By: Armend Lokku Supervisor: Dr. Lucia Mirea. Maternal-Infant Care Research Center, Mount Sinai Hospital

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1 By: Armend Lokku Supervisor: Dr. Lucia Mirea Maternal-Infant Care Research Center, Mount Sinai Hospital

2 Background 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. 28/11/2013 MiCare Practicum Project Presentation 2

3 Background Cont d 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. 28/11/2013 MiCare Practicum Project Presentation 3

4 PDA 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). 28/11/2013 MiCare Practicum Project Presentation 4

5 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. 28/11/2013 MiCare Practicum Project Presentation 5

6 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. 28/11/2013 MiCare Practicum Project Presentation 6

7 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 among very preterm infants born at 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 to in Canada. 28/11/2013 MiCare Practicum Project Presentation 7

8 Infant eligibility for study ( , ) Infants born at weeks GA admitted to CNN NICUs during ( , ) 27,307 (10,629, 16,678) No/Missing PDA 19,936 (7,945, 11,991) 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 and (0, 101) Eligible infants 6,563 (2,377, 4,186) 28/11/2013 MiCare Practicum Project Presentation 8

9 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 ( , ) were assessed using: Pearson Chi-square/Fisher exact tests for categorical variables. One-way ANOVA F-tests for continuous variables. 28/11/2013 MiCare Practicum Project Presentation 9

10 Distribution of Covariates by PDA Treatment and Time Period GA weeks mean (SD) Female sex N (%) Outborn N (%) SNAP II > 20 N (%) SGA N (%) Cesarean N (%) Diabetes N (%) Characteristic Conservative Management Pharmacologiconly PDA Treatment Ligation-only Both Pharmacologic and Ligation 28/11/2013 MiCare Practicum Project Presentation 10 P Value (2.3) 27.0 (2.1) 26.0 (2.1) 25.6 (1.7) < (2.3) 26.6 (1.9) 26.0 (1.9) 25.4 (1.7) < 0.01 P Value 0.39 < (43) 651 (47) 74 (39) 190 (50) (46) 967 (44) 55 (43) 255 (49) 0.22 P Value (22) 276 (20) 84 (45) 72 (19) < (18) 381 (17) 44 (34) 75 (14) < 0.01 P Value (28) 401 (29) 62 (33) 150 (39) < (26) 684 (31) 44 (34) 240 (46) < 0.01 P Value (11) 125 (9.1) 31 (17) 31 (8.1) < (10) 201 (9.2) 10 (7.8) 46 (8.8) 0.68 P Value (61) 837 (61) 101 (53) 210 (55) (61) 1297 (59) 65 (50) 287 (55) 0.02 P Value (10) 97 (7.2) 4 (2.3) 15 (3.9) < (11) 153 (7.3) 7 (6.3) 33 (6.7) < 0.01 P Value

11 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 , 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 (personal communication based on unpublished results). 28/11/2013 MiCare Practicum Project Presentation 11

12 Analyses: PDA Treatment Trends ( ) 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. 28/11/2013 MiCare Practicum Project Presentation 12

13 Analyses: PDA Treatment Trends ( ) PDA Treatment Year N(%) 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) 28/11/2013 MiCare Practicum Project Presentation 13

14 PDA Treatment Trends ( ) 28/11/2013 MiCare Practicum Project Presentation 14

15 Conservative Management Trend ( ) 28/11/2013 MiCare Practicum Project Presentation 15

16 Analyses: PDA Treatment Trends ( ) 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 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. 28/11/2013 MiCare Practicum Project Presentation 16

17 Composite Outcomes When dealing with binary outcomes (Y i i=1,,n), a composite outcome (Y*) is defined as: Y* = 1 if any y i = 1 0 if all y i = 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 Y 1, Y 2,, Y n. 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. 28/11/2013 MiCare Practicum Project Presentation 17

18 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 ( , ) were assessed using: Pearson Chi-square/Fisher exact tests. 28/11/2013 MiCare Practicum Project Presentation 18

