By: Armend Lokku Supervisor: Dr. Lucia Mirea

Maternal-Infant Care Research Center, Mount Sinai Hospital

My practicum placement was at the Maternal-Infant Care Research Center (MiCare) at Mount Sinai hospital under the supervision of Dr. Lucia Mirea.

MiCare houses data from the Canadian Neonatal Network (CNN), a large national neonatal archive.

CNN research aims to improve performance and efficiency of neonatal care in Canada.

CNN collects extensive data on infants admitted to Level III neonatal intensive care units (NICUs).

Our study was a large observational study.

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Background

Preterm birth is the leading cause of infant mortality and severe morbidities.

Our study investigated infants with a congenital heart disorder called Patent Ductus Arteriosus (PDA) where the a blood vessel (ductus arteriosus) fails to close after birth.

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Background – Cont’d

Every infant is born with their ductus arteriosus patent:

For healthy infants, the ductus arteriosus closes soon after birth. Infants born very preterm are at high risk of developing a PDA. A patent ductus arteriosus initially results in irregular transmission of

blood between the pulmonary artery and the aorta.

PDA in preterm infants has been shown to be associated with:

Mortality. Severe necrotizing enterocolitis (NEC). Retinopathy of prematurity (ROP). Intraventricular hemorrhage (IVH). Periventricular leukomalacia (PVL). Bronchopulmonary dysplasia (BPD).

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PDA

PDA Management Strategies

Management strategies of PDAs in preterm infants include:

Conservative management via fluid restriction or respiratory support. Pharmacologic treatment (Indomethacin or Ibuprofen). Surgical ligation. Initial pharmacologic treatment followed by surgical ligation.

The risks and benefits of pharmacologic and/or surgical ligation of a persistent PDA have been examined by a few randomized trials more than 15 years ago with variable results.

A few recent observational studies have also attempted to identify optimal PDA management strategies but results have been inconclusive and even conflicting.

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Research Objectives

• Presently, there is no consensus on PDA management strategies, and clinical practices are inconsistent.

• Of great concern are findings demonstrating higher adverse outcomes after pharmacologic and/or surgical ligation treatment.

• Canadian researchers have premised that less aggressive PDA management strategies may reduce neonatal mortality/morbidities, and thus motivated concerted efforts towards conservative management in recent years.

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Research Objectives – Cont’d

• The impact of changing PDA treatment rates in Canada on neonatal mortality/morbidities and prevalence of PDA treatments remains unknown.

• Primary Research Objective: to report trends in PDA management strategies from 2006-2012 among very preterm infants born at 23-32 weeks gestational age (GA) and admitted to a Level III NICU in Canada.

• Secondary Research Objective: to examine changes in the association of PDA management strategies and adverse neonatal outcomes over 2006-2008 to 2009-2012 in Canada.

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Infant eligibility for study (2006-2008, 2009-2012)

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No/Missing PDA 19,936 (7,945, 11,991)

Eligible infants 6,563 (2,377, 4,186)

PDA Diagnosis 7,371 (2,684, 4,687)

Moribund 1 (0, 1) Death within 72 hours after birth 82 (22, 60) Missing gender or birth-date 11 (7, 4) Major congenital anomaly 613 (278, 335)

Sites not participating during both 2006-2008

and 2009-2012 101 (0, 101)

Infants born at 23-32 weeks GA admitted to CNN NICUs during 2006-2012 (2006-2008, 2009-2012)

27,307 (10,629, 16,678)

Covariates/Prognostic factors • The CNN records and maintains an extensive database on patient

characteristics and multiple important risk factors. • Hundreds of patient characteristics available.

• In observational studies, a major issue is confounding by indication: Confounding by indication occurs when treatment assignment is

dependent on prognostic factors. There can be factors which influence treatment assignment that are

either unmeasured or unquantifiable. Imbalances in prognostic factors between treatment groups must be

statistically assessed to identify potential confounding variables.

