and necrotizing enterocolitis were not significantly different. Conclusion Maternal smoking during pregnancy is associated with severe neurological injury and bronchopulmonary dysplasia in preterm infants.

The prevalence of smoking among women is high in developed countries, such as the United States (14%), Canada (13%), and the United Kingdom (20%).1 Maternal smoking during pregnancy is concerning because it is associated with various adverse pregnancy outcomes,2 including fetal growth restriction, preterm birth, spontaneous abortions, stillbirth, and placental abruption along with adverse morbidities in offspring, including sudden infant death syndrome

and respiratory morbidities in infancy and childhood.3,4 In contrast to these plentiful data related to general adverse impact on pregnancy and offspring, the information about specific effects of maternal smoking during pregnancy on preterm infants, who are more vulnerable than mature infants, is limited. Therefore, this study aims to examine the effect of maternal smoking during pregnancy on neonatal outcomes of preterm infants in Canada.

received August 22, 2014 accepted after revision February 12, 2015 published online March 31, 2015

Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0035-1548728. ISSN 0735-1631.

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Am J Perinatol 2015;32:1105–1111.

Adverse Impact of Maternal Cigarette Smoking

Isayama et al.

Methods This population-based retrospective cohort study included preterm infants born at < 33 weeks gestational age admitted to neonatal intensive care units (NICUs) in the Canadian Neonatal Network (CNN) between January 2003 and December 2011. We excluded infants with major congenital anomalies and those who were moribund (where a decision was made at birth not to provide resuscitative care) from the analysis. The CNN has maintained a standardized NICU database since 1996 that includes maternal and infant data for all admissions to the NICUs participating in the CNN. Details of the data collection and management have been published previously.5 Study variables were defined according to the CNN Abstractor’s Manual.5 Maternal smoking was defined as any cigarette smoking during pregnancy and included mothers who smoked while unaware of their pregnancy and stopped after they became aware of their pregnancy. Data on maternal smoking, reported by the mothers at any of the prenatal visits, were collected from mothers’ charts by trained research assistants at each site. Data on smoking status was obtained from prenatal records.6 Data on duration and frequency of smoking were not collected as part of routine surveillance data for the CNN. Gestational age was defined as the best obstetric estimate, based on early prenatal ultrasound, obstetric examination, and obstetric history, followed by pediatric estimate. If the postnatal pediatric estimate of gestation differed from the obstetric estimate by more than 2 weeks, the pediatric estimate was used. Small for gestational age (SGA) was defined as birth weight less than 10th percentile for gestational age and sex.7 The Score for Neonatal Acute Physiology-Version II was calculated to assess the illness severity on admission.8 Maternal hypertension and diabetes included both gestational conditions and those existing before pregnancy. Infants were considered to have been exposed to antenatal steroids if at least one dose was given before delivery. Maternal substance abuse (self-reporting) included use of all recreational drugs, such as marijuana, cocaine, heroin, codeine, and methadone. Our outcomes included rates of death in the NICU, bronchopulmonary dysplasia (BPD), severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), nosocomial infection, respiratory distress syndrome, air leak, and patent ductus arteriosus. A composite outcome was defined as death in the NICU or any major morbidity including BPD, severe neurological injury (severe IVH and/or PVL), ROP, and NEC. We also examined NICU resource use including days of supplemental oxygen use, continuous positive airway pressure, mechanical ventilation, and hospital stay. BPD was defined as supplemental oxygen use at 36 weeks corrected gestational age9 or at discharge to level 1 or 2 centers. Severe IVH was defined as grade 3 or 4 IVH according to the criteria of Papile et al.10 PVL was diagnosed based on ultrasound findings after 21 days of life. NEC was defined according to Bell’s criteria (
stage 2).11 ROP was defined according to the international classification (
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3 in either eye).12 Nosocomial infection was defined as culture-positive sepsis or meningitis at > 48 hours of age. Patent ductus arteriosus was defined as clinically significant patent ductus arteriosus. Descriptive statistical methods were used to summarize the study population. The trend in the rate of maternal smoking from 2003 to 2011 was examined using the Cochran–Armitage trend test.13 Infant characteristics and neonatal outcomes were then compared between infants exposed to maternal smoking during pregnancy (smoking group) and those unexposed (nonsmoking group) using the Chi-square test for categorical variables and Student t-test or the Wilcoxon Rank Sum test, as appropriate, for continuous variables. Multivariable logistic regression analyses were further conducted to determine the impact of maternal smoking on binary neonatal outcomes. The covariates included were gestational age at birth, gender, SGA, Apgar score < 7 at 5 minutes, outborn, singleton, maternal age, cesarean birth, maternal hypertension, maternal diabetes, antenatal steroids, substance use, and chorioamnionitis. Odds ratios were estimated based on final models derived by stepwise variables selection procedures. Interactions between smoking and gestational age groups (infants born at < 26, 26–28, and 29–32 weeks gestational age) were also assessed and subgroup multivariable logistic regression analyses were conducted in infants stratified by gestational age groups. As NICU resource use, such as the duration of hospital stay, the duration of oxygen support, continuous positive airway pressure, and ventilation, was highly positively skewed, the differences in resource use between the smoking and nonsmoking groups were examined using a linear regression model for log-transformed outcomes or zero-inflated negative binomial models, as appropriate, adjusted for aforementioned potential confounders and risk factors. Data management and statistical analyses were performed using SAS 9.3 (SAS Institute, Inc., Cary, NC). A two-sided p-value of 0.05 was used to determine statistical significance. This study was approved by the steering committee of the CNN. Data collection was approved by either a research ethics board or an appropriate quality and data control committee at each institution in the CNN.

