Research Methodology
| Course Status : | Completed |
| Course Type : | Elective |
| Duration : | 12 weeks |
| Category : | |
| Credit Points : | 3 | Postgraduate |
| Start Date : | 24 Jan 2022 |
| End Date : | 06 May 2022 |
| Enrollment Ends : | 07 Feb 2022 |
| Exam Date : | 23 Apr 2022 IST |
| Research Methodologies | Queen Mary University of London |
| Understanding Research Methods | University of London |
| Understanding Clinical Research: Behind the Statistics | University of Cape Town |
| Quantitative and Qualitative Research for the Beginners | National University of Singapore (NUS) |
| Comparative Research Designs and Methods | Federica Web Learning |
| Biospecimen Research Methods | University of British Columbia |
| Certificate Course in Research Theory, Design, and Methods | Indian Institute of Corporate Affairs (IICA) |
| Udemy Research Methods Courses | Udemy |
| Research Methodology | Swayam |
| Essentials of Research Methodology | Alison |
This Blog Includes:
Research methodologies, understanding research methods, understanding clinical research: behind the statistics, quantitative and qualitative research for beginners, comparative research designs and methods, biospecimen research methods, certificate course in research theory, design, and methods, udemy research methods courses , research methodology, essentials of research methodology, 10 best research methodology online course.
Proper research methods can ensure that research is conducted in a systematic, and objective manner. Thus, minimizing any chance of bias and increasing the credibility of the findings. Here is a list of the 10 best research methodology online courses. The course level, duration, and other details are provided for your reference.
The Queen Mary University of London is offering a course on research methodologies. The course is meant for beginners and covers topics such as types of research methodologies, different sampling approaches, and [primary and secondary data collection approaches. The course is meant for beginners and has a 4,.7 rating on Coursera. Students can dedicate 19 hours to learning this course.
| Level | Beginner |
| Duration | 19 hours (approximately) |
| Fees | NA |
| Certification | Yes |
Website: https://www.coursera.org/learn/research-methodologies
Here is how you can become a researcher
The University of London MOOC is offering an Understanding Research Methods. This is one of the top research methodology online courses. The course consists of 4 modules covering several topics. For example, what is research and what makes a good research question? What is a literature review and why do we need one? Why are planning and management skills important? The course has video-based content, reading, and peer review systems. It has been rated 4.6 on Coursera.
| Level | Beginner |
| Duration | 5 hours |
| Fees | NA |
| Certification | Yes |
Website: https://www.coursera.org/learn/research-methods
The University of Cape Town is offering another excellent research methodology online course. The program helps a student make sense of the statistical results presented in the published literature and research. Students will also get an overview of widely used statistical analysis techniques and will learn to interpret results. The course is meant for beginners and has a 4.8 rating on Coursera.
| Level | Beginner Advanced |
| Duration | 27 hours |
| Fees | NA |
| Certification | Yes |
Website: https://www.coursera.org/learn/clinical-research
The National University of Singapore (NUS) is providing one of the leading research methodology courses online. This is an introductory course that is useful across disciplines. Students will receive both a theoretical and practical understanding of research techniques for all stages of the research process. This is a self-paced course that can be completed in 8 weeks. It has a 4.5 rating on Edx.
| Level | Beginner |
| Duration | 8 weeks |
| Fees | INR 8,204 |
| Certification | Yes |
Website: https://www.edx.org/learn/research/
Comparative Research Designs and Methods is an excellent research methodology online course. The course provided by Federica Web Learning helps students to get an understanding of comparative analysis and its importance in social sciences for explanation and theory building. Students will also learn to apply systematic comparative analysis to politics in the real world. There is no prerequisite for taking this course. However, those with basic quantitative or qualitative methodological training can find this course easy.
| Level | Intermediate |
| Duration | 6 weeks |
| Fees | INR 4,060 |
| Certification | Yes |
Website: https://www.edx.org/learn/social-science/
The University of British Columbia is offering the course ‘Biospecimen Research Methods’. The course is useful in improving the research quality. Students will learn to apply the best practices to collect, store, and use biospecimens in their laboratory. The course is held for 6 weeks and is taught by professionals who have extensive experience in biobanking from the University of British Columbia and BC Cancer. The course is meant for advanced learners.