• Differences in covariate distributions across i) PDA treatments and ii) time period (2006-2008, 2009-2012) were assessed using: Pearson Chi-square/Fisher exact tests for categorical variables. One-way ANOVA F-tests for continuous variables.

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Distribution of Covariates by PDA Treatment and Time Period

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Characteristic

PDA Treatment

P Value Conservative Management

Pharmacologic-only Ligation-only

Both Pharmacologic and Ligation

GA weeks mean (SD)

2006-2008 28.1 (2.3) 27.0 (2.1) 26.0 (2.1) 25.6 (1.7) < 0.01 2009-2012 28.2 (2.3) 26.6 (1.9) 26.0 (1.9) 25.4 (1.7) < 0.01

P Value 0.39 < 0.01 0.92 0.30 Female sex N (%)

2006-2008 185 (43) 651 (47) 74 (39) 190 (50) 0.06 2009-2012 614 (46) 967 (44) 55 (43) 255 (49) 0.22

P Value 0.41 0.07 0.56 0.84 Outborn N (%)

2006-2008 93 (22) 276 (20) 84 (45) 72 (19) < 0.01 2009-2012 241 (18) 381 (17) 44 (34) 75 (14) < 0.01

P Value 0.07 0.04 0.07 0.08 SNAP II > 20 N (%)

2006-2008 119 (28) 401 (29) 62 (33) 150 (39) < 0.01 2009-2012 341 (26) 684 (31) 44 (34) 240 (46) < 0.01

P Value 0.32 0.17 0.78 0.04 SGA N (%)

2006-2008 47 (11) 125 (9.1) 31 (17) 31 (8.1) < 0.01 2009-2012 136 (10) 201 (9.2) 10 (7.8) 46 (8.8) 0.68

P Value 0.59 0.95 0.03 0.72 Cesarean N (%)

2006-2008 259 (61) 837 (61) 101 (53) 210 (55) 0.06 2009-2012 825 (61) 1297 (59) 65 (50) 287 (55) 0.02

P Value 0.81 0.38 0.62 0.94 Diabetes N (%)

2006-2008 41 (10) 97 (7.2) 4 (2.3) 15 (3.9) < 0.01 2009-2012 142 (11) 153 (7.3) 7 (6.3) 33 (6.7) < 0.01

P Value 0.59 0.99 0.12 0.10

PDA Treatment Trends Within the neonatal community, wide variations in PDA treatment rates

are known. Such differences have been confirmed by internal reports from the International Network for Evaluating Outcomes of Very Low Birth Weight, Very Preterm Neonates (iNEO), a multi-national collaboration.

During 2007-2010, rates of conservative management in iNEO countries ranged from 0-72% with the Canadian rate consistent with two other countries, but significantly lower than two other countries and significantly higher than two other countries.

Similar variation exists for the rate of pharmacologic-only treatment in Canada, which was comparable with two other countries, higher than one other, but was lower than three other countries.

Despite reductions in the rates of PDA ligation-only and both pharmacologic and ligation treatment in Canada, these rates were significantly higher than five other iNEO countries during 2007-2010 (personal communication based on unpublished results).

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Analyses: PDA Treatment Trends (2006 - 2012) Trends in PDA treatment rates was assessed on each of the four

treatments separately using: Graphs. The Cochrane-Armitage test (unadjusted trend test). A multivariate logistic regression model.

The Cochrane-Armitage test is a modified Pearson Chi-square

test used in “Kx2” tables where it is suspected that there is an ordering of effects across variable with k categories.

The multivariate logistic regression model was adjusted for suspected confounders of the association with admission year and PDA treatment.