Results A total of 31,020 eligible preterm infants were admitted to the NICUs in the CNN during the study period. Among them, 1,949 (6.3%) infants who were diagnosed with major congenital anomalies and 20 (0.06%) infants with missing data regarding maternal smoking were excluded. The remaining 29,051 infants, of which 4,053 (14%) were in the smoking group, were included in this study. No significant change in the maternal cigarette smoking rate was observed over time during the study period (Cochran–Armitage trend test: p ¼ 0.26). The maternal and infant characteristics are presented in ►Table 1. The smoking group had higher rates of multigravida, outborn status, chorioamnionitis, and substance use, and lower rates of cesarean birth, maternal hypertension,

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Discussion In this large population-based cohort study, we identified a significant adverse impact of maternal cigarette smoking during pregnancy on preterm neonates, including higher rates of a composite adverse outcome, severe IVH/PVL, BPD, and longer durations of supplemental oxygen use, mechanical ventilation, and hospital stay. Previous studies investigating the effects of smoking during pregnancy on preterm infants have reported inconsistent results.14–16 Consistent with our study, some studies reported the associations between maternal smoking during pregnancy and grade 2 or more IVH15 and BPD defined as supplemental oxygen use at 28 days of age with chest radiographic changes17; however, others have found no such associations.14,16 A Swedish cohort study examining 497 surviving extremely preterm infants (born at < 27 weeks gestational age) reported an association between maternal smoking and a reduction in ROP but no association with severe IVH, PVL, BPD, or NEC.14 A recent single-center casecontrol study reported maternal cigarette smoking as a risk factor of NEC.18 One of the reasons for the inconsistent results

Table 1 Maternal and infant characteristics of infants born at < 33 weeks gestation to mothers who smoked during pregnancy (smoking group) compared with those born to mothers who did not (nonsmoking group) Characteristicsa

Smoking group n ¼ 4,053

Nonsmoking group n ¼ 24,998

p-Valueb

Maternal age (y), mean (SD)

27 (6.0)

31 (5.8)

< 0.01

Gravida (> 1)

3,045 (76%)

15,368 (62%)

< 0.01

Substance use

823 (20%)

345 (1%)

< 0.01

Hypertension

505 (13%)

4,784 (20%)

< 0.01

Diabetes

286 (7%)

2,209 (9%)

< 0.01

Antenatal steroid use

2,435 (62%)

15,500 (65%)

< 0.01

Chorioamnionitis

676 (20%)

2,845 (13%)

< 0.01

Cesarean birth

1,520 (53%)

10,797 (59%)

< 0.01

Male gender

2,139 (53%)

13,557 (54%)

0.08

Singleton

3,127 (77%)

16,746 (67%)

< 0.01

Outborn

818 (20%)

4,281 (17%)

< 0.01

Gestational age (wk), mean (SD)

29.0 (2.5)

28.9 (2.6)

0.03

Gestational age group

0.42

< 26 wk

453 (11%)

3,294 (13%)

26–28 wk

1,123 (28%)

6,592 (26%)

29–32 wk

2,477 (61%)

15,112 (60%)

1,333 (450)

1,310 (457)

Birth weight (g), mean (SD)

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< 0.01

SGA

379 (9%)

2,452 (10%)

0.35

Apgar score < 7 at 5 min

949 (24%)

5,466 (22%)

0.02

SNAP II score (> 20)

718 (18%)

4,162 (17%)

0.09

Abbreviations: SD, standard deviation; SGA, small for gestational age; SNAP II, Score for Neonatal Acute Physiology-Version II. a Unless otherwise stated, values are the number of infants with percentage of total group in parentheses. b A p-value < 0.05 was considered statistically significant.