| Level | Advanced |
| Duration | 6 weeks |
| Fees | INR 8,204 |
| Certification | Yes |
Website: https://www.edx.org/learn/biology/
Here is how you can become a clinical research associate
The Indian Institute of Corporate Affairs (IICA) is offering a 3-month research methodology online course. The Certificate Course in Research Theory, Design, and Methods is suitable for those who have an understanding of research approaches and want to use them in their studies or professional practice. The course will outline the fundamentals of research methods and is targeted towards postgraduate studies or students preparing for higher education. The course is interactive and consists of several discussions and practical exercises. The online classes start in October.
| Level | Intermediate, Advanced |
| Duration | 3 months |
| Fees | NA |
| Certification | Yes |
Website: https://iica.nic.in/
Udemy is offering some of the best short research methodology online courses. Each course on this platform covers a unique topic. Some of the popular courses available on this platform are Quantitative Research Design for a Proposal, Research Methodology: Complete Research Project Blueprint, and UX Design & Research: Better UX using Heuristic Evaluation, among others. The courses consist of on-demand videos and articles. Certification is available.
| Level | Beginner, intermediate |
| Duration | Varies |
| Fees | Starts at INR 2499 per course |
| Certification | Yes |
Website: https://www.udemy.com/topic/research-methods/
Swayam is offering another excellent research methodology course online. The course is meant for PhD students and covers all conceptual and methodological issues involved in conducting successful research. A certificate is available for students. However, students need to meet the assignment score and the final exam score for the same. The course is taught by Prof. Soumitro Banerjee a faculty member of the Indian Institute of Technology, Kharagpur,
| Level | Advanced |
| Duration | 12 weeks |
| Fees | NA |
| Certification | Yes |
Website: https://onlinecourses.nptel.ac.in/noc22_ge08/preview
Check out the Types of Research Design: Process and Elements
Alison is offering one of the leading research methodology online courses. The course teaches a student to design, conduct, and document a scientific research project. Students will also learn to collect, process, analyze, and present data for a research report. The course is held for 1.5-3 Hours of Learning and has CPD accreditation. Students will have to complete a final assessment to obtain a certificate.
| Level | Beginner |
| Duration | 1.5 -3 hours |
| Fees | Free |
| Certification | Yes |
Website: https://alison.com/course/essentials-of-research-methodology
Related Articles:
Yes. There are several online research methodology online courses for PhD students. For example, on LinkedIn Learning students can access courses like understanding research methods and how to write and publish a scientific paper. Alision also provides free online research methodology courses with certification.
IGNOU is offering several PhD programs that consist of research methodology as a subject. Aside from that, IGNOU is holding workshops for research methodology. However, there is no separate IGNOU research methodology online course that students can enroll in.
Alison Essentials of Research Methodology course is a completely free online course with certification. Students can also enroll for Research Methodology related courses on Coursera or Edx. However, it is important to note that only the audit of these courses is available for free. Certification requires payment.
Hope this blog provides you with all the important details. For more information about such courses, visit our online courses page .
Blessy George
Blessy George is a Content Marketing Associate at Leverage Edu, boasting over a year of experience in the industry. Her expertise lies in crafting compelling content tailored to online courses, making her a go-to source for those navigating the vast landscape of digital learning. In addition to online classes, she writes content related to study abroad, English test preparation and visas. She has completed her MA degree in Political Science and has gained valuable experience as an intern.She is known for her extensive writing on various aspects of international education, garnering recognition for her insights and contributions. Apart from her professional pursuits, Blessy is passionate about creative writing, particularly poetry and songwriting.
Leave a Reply Cancel reply
Save my name, email, and website in this browser for the next time I comment.
Contact no. *
Leaving already?
8 Universities with higher ROI than IITs and IIMs
Grab this one-time opportunity to download this ebook
Connect With Us
45,000+ students realised their study abroad dream with us. take the first step today..
Resend OTP in
Need help with?
Study abroad.
UK, Canada, US & More
IELTS, GRE, GMAT & More
Scholarship, Loans & Forex
Country Preference
New Zealand
Which English test are you planning to take?
Which academic test are you planning to take.
Not Sure yet
When are you planning to take the exam?
Already booked my exam slot
Within 2 Months
Want to learn about the test
Which Degree do you wish to pursue?
