Association of inotrope use with neurodevelopmental outcomes in infants <29 weeks gestation: a retrospective cohort study

Abstract

Objective

The primary objective was to compare neurodevelopmental (ND) outcomes at 18–24 months in preterm infants <29 weeks gestational age (GA) who received versus those who did not receive inotropes in the first week of life. The secondary objective was to assess ND outcomes according to the duration of inotropic support in the first week of life (≤3 or >3 days).

Study design

Retrospective population-based cohort study of preterm infants <29 weeks GA admitted to participating neonatal intensive care units (NICUs) of the Canadian Neonatal Network (CNN) from January 2010 to September 2011 with follow-up data available at 18–24 months. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Long-term outcomes were categorized as neurodevelopmental impairment (NDI) and significant neurodevelopmental impairment (sNDI), and effect modification due to other neonatal morbidities including receipt of antenatal steroids, GA, small for gestational age (SGA) status, sex, score for neonatal acute physiology (SNAP-II) >20, postnatal steroids, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) grade ≥3/periventricular leukomalacia (PVL), early- and late-onset sepsis, retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC) was assessed. Maternal and infant demographic characteristics and short- and long-term outcomes were compared using Pearson’s Chi-square test for categorical variables and Student’s t-test or the Wilcoxon rank test for continuous variables. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated using multivariable regression analysis.

Results

Of the 491 (18.7%) eligible preterm infants who received inotropes during the first week of life, 314 (64%) survived to NICU discharge and 245 (78%) had ND outcome data available. A total of 1775 eligible preterm infants did not receive inotropes in the first week of life; 1647 (92.7%) survived to NICU discharge and 1149 (70%) had ND outcome data. Maternal and infant characteristics associated with infants receiving inotropes included: younger maternal age, clinical chorioamnionitis, no antenatal steroids, outborn, lower GA, BW and Apgar scores at both one and five minutes; and higher SNAP-II scores (p < .05). Infants who received inotropes in the first week of life were more likely to be require postnatal steroids, had higher rates of BPD, IVH grade ≥3/PVL, early- and late-onset sepsis, ROP, NEC and mortality (p < .05). Infants who received inotropes in the first week of life also had higher rates of sensorineural or mixed hearing loss with an AOR (95% CI) of 1.99 (1.13, 3.49). After adjusting for confounding variables, there was no difference in the risk of NDI or sNDI between infants who did and did not receive inotropes in the first week of life. Of the infants with neurodevelopmental outcome data available, 186 received inotropes for ≤3 days and 59 for >3 days. After adjusting for confounding variables there was no difference in the risk of NDI or sNDI. Infants who received inotropes for >3 days were more likely to have lower BSID-III cognitive [AOR 2.43 95% CI (1.03, 5.76)] and motor scores <85 [AOR 2.38 95% CI (1.07, 5.30)] respectively.

Conclusions

In this large, population-based cohort, infants who received inotropes in the first week of life were at increased risk for sensorineural or mixed hearing loss. There was no difference in NDI or sNDI after adjusting for confounding variables. A longer duration of inotrope use in the first week of life was associated with lower BSID-III cognitive and motor scores, but no difference in overall NDI or sNDI.

Keywords:

• Preterm infant
• hypotension
• neurodevelopmental outcome

Acknowledgements

The authors gratefully acknowledge all site investigators and abstractors of the Canadian Neonatal Network (CNN) and Canadian Neonatal Follow-up Network (CNFUN). We thank the staff at the Maternal-Infant Care (MiCare) Research Centre at Mount Sinai Hospital, Toronto, Ontario for organizational support of the CNN, CNFUN, and this project. We also thank Junmin Yang for biostatistical support in the preparation of this manuscript. Last, we thank Sarah Hutchinson, PhD, from MiCare for editorial assistance in the preparation of this manuscript. MiCare is supported by a team grant from the Canadian Institutes of Health Research (CTP 87518), the Ontario Ministry of Health, and support from participating hospitals.