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diabetes, and exposure to antenatal steroids than the nonsmoking group (►Table 1). Gestational age and rates of SGA were not significantly different between the two groups. The comparison of infant outcomes revealed significantly higher odds of the composite outcome, severe IVH/PVL, and BPD in the smoking group after adjustment for confounding variables (►Table 2). Significant interactions were detected between smoking exposure and gestational age groups in the composite outcome, mortality, and severe IVH/PVL (►Table 3). The subsequent subgroup analyses stratified by the gestational age group detected significant higher adjusted odds ratio of composite outcome, mortality, severe IVH, BPD, and nosocomial infection in the smoking group only in the 29 to 32 weeks gestational age group (►Table 3). Although the rate of substance use was much higher in the smoking group, there were no interactions between the substance use and maternal smoking in all outcomes assessed (p ¼ 0.28–0.91). The durations of supplemental oxygen, mechanical ventilation, and hospital stay were longer in the smoking group than the nonsmoking group, even after adjustment (►Table 4).

Isayama et al.

Adverse Impact of Maternal Cigarette Smoking

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Table 2 Comparison of neonatal outcomes of infants born at < 33 weeks gestation between the smoking and nonsmoking groups Outcomes

Smoking group n/N (%)

Nonsmoking group, n/N (%)

p-Valuea

Adjusted ORb (95% CI)

Composite outcomec

1,435/4,053 (35.4%)

8,389/24,998 (33.6%)

0.02

1.17 (1.04, 1.32)

Mortality

321/4,053 (7.9%)

1,976/24,998 (7.9%)

0.97

1.13 (0.93, 1.37)

BPD

800/3,722 (21.5%)

4,692/22,924 (20.5%)

0.15

1.16 (1.02, 1.33)

Severe IVH/PVL

463/3,089 (15.0%)

2,387/19,240 (12.4%)

< 0.01

1.21 (1.04, 1.41)

ROP

172/1,707 (10.1%)

1,126/10,365 (10.9%)

0.33

1.02 (0.80, 1.32)

NEC

204/4,020 (5.1%)

1,193/24,614 (4.8%)

0.53

1.05 (0.85, 1.30)

Air leak

159/4,053 (3.9%)

869/24,952 (3.5%)

0.16

1.17 (0.93, 1.47)

Nosocomial infection

575/4,053 (14%)

3,407/24,998 (13.6%)

0.34

1.12 (0.98, 1.28)

PDA

994/3,931 (25.3%)

6,590/24,263 (27.2%)

0.01

0.92 (0.81, 1.04)

Abbreviations: CI, confidence interval; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; n/N, number of cases/total number of infants assessed; NEC, necrotizing enterocolitis; OR, odds ratio; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity. a p-values were based on Chi-square test for comparisons between the smoking group and the nonsmoking group without adjustment. b Adjusted OR was based on the final multiple logistic regression models derived by stepwise covariate selection procedure. c Composite outcome: Death or any major morbidity, including severe IVH or PVL, NEC, BPD, and severe ROP.

is the small sample sizes and lack of appropriate adjustments for various confounding variables in these studies. In contrast, our study was able to adjust for broad range of multiple potential confounders using large sample size. An interesting finding in this study is the increased rate of brain injuries in the smoking group. The pathophysiology of how exposure to prenatal smoking in preterm infants might increase brain injury remains unclear. Two major causes of IVH in preterm infants are cerebral hemodynamic fluctuation exacerbated by impaired auto-regulation of cerebral blood flow19 and inherent fragility of the vasculature-rich germinal matrix.20 Infants born to mothers who smoked during pregnancy have been reported to have cardiovascular stress hyperactivity21 and increased blood pressure22 after birth. These disturbed hemodynamic responses may cause cerebral hemodynamic instabilities resulting in IVH. In addition, maternal smoking causes fetal hypoxemia via contraction of the placental vessels by nicotine23 and carbon monoxide binding to fetal hemoglobin24 and may lead to IVH25 and PVL.26 The increased rate of BPD in the smoking group accompanied by longer days on supplemental oxygen and mechanical ventilation was another intriguing finding. The respiratory morbidities of infants related to maternal smoking during pregnancy have been well documented3; however, a few studies have reported the role of maternal smoking in the development of BPD.17 The increased rate of BPD observed in the smoking group may be caused by direct lung injuries from the components of tobacco, especially nicotine. Animal studies have reported that nicotine injures the developing lung resulting in abnormal lung development, including decreased lung weight and volume,27 lung alveolar hypoplasia,28 and reduced lung function.27 Human studies have reported that maternal smoking during pregnancy is associated with impaired respiratory function in term29 and preterm30 infants and increased American Journal of Perinatology