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Analyses: PDA Treatment Trends (2006 - 2012)

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PDA Treatment Year N(%)

2006 2007 2008 2009 2010 2011 2012 Conservative Management 109 (14) 126 (16) 192 (24) 201 (23) 364 (32) 355 (34) 426 (38)

Pharmacologic- Only 448 (58) 474 (60) 457 (56) 518 (59) 569 (50) 555 (53) 548 (49)

Ligation- Only 55 (7.1) 72 (9.1) 61 (7.5) 60 (6.8) 21 (1.9) 20 (1.9) 28 (2.5)

Both Pharmacologic and Ligation 166 (21) 116 (15) 102 (13) 103 (12) 183 (16) 117 (11) 118 (11)

PDA Treatment Trends (2006 - 2012)

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Conservative Management Trend (2006 - 2012)

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Analyses: PDA Treatment Trends (2006 - 2012)

Significant trends were detected for each PDA treatment in the unadjusted and adjusted analyses (all P-values < 0.005).

Conservative management was the only treatment with

increasing rates from 2006 to 2012. Covariate adjustment had minimal impact on association

estimates or significance between PDA treatments and admission year: Negligible confounding of the relationship between PDA treatment and

admission year.

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Composite Outcomes • When dealing with binary outcomes (Yi i=1,…,n), a composite

outcome (Y*) is defined as: Y* = 1 if any yi = 1

0 if all yi = 0

• Using composite outcomes is a controversial issue and has been criticized by many researchers: Individual outcomes that are arbitrarily defined may potentially distort

results. A subset of outcomes can drive your results. Implicitly assuming equal weighting of Y1, Y2, … , Yn. Is this always

appropriate? If it is deemed that equal weighting is inappropriate, how does one

allocate the weighting scheme?

• However…the goal of neonatology is survival of infants without severe morbidities.

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Analyses: Primary Outcome • Defined a composite outcome to indicate mortality or any of

the following morbidities: Intraventricular hemorrhage (IVH) grades ≥ 3 or PVL. Retinopathy of prematurity (ROP) stages ≥ 3. Bronchopulmonary dysplasia (BPD) at 36 weeks. Necrotizing enterocolitis (NEC) stages ≥ 2.

• These criterion were agreed upon by leading clinicians and are still commonly used for classifying severe neonatal morbidities.

• Differences in outcome distributions across i) PDA treatments and ii) time period (2006-2008, 2009-2012) were assessed using: Pearson Chi-square/Fisher exact tests.

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Outcome

PDA Treatment

Pvalue Conservative Management

Pharmacologic-only

Ligation- Only

Both Pharmacologic and Ligation

Mortality 2006-2008 61 (14) 145 (11) 22 (12) 35 (9.1) 0.09 2009-2012 139 (10) 262 (12) 20 (16) 30 (5.8) < 0.01

Crude P Value 0.03 0.20 0.40 0.07

BPD at 36 wks 2006-2008 97 (27) 518 (42) 122 (71) 267 (74) < 0.01 2009-2012 293 (24) 906 (46) 69 (60) 361 (72) < 0.01

Crude P Value 0.33 0.01 0.05 0.45

IVH (grades ≥ 3) or PVL

2006-2008 83 (19) 241 (17) 41 (22) 94 (25) 0.02 2009-2012 223 (17) 435 (20) 46 (36) 144 (28) < 0.01

Crude P Value 0.17 0.08 0.01 0.30

NEC (stages ≥ 2)

2006-2008 34 (8.0) 106 (7.8) 40 (21) 51 (13) < 0.01 2009-2012 98 (7.3) 192 (8.8) 25 (20) 55 (11) < 0.01

Crude P Value 0.60 0.29 0.78 0.21

ROP (stages ≥ 3)

2006-2008 15 (7.1) 127 (13) 42 (35) 123 (42) < 0.01 2009-2012 50 (7.1) 215 (14) 33 (27) 167 (37) < 0.01

Crude P Value 0.99 0.86 0.29 0.22

Composite outcome

2006-2008 205 (48) 807 (59) 153 (81) 331 (86) < 0.01 2009-2012 565 (42) 1400 (64) 104 (81) 448 (86) < 0.01

Crude P Value 0.03 < 0.01 0.87 0.85

Distribution of Outcomes by PDA Treatment and Time Period

Analyses: Effect Modification Our secondary research objective was to assess potential

changes in the associations between PDA treatment and the composite outcome over time period (2006-2008, 2009-2012).