When do you want to start studying abroad.
January 2024
September 2024
What is your budget to study abroad?
How would you describe this article ?
Please rate this article
We would like to hear more.
Have something on your mind?
Make your study abroad dream a reality in January 2022 with
India's Biggest Virtual University Fair
Essex Direct Admission Day
Why attend .
Don't Miss Out
Alison's New App is now available on iOS and Android! Download Now
Do you represent a business or organization that would like to train and upskill their employees?
If yes, check out Alison’s Free LMS here!
header.all_certificate_courses
Personal development, sales & marketing, engineering & construction, teaching & academics.
Become an Alison Affiliate in one click, and start earning money by sharing any page on the Alison website.
- Change Language
Understanding Research Methods and Approaches
This free online course includes:.
- Hours of Learning
- CPD Accreditation
- Final Assessment
Rate This Course & Get Better Recommendations!
Thanks for your review, in this free course, you will learn how to.
‘Understanding Research Methods and Approaches’ is a free online course that provides you with a general introduction to widely used research methods such as diary studies, case-study research and focus groups. See how researchers use multiple methods and approaches to conduct case studies and use diaries as a reflexive research tool. By taking this course, you will learn the purpose of a ‘literature study’ and how to use it to analyze a published body of knowledge through summary, classification and comparison.
Next, you will learn about qualitative research methods, what they entail and when they are most effective for undertaking research projects. How to get a community or group of people involved in the research process to increase the participatory process will be discussed in detail. Finally, this course will teach you how to analyze the data once it is collected. It will help you to develop your critical thinking expertise, as well as analytical, research, and communication skills that are globally sought-after and incredibly beneficial.
Those who understand the research methods in Development Studies have a wide range of career options. Careers in development research organizations, charities, lobby groups or roles in government are all possibilities. If you are interested in a career where you can create real-world change, then this course is for you. Start this course today and become an expert in understanding the various research methods and approaches in the exciting and growing field of Developmental Studies.
All Alison courses are free to enrol study and complete. To successfully complete this course and become an Alison Graduate, you need to achieve 80% or higher in each course assessment. Once you have completed this course, you have the option to acquire an official Diploma, which is a great way to share your achievement with the world.
Your Alison is:
- Ideal for sharing with potential employers
- Great for your CV, professional social media profiles and job applications.
- An indication of your commitment to continuously learn, upskill & achieve high results.
- An incentive for you to continue empowering yourself through lifelong learning.
Alison offers 3 types of Diplomas for completed Diploma courses:
- Digital : a downloadable in PDF format immediately available to you when you complete your purchase.
- : a physical version of your officially branded and security-marked , posted to you with FREE shipping.
- Framed : a physical version of your officially branded and security marked in a stylish frame, posted to you with FREE shipping.
All s are available to purchase through the Alison Shop . For more information on purchasing Alison , please visit our FAQs . If you decide not to purchase your Alison , you can still demonstrate your achievement by sharing your Learner Record or Learner Achievement Verification, both of which are accessible from your Account Settings . For more details on our pricing, please visit our Pricing Page
Knowledge & Skills You Will Learn
Complete this cpd accredited course & get your certificate , certify your skills, stand out from the crowd, advance in your career.
Learner Reviews & Feedback For Understanding Research Methods and Approaches
Want to create a customised learning path for your team.
Our dedicated Learning Advisors are here to help you curate a customised learning path tailored to your organisation's needs and goals.
Explore Careers Related To This Course
Not sure where to begin or even what you want to do.
Discover the career most suitable for you and get started in the field with a step-by-step plan.
About Your Alison Course Publisher
- alison stats, more free online courses by this publisher, learners who took this course also enrolled in, explore subjects related to this course.
Join our community of 40 million+ learners, upskill with CPD UK accredited courses, explore career development tools and psychometrics - all for free.