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inner airway thickness was detected in infants who died from sudden infant death syndrome.31 These structural and functional changes caused by maternal smoking may be related to the increased rate of BPD and need for respiratory support detected in this study. The similar rates of SGA in the smoking and nonsmoking groups in this cohort were an unexpected finding because many previous studies have consistently reported an association of maternal smoking during pregnancy with fetal growth retardation (FGR) resulting in SGA.2 The finding may be because we included only very preterm infants born at < 33 weeks gestational age. FGR caused by maternal smoking generally occurs toward the end of the pregnancy period, especially
32 weeks gestational age,32 although others have reported that maternal smoking may cause FGR as early as the 1st or 2nd trimesters.33 Some of the adverse effects of maternal smoking (composite outcome, mortality, and severe IVH/PVL) were modified by infant gestational age and were larger in infants at 29 to 32 weeks gestational-age group than immature infants. The reason of this effect modification is not known. It is possible that there was a potential threshold duration of fetal exposure to maternal smoking to have a significant effect and only relatively mature infants (> 28 weeks gestational age) had adverse impact from maternal smoking.34 The strengths of our study include the use of a populationbased cohort with a large sample size and standardized data collection, analysis focusing on preterm infants, and inclusion of multivariable analyses adjusted for potential confounders and risk factors, including maternal substance use. However, some limitations are worth noting. The rate of maternal smoking might have been underestimated because of the use of retrospective data collection from maternal or infant charts in addition to possible underreporting by mothers due to feelings of guilt. We also could not assess any dose-effect

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Table 3 Comparison of neonatal outcomes between the smoking and nonsmoking groups for each gestational age subgroups Gestational age (wk)

Smoking group, % (n/N)

Nonsmoking group, % (n/N)

Adjusted ORa (95% CI)

Composite outcomeb

< 26

85.7 (388/453)

87.5 (2,881/3,294)

0.90 (0.59, 1.36)

Mortality

BPD

Severe IVH/PVL

ROP

NEC

Air leak

Nosocomial infection

PDA

c

26–28

56.1 (630/1,123)

51.6 (3,401/6,592)

1.05 (0.88, 1.25)

29–32

16.8 (417/2,477)d

13.9 (2,107/15,112)

1.30 (1.10, 1.54)

< 26

34.9 (158/453)

36.2 (1,192/3,294)

0.74 (0.54, 1.02)

26–28

9.6 (108/1,123)

8.1 (531/6,592)

1.24 (0.91, 1.67)

29–32

2.2 (55/2,477)

1.7 (253/15,112)

1.63 (1.11, 2.38)

< 26

64.3 (193/300)

64.5 (1,356/2,102)

0.99 (0.70, 1.40)

26–28

39.3 (397/1,011)

36.2 (2,183/6,039)

1.16 (0.96, 1.40)

29–32

8.7 (210/2,411)

7.8 (1,153/14,783)

1.32 (1.08, 1.61)

< 26

33.6 (135/402)

32.8 (905/2,762)

0.95 (0.69, 1.30)

26–28

17.2 (178/1,035)

15.3 (933/6,098)

0.94 (0.74, 1.20)

29–32

9.1 (150/1,652)

d

5.3 (549/10,380)

1.83 (1.42, 2.36)

< 26

31.3 (89/284)

37.0 (720/1,946)

0.87 (0.60, 1.25)

7.8 (357/4,603)

1.29 (0.91, 1.84)

1.3 (49/3,816)

1.01 (0.38, 2.63)

e

26–28

9.9 (75/757)

29–32

1.2 (8/666)

< 26

10.4 (46/443)

10.8 (339/3,135)

1.01 (0.65, 1.56)

26–28

7.6 (84/1,111)

7.1 (458/6,500)

0.89 (0.63, 1.24)

29–32

3.0 (74/2,466)

2.6 (396/14,979)