To assess effect modification of time period on the relationship of PDA treatment with the composite outcome, statistical interactions between PDA treatments and time period were tested in multivariable logistic regression analyses examining the composite outcome.

Subsequent analyses were stratified by time period. Odds ratios (OR) and corresponding 95% confidence intervals

(CI) for the association of PDA treatments with the composite outcome were estimated.

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Methods for Treatment Selection Bias A limitation of observational studies is that treated subjects may

differ systematically from untreated subjects: For PDA management, it has been suspected that infants with more severe

symptoms may be more likely to be treated aggressively (pharmacologic and/or surgical ligation treatments).

Failure to account for this preferential selection can result in biased estimation of the true treatment effect. Often referred to as treatment selection bias.

To correctly assess effect modification in this setting, we must account for the presence of treatment selection bias in our analyses.

Can correct for treatment selection bias using several methods including: Regression analyses adjusted for baseline prognostic factors. Propensity Score (PS) methods.

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Propensity Scores The propensity score (PS) for a subject is the probability of

being assigned to a treatment conditional on their observed baseline covariates (Rosenbaum,1983):

PSij = Pr [Tij = tij | X1i = x1i, ... , Xpi = xpi]

Conditional on the PS, the distribution of observed baseline covariates will be similar between treatment groups.

Some popular application of PS include: PS matching which mimic randomized controlled trials (RCTs). PS stratification where strata based on PS are created and can perform

strata-based analyses. Using PS to define various weights.

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Propensity Score Methods Propensity score methods are 2-Stage approaches: 1st stage:

Develop a model for the probability of treatment and obtain predicted probabilities

For PDA treatments with 4 levels, can use a multinomial regression model where conservative management is the reference category:

Log(πij/πic) = αj + Xi'Bj 2nd stage:

Propensity score adjustment: Use predicted probabilities for adjustment as scalar covariate, stratification or matching

Propensity score weighting: Use predicted probabilities to modify crude analyses by weighting each subject by the inverse probabilities

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Propensity Score Weighting

Weighting methods are useful when certain groups are under-represented in the data. Don’t have to discard observations like in PS matching.

Weighting attaches larger weights to under-represented subjects and smaller weights to over-represented subjects to attain balance. If a subject is estimated to have a low probability of receiving a treatment, we

attach a larger weight to that subject. The simplest weighting method is inverse probability weighting (IPW):

Weights are simply the inverse of the propensity score ->Wij = (PSij)-1

IPW methods can suffer from undesired variability because small estimated PS can artificially inflate the weights.

Marginal structural models (MSM) attempt to stabilize IPW weights by accounting for the marginal probability of treatment:

Wij = P[Tij = tij] / PSij

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Results – PDA Treatment by Time Period Interactions

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Analyses

PDA Treatment Comparisons

Pharmacologic-only vs.

Conservative

Ligation-only vs.

Conservative

Both Pharmacologic and Ligation

vs. Conservative

2006-2008 2009-2012 2006-2008 2009-2012 2006-2008 2009-2012

Unadjusted Model 1.53 (1.23, 1.90)

2.45 (2.13, 2.82)

4.73 (3.13, 7.16)

5.75 (3.67, 9.02)

6.89 (4.86, 9.77)

8.48 (6.47, 11.11)

Interaction Pvalues < 0.01 0.53 0.36

Covariate-adjusted Model

1.09 (0.84, 1.42)

1.68 (1.43, 1.99)

2.13 (1.29, 3.52)

3.26 (1.96, 5.43)

3.19 (2.11, 4.81)

3.70 (2.73, 5.01)

Interaction Pvalues 0.04 0.56 0.87

MSM 0.86 (0.69, 1.08)

1.49 (1.29, 1.72)

1.59 (1.08, 2.33)

2.44 (1.65, 3.63)

3.03 (2.19, 4.20)

2.72 (2.16, 3.44)

Interaction Pvalues < 0.01 0.12 0.60

Results The odds of the composite outcome for infants with pharmacologic-

only vs. conservative management were not significantly different in 2006-2008, but significantly increased during 2009-2012 for the adjusted methods.