- Reset password form here
- NIH Employee Intranet
- Staff Directory
- En Español
OCRECO Home > Clinical Research Education > Introduction to the Principles and Practice of Clinical Research (IPPCR)
OFFICE OF CLINICAL RESEARCH EDUCATION AND COLLABORATION OUTREACH
- Clinical Research Education
- Funding Opportunities
Introduction to the Principles and Practice of Clinical Research (IPPCR)
- Course Information
- Description
- Registration
- Course Login
Description Important Dates General Information Course Objectives Individual (Non-Registered) Lecture Option Texbook Contact --> Welcome
The Introduction to the Principles and Practice of Clinical Research (IPPCR) course trains registrants on how to effectively and safely conduct clinical research. The course focuses on the spectrum of clinical research and the research process by highlighting biostatistical and epidemiologic methods, study design, protocol preparation, patient monitoring, quality assurance, ethical and legal issues, and much more.
Course Objectives
Provide an overview of basic biostatistical and epidemiologic methods involved in conducting clinical research.
Describe the principles involved in the ethical, legal, and regulatory issues in clinical human subjects research, including the role of Institutional Review Boards (IRBs).
Describe principles and issues involved in monitoring patient-oriented research.
Describe the infrastructure required in performing clinical research and the steps involved in developing and funding research studies.
Intended Audience
This course will be of interest to physicians, scientists, medical and dental students, nurses, public health professionals, and others conducting or planning a career in clinical research.
Course Directors
| – Course Co-Director Dr. Zajicek is a board certified pediatrician and pediatric clinical pharmacologist who currently serves as Program Director of the Office of Clinical Research Education and Collaboration Outreach at the National Institutes of Health. | |
| – Course Co-Director Dr. Lisa M. Cordes is an Oncology Clinical Pharmacy Specialist and Educator for the National Institutes of Health. In her current position, she provides clinical and protocol support to the Genitourinary Malignancies Branch and the Clinical Pharmacology Program of the National Cancer Institute, and is co-director of the Principles of Clinical Pharmacology course. | |
| – Course Co-Director Laura Lee Johnson, Ph.D. is the patient focused drug development liaison and the division director for the Office of Biostatistics at the U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER). She specializes in design, logistics, implementation, and analysis of research studies of all sizes and in measurement tool and endpoint development. Prior to working at the FDA she spent over a decade at the U.S. National Institutes of Health working on and overseeing clinical research and research support programs. | |
| – Course Co-Director (retired) Dr. John Gallin served as the National Institutes of Health's Associate Director for Clinical Research and Chief Scientific Officer of the NIH Clinical Center from 2017-2023. He has published more than 365 articles in scientific journals and has edited two textbooks – "Inflammation, Basic Principles and Clinical Correlates" (Lippincott, Williams, and Wilkins, 1999, now in 3rd edition) and "Principles and Practice of Clinical Research" (Academic Press, now in 4th edition, 2018). Dr. Gallin is a member of the American Society for Clinical Investigation, the Association of American Physicians, the National Academy of Medicine, and he is a Master of the American College of Physicians. |
Social Media Links
- Bookmark & Share
- E-mail Updates
Page Footer
- Visitor Information
- Privacy Notice
- Accessibility
- No Fear Act
- U.S. Department of Health and Human Services
- USA.gov – Government Made Easy
- HHS Vulnerability Disclosure
National Institutes of Health (NIH), 9000 Rockville Pike, Bethesda, Maryland 20892
NIH…Turning Discovery Into Health®
More From Forbes
Top 5 online certificates in 2024, from research.
- Share to Facebook
- Share to Twitter
- Share to Linkedin
Employers should be aware of what certifications and courses are in demand so they can tailor their ... [+] L&D approach and retain their employees, catering to their needs
By now, it's very apparent that continuous learning can make or break your career. Career growth and progression hinges on the steps you take now to improve and develop your skills.
And thankfully, more than ever before, professionals around the world now have access to an unlimited universe of opportunities for learning and development.
According to research and analysis by Statista, the global e-learning market is projected to reach a value of $400 billion by 2026, with thousands of established and newer providers (including independent consultants and thought leaders) offering unprecedented access to a wide array of courses and certifications to enhance your skills and career prospects.
Leading industry players, such as Coursera, PMI (the Project Management Institute) and Amazon's AWS, have revamped their online educational offerings to meet the evolving needs of workers seeking to upskill in tandem with recent industry changes, such as AI (artificial intelligence) and the pressing demand for high-income technical and soft skills. Other providers are also following suit.
With the wide array of online courses and certificates available (many of which are free or relatively low-priced), it appears that workers are turning to specific courses more than others, in a bid to become relevant in their line of work and upskill.