1.27 (0.91, 1.77)

< 26

11.7 (53/453)

e

8.7 (286/3,288)

0.97 (0.61, 1.52)

26–28

5.0 (56/1,123)

4.0 (264/6,579)

1.40 (0.95, 2.07)

29–32

2.0 (50/2,477)

2.1 (319/15,085)

1.15 (0.79, 1.69)

31.1 (1,024/3,294)

1.27 (0.95, 1.68)

< 26

35.8 (162/453)

e

26–28

21.2 (238/1,123)

21.6 (1,424/6,592)

0.98 (0.80, 1.20)

29–32

7.1 (175/2,477)

6.4 (959/15,112)

1.33 (1.06, 1.67)

< 26

67.5 (284/421)

69.5 (2,109/3,034)

0.84 (0.62, 1.13)

26–28

43.7 (478/1,095)

46.0 (2,970/6,453)

0.97 (0.81, 1.16)

29–32

9.6 (232/2,415)

10.2 (1,511/14,776)

0.99 (0.80, 1.23)

Interaction p-Value < 0.05

< 0.01

NS

< 0.01 NS

NS

NS

NS

NS

Abbreviations: CI, confidence interval; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; n/N, number of cases/total number of infants assessed; NEC, necrotizing enterocolitis; NS, not significant (p > 0.05); OR, odds ratio; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity. a Adjusted OR was based on the final multiple logistic regression models derived by stepwise covariate selection procedure. b Composite outcome: Death or any major morbidity, including severe IVH or PVL, NEC, BPD, and severe ROP. c p < 0.01. d p < 0.001. e p < 0.05, based on Chi-square test for the comparison between the two groups without adjustment.

relationships between the amount of smoking and infant outcomes and the influence of quitting smoking during pregnancy. However, both the underestimation of smoking rates and the inclusion of mothers who quit smoking or smoked less during their pregnancy in smoking group caused contamination between smoking and nonsmoking groups, which would reduce the estimated strength of the association between maternal smoking and infant outcomes. Therefore, the true association could be greater than that detected in this study. The large sample size in our study enabled us to detect these diluted effects of maternal smoking on infant outcomes. Other unmeasured confounders such as ethnicity, socioeco-

nomic status, and maternal alcohol consumption, which were not available in our database, might introduce biases and they need to be addressed in future work. This study revealed the significant association between maternal cigarette smoking during pregnancy and detrimental impacts on preterm infants, including increased IVH/PVL and BPD. In spite of enormous efforts to dissuade pregnant women from smoking, the smoking rate has remained high especially in developed countries. The new findings in this study could be powerful information to use in counseling pregnant women to quit smoking, as well as to promote a movement for building a smoke-free society in the future. American Journal of Perinatology

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Table 4 Comparison of neonatal intensive care unit resource use between the smoking and nonsmoking groups Outcomes (d)

Smoking group

Nonsmoking group

p-Valuea

Adjusted ratiob (95% CI)

Supplemental oxygen, median (IQR)

1 (0–12)

1 (0–9)

NA

1.25 (1.14, 1.37)

CPAP, median (IQR)

2 (0–12)

2 (0–13)

NA

0.98 (0.73, 1.33)

Mechanical ventilation, median (IQR)

2 (0–7)

1 (0–6)

0.07

1.15 (1.08, 1.23)

Hospital stay, geometric mean (SD)

28.0 (2.84)

25.5 (3.04)

< 0.01

1.11 (1.06, 1.16)

Abbreviations: CI, confidence interval; CPAP, continuous positive airway pressure; IQR, interquartile range; NA, not available; SD, standard deviation. a p-values were based on the Wilcoxon Rank Sum test for mechanical ventilation or Student t-test for hospital stay in comparisons between the smoking and nonsmoking groups without adjustment. b Zero-inflated negative binomial models were used with the exception of hospital stay, for which multivariable linear regression models were used in log scale. Ratio: ratio of means of outcomes (smoking group vs. nonsmoking group).

Acknowledgments We would like to thank the Canadian Institutes of Health Research team in Maternal-Infant Care for providing organizational support to the Canadian Neonatal Network. We also thank Dr. Ruth Warre from the Maternal-Infant Care Research Centre, Mount Sinai Hospital, Toronto, Canada, for editorial help. Prakesh Shah is supported by an Applied Research Chair in Reproductive and Child Health Services and Policy Research support from the Canadian Institute of Health Research.

12 International Committee for the Classification of Retinopathy of

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