The composite outcome was higher after surgical ligation vs. conservative management, with association estimates more pronounced during the later years 2009-2012, but no significant differences were detected between time periods. Possible lack of power to detect effect modification?

The covariate-adjusted and MSM models produced comparable odds ratios. MSM model yielded a decrease in the composite outcome for both

pharmacologic and ligation treatment vs. conservative management from 2006-2008 to 2009-2012 but it was not significant.

Negated bias slightly more effectively? MSM yielded narrower confidence intervals than covariate-adjusted model.

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Discussion – What conclusions can we draw? It was expected that infants with more severe symptoms would be

treated more aggressively (Ie. Any ligation). The largest bias (difference in the odds ratio estimates between the

unadjusted and adjusted analyses) was observed for subjects who received any ligation.

In Canada, during 2006-2012, PDA conservative management

increased while pharmacologic and/or ligation treatment decreased.

Simultaneously, increases in the composite outcome after pharmacologic and/or surgical ligation treatment vs. conservative management during the later years suggests changes in the selection of infants for treatment 28/11/2013 MiCare Practicum Project Presentation 27

Discussion – Comparison with Japan A Japanese study comparing preterm infants born 2006-2008 detected

significantly higher rates of pharmacologic-only treatment and lower rates of conservative management in Japan compared to Canada; however no association with a composite mortality/morbidities outcome as defined in this study (Isayama et al. 2014).

We detected a higher composite outcome for infants treated with pharmacologic-only vs. conservative management during 2009-2012, after trends in treatment with pharmacologic-only decreased and conservative management increased in Canada, which is opposite to the rates in Japan.

Japan showed no association between any ligation vs. conservative management and the composite outcome: Significantly higher mortality/morbidities were detected in Canada during the

entire study period with estimates more elevated during the later years (2009-2012).

These findings suggest that the selection of infants for PDA treatment in Canada may differ from Japan.

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Discussion – Strengths and Limitations A limitation of our study was the possible existence of unmeasured

variables that could contribute to treatment selection bias. Certain potential confounders may not be easily obtained or

quantifiable such as a physician’s personal preference in treatment selection or NICU management style.

The adjusted models are both limited because they cannot adjust for hidden confounding variables. PS methods have been shown to suffer from PS model

misspecification. Possible remedies for these various short-comings could include a

more systematic and detailed collection of baseline prognostic factors or by well-designed randomized controlled trials.

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Acknowledgments

Thanks to Lucia Mirea and Junmin Yang Thanks to the staff and participants of Canadian Neonatal

Network (CNN)

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References Mirea L, Sankaran K, Seshia M, Ohlsson A, Allen A, Aziz K, Lee S and

Shah P (2012). Treatment of Patent Ductus Arteriosus and Neonatal Mortality/Morbidities: Adjustment for Treatment Selection Bias. J Pediatr 2012;161:689-94.

Madan J, Kendrick D, Hagadorn J, and Frantz I (2009). Patent Ductus Arteriosus Therapy: Impact on Neonatal and 18-Month Outcome. Pediatrics 2009;123;674-681.

Chorne N, Leonard C, Piecuch R, and Clyman R (2007). Patent Ductus Arteriosus and Its Treatment as Risk Factors for Neonatal and Neurodevelopmental Morbidity. Pediatrics 2007;119;1165-1174.

Isayama T, Mirea L, Mori R, Kusuda S, Fujimura M, Shah P. Management and outcomes of Neonates with Patent Ductus Arteriosus in Japan and Canada.2014; under review.

Isayama T, Lee S, Mirea L, Mori R, Kusuda S, Fujimura M, Shah P. PDA Management and Neonatal Mortality/morbidities in Japan and Canada: Comparison between Japanese Proactive Versus Canadian Reactive Management. J Pediatrics 2013; 130: 957-65.

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