Canadian Neonatal Network Investigators: Prakesh S Shah, MD, MSc (Director, Canadian Neonatal Network and Site Investigator), Mount Sinai Hospital, Toronto, Ontario; Marc Beltempo, MD, (Associate Director, Canadian Neonatal Network and Site Investigator), Montreal Children’s Hospital at McGill University Health Center, Montréal, Québec; Jaideep Kanungo, MD, Victoria General Hospital, Victoria, British Columbia; Joseph Ting, MD, B.C. Women’s Hospital and Health Center, Vancouver, British Columbia; Zenon Cieslak, MD, Royal Columbian Hospital, New Westminster, British Columbia; Rebecca Sherlock, MD, Surrey Memorial Hospital, Surrey, British Columbia; Ayman Abou Mehrem, MD, Foothills Medical Center, Calgary, Alberta; Jennifer Toye, MD, Royal Alexandra Hospital, Edmonton, Alberta; Carlos Fajardo, MD, Alberta Children’s Hospital, Calgary, Alberta; Zarin Kalapesi, MD, and Jaya Bodani, MD, Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, MD, MBBS, and Lannae Strueby, MD, Royal University Hospital, Saskatoon, Saskatchewan; Mary Seshia, MBChB, and Deepak Louis, MD, Winnipeg Health Sciences Center, Winnipeg, Manitoba; Ruben Alvaro, MD, St. Boniface General Hospital, Winnipeg, Manitoba; Amit Mukerji, MD, Hamilton Health Sciences Center, Hamilton, Ontario; Orlando Da Silva, MD, MSc, London Health Sciences Center, London, Ontario; Mohammad Adie, MD, Windsor Regional Hospital, Windsor, Ontario; Kyong-Soon Lee, MD, MSc, Hospital for Sick Children, Toronto, Ontario; Eugene Ng, MD, Sunnybrook Health Sciences Center, Toronto, Ontario; Brigitte Lemyre, MD, Children’s Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, Ontario; Faiza Khurshid, MD, Kingston General Hospital, Kingston, Ontario; Ermelinda Pelausa, MD, Jewish General Hospital, Montréal, Québec; Keith Barrington, MBChB, Anie Lapoint, MD, and Guillaume Ethier, NNP, Hôpital Sainte-Justine, Montréal, Québec; Christine Drolet, MD, and Bruno Piedboeuf, MD, Center Hospitalier Universitaire de Québec, Sainte Foy, Québec; Martine Claveau, MSc, LLM, NNP, and Marc Beltempo, MD, Montreal Children’s Hospital at McGill University Health Center, Montréal, Québec; Valerie Bertelle, MD, and Edith Masse, MD, Center Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec; Roderick Canning, MD, Moncton Hospital, Moncton, New Brunswick; Hala Makary, MD, Dr. Everett Chalmers Hospital, Fredericton, New Brunswick; Cecil Ojah, MBBS, and Luis Monterrosa, MD, Saint John Regional Hospital, Saint John, New Brunswick; Julie Emberley, MD, Janeway Children’s Health and Rehabilitation Center, St. John’s, Newfoundland; Jehier Afifi, MB BCh, MSc, IWK Health Center, Halifax, Nova Scotia; Andrzej Kajetanowicz, MD, Cape Breton Regional Hospital, Sydney, Nova Scotia; Shoo K Lee, MBBS, PhD (Chairman, Canadian Neonatal Network), Mount Sinai Hospital, Toronto, Ontario.

CNFUN investigators and Steering Committee: Thevanisha Pillay, MD, Victoria General Hospital, Victoria, British Columbia; Anne Synnes, MDCM, MHSC (Director), Ruth Grunau PhD (Steering committee) British Columbia Women’s Hospital, Vancouver, British Columbia; Jill Zwicker PhD (Steering committee); Rebecca Sherlock MD, Surrey Memorial Hospital, Surrey, British Columbia; Miroslav Stavel MD, Anitha Moodley MD, Royal Columbian Hospital, New Westminister, British Columbia; Leonora Hendson MB.BCH, MSc, Alberta’s Children’s Hospital, Foothills Medical Centre, Calgary, Alberta; Amber Reichert, MD, Matthew Hicks, MD, PhD, Glenrose Rehabilitation Hospital, Edmonton, Alberta; Jaya Bodani, MD, Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, MD, Royal University Hospital, Saskatoon, Saskatchewan; Diane Moddemann, MD (steering committee), Cecilia de Cabo MD, Winnipeg Health Sciences Centre, St. Boniface General Hospital, Winnipeg, Manitoba; Chukwuma Nwaesei, MD, Windsor Regional Hospital, Windsor, Ontario; Thierry Daboval, MD, Children’s Hospital of Eastern Ontario, Ottawa, Ontario; Sarah McKnight MD, Kingston General Hospital, Kingston, Ontario; Kevin Coughlin, MD (Steering committee), Lynn Whitty RN (Steering committee), Children’s Hospital London Health Sciences Centre, London, Ontario; Linh Ly, MD, Hospital for Sick Children, Toronto, Ontario; Edmond Kelly, MD, Mount Sinai Hospital, Toronto, Ontario; Karen Thomas MD, Hamilton Health Sciences Centre, Hamilton, Ontario; Paige Church, MD, Rudaina Banihani MD (Steering committee) Sunnybrook Health Sciences Centre, Toronto, Ontario; Ermelinda Pelausa, MD, Kim-Anh Nguyen MD, Jewish General Hospital, Montréal, Québec; May Khairy, MD, Marc Beltempo, MD, Montréal Children’s Hospital, Royal Victoria Hospital, Montréal, Québec; Veronique Dorval MD, Thuy Mai Luu MD, MSc (Co-director), Centre Hospitalier Universitaire Sainte-Justine, Montréal, Québec; Charlotte Demers,MD, Alyssa Morin MD, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec; Sylvie Bélanger, MD, Centre Hospitalier Universitaire de Québec, Québec City, Québec; Roderick Canning, MD, Moncton Hospital, Moncton, New Brunswick; Luis Monterrosa, MD, Saint John Regional Hospital, Saint John, New Brunswick; Hala Makary, MD, Dr. Everett Chalmers Hospital, Fredericton, New Brunswick; Jehier Afifi, MB BCh, MSc, (Steering committee) IWK Health Centre, Halifax, Nova Scotia; Phil Murphy, Charles Janeway Children’s Health and Rehabilitation Centre, St. John’s, Newfoundland.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Although no specific funding was received for this study, organizational support for the Canadian Neonatal Network was provided by the Maternal-Infant Care Research Center (MiCare) at Mount Sinai Hospital in Toronto, Ontario, Canada. MiCare is supported by a Canadian Institute of Health Research (CIHR) Team Grant [CTP 87518], the Ontario Ministry of Health, and support from participating hospitals. The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.