19 Distribution of Outcomes by PDA Treatment and Time Period Outcome Conservative Management Pharmacologiconly PDA Treatment Ligation- Only Both Pharmacologic and Ligation Pvalue Mortality (14) 145 (11) 22 (12) 35 (9.1) (10) 262 (12) 20 (16) 30 (5.8) < 0.01 Crude P Value BPD at 36 wks (27) 518 (42) 122 (71) 267 (74) < (24) 906 (46) 69 (60) 361 (72) < 0.01 Crude P Value IVH (grades 3) or PVL NEC (stages 2) ROP (stages 3) (19) 241 (17) 41 (22) 94 (25) (17) 435 (20) 46 (36) 144 (28) < 0.01 Crude P Value (8.0) 106 (7.8) 40 (21) 51 (13) < (7.3) 192 (8.8) 25 (20) 55 (11) < 0.01 Crude P Value (7.1) 127 (13) 42 (35) 123 (42) < (7.1) 215 (14) 33 (27) 167 (37) < 0.01 Crude P Value Composite (48) 807 (59) 153 (81) 331 (86) < 0.01 outcome (42) 1400 (64) 104 (81) 448 (86) < /11/2013 Crude P Value 0.03 MiCare Practicum Project < 0.01 Presentation

20 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 ( , ). 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. 28/11/2013 MiCare Practicum Project Presentation 20

21 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. 28/11/2013 MiCare Practicum Project Presentation 21

22 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): PS ij = Pr [T ij = t ij X 1i = x 1i,..., X pi = x pi ] 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. 28/11/2013 MiCare Practicum Project Presentation 22

23 Propensity Score Methods Propensity score methods are 2-Stage approaches: 1 st 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(π ij /π ic ) = α j + X i 'B j 2 nd 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 28/11/2013 MiCare Practicum Project Presentation 23

24 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 ->W ij = (PS ij ) -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: W ij = P[T ij = t ij ] / PS ij 28/11/2013 MiCare Practicum Project Presentation 24

25 Results PDA Treatment by Time Period Interactions Analyses Unadjusted Model Interaction Pvalues Covariateadjusted Model Interaction Pvalues MSM PDA Treatment Comparisons Both Pharmacologic and Pharmacologic-only Ligation-only Ligation vs. vs. vs. Conservative Conservative Conservative (1.23, 1.90) 1.09 (0.84, 1.42) 0.86 (0.69, 1.08) 2.45 (2.13, 2.82) 4.73 (3.13, 7.16) 5.75 (3.67, 9.02) 6.89 (4.86, 9.77) < (1.43, 1.99) 2.13 (1.29, 3.52) 3.26 (1.96, 5.43) 3.19 (2.11, 4.81) (1.29, 1.72) 1.59 (1.08, 2.33) 2.44 (1.65, 3.63) 3.03 (2.19, 4.20) 8.48 (6.47, 11.11) 3.70 (2.73, 5.01) 2.72 (2.16, 3.44) Interaction < Pvalues 28/11/2013 MiCare Practicum Project Presentation 25

26 Results The odds of the composite outcome for infants with pharmacologiconly vs. conservative management were not significantly different in , but significantly increased during for the adjusted methods. The composite outcome was higher after surgical ligation vs. conservative management, with association estimates more pronounced during the later years , 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 to but it was not significant. Negated bias slightly more effectively? MSM yielded narrower confidence intervals than covariate-adjusted model. 28/11/2013 MiCare Practicum Project Presentation 26

27 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 , 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

28 Discussion Comparison with Japan A Japanese study comparing preterm infants born 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 , 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 ( ). These findings suggest that the selection of infants for PDA treatment in Canada may differ from Japan. 28/11/2013 MiCare Practicum Project Presentation 28

29 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. 28/11/2013 MiCare Practicum Project Presentation 29

30 Acknowledgments Thanks to Lucia Mirea and Junmin Yang Thanks to the staff and participants of Canadian Neonatal Network (CNN) 28/11/2013 MiCare Practicum Project Presentation 30

31 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: Madan J, Kendrick D, Hagadorn J, and Frantz I (2009). Patent Ductus Arteriosus Therapy: Impact on Neonatal and 18-Month Outcome. Pediatrics 2009;123; 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; 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: /11/2013 MiCare Practicum Project Presentation 31