Semrush analysis of professionals seeking to gain certifications to add to their resume (through analyzing Semrush search results) reveals the current sentiment among workers, and shows areas of demand which are gaining widespread popularity as the most-sought-after courses and certificates.
‘House Of The Dragon’ Season 2, Episode 6 Recap And Review: The Flight Of The Dragonriders
Presidential odds shakeup as kamala harris now leading democratic challenger to donald trump, as armored vehicles run out, russian brigades are adding dirt bike training for some new troops.
Understanding what these top five in-demand certifications and online courses are can be helpful in several ways:
First, it enables you to understand what are the relevant skills that you need to enhance your credibility and employment prospects as a professional. If more people are searching for it, this indicates high interest, and for good reason.
From an employer perspective, knowing the most sought after online certificates can help you become highly attractive as an employer, because you will be investing in the right training for your employees, which leads to increased productivity, innovation, and high employee retention rates.
(Employees value when an employer contributes to their career and professional development, making this a high priority and even walking out of their jobs if necessary.) Therefore, identifying the most valued courses can help shape your corporate training programs and future professional development strategies.
And for businesses and course providers in general, these insights are useful for providing actionable data from industry trends that can help inform future online educational offerings based on what employers and learners are seeking.
Top 5 Most Sought-After Certificates In 2024
Project management ranks just as highly as the BLS and CPR certifications, in monthly search volume
1. BLS Certification
With a search volume of 110,000 on Semrush, the BLS certification (basic life support) is offered by the American Red Cross and is suitable for a wide array of professions, ranging from nursing, to fire fighting, to educational roles and policing. It is offered as a combination class, through in-person and online training.
2. CPR Certification
Coming in second in the list, CPR (which means cardiopulmonary resuscitation) is a must-have for anyone, especially if you work in risk-prone work environments or operate in a physical office location. This certification shares the same search volume as BLS.
3. PMP Certification
Project management certifications are also in significant demand, especially the PMP (Project Management Professional) offered by the Project Management Institute, which has witnessed a surge of monthly searches exactly equal to the BLS and CPR certifications—110,000. This evidences the pressing need for PM professionals worldwide, whose functions lie are the core of every initiative, business, industry, and sector you can think of.
4. AWS Certification
AWS (Amazon Web Services) offer a range of online certifications and exams to help boost the skills of cloud engineers, developers, and solutions architects. They recently debuted their AI skills training, offering two new certifications for those professionals seeking to level up their AI skills for work: the AWS Certified AI Practitioner, and the AWS Certified Machine Learning Engineer—Associate. Their certificates are globally recognized and well-esteemed by employers.
5. CNA Certification
The CNA (Certified Nursing Assistant) is a certification that you can earn online, leading to a rewarding career within the healthcare industry. Upon gaining this state-approved certification and passing the exam, you can work in a variety of settings such as care homes, hospitals, hospices, and other community facilities.
AWS has recently introduced AI training into their course portfolio
By considering any of these top five online courses and certificates in 2024, you can stay ahead of the curve—whether you are a learner, course provider, educator, or employer. You, your learners, and your team will be equipped with the skills and knowledge necessary to have thriving careers.
- Editorial Standards
- Reprints & Permissions
Join The Conversation
One Community. Many Voices. Create a free account to share your thoughts.
Forbes Community Guidelines
Our community is about connecting people through open and thoughtful conversations. We want our readers to share their views and exchange ideas and facts in a safe space.
In order to do so, please follow the posting rules in our site's Terms of Service. We've summarized some of those key rules below. Simply put, keep it civil.
Your post will be rejected if we notice that it seems to contain:
- False or intentionally out-of-context or misleading information
- Insults, profanity, incoherent, obscene or inflammatory language or threats of any kind
- Attacks on the identity of other commenters or the article's author
- Content that otherwise violates our site's terms.
User accounts will be blocked if we notice or believe that users are engaged in:
- Continuous attempts to re-post comments that have been previously moderated/rejected
- Racist, sexist, homophobic or other discriminatory comments
- Attempts or tactics that put the site security at risk
- Actions that otherwise violate our site's terms.
So, how can you be a power user?
- Stay on topic and share your insights
- Feel free to be clear and thoughtful to get your point across
- ‘Like’ or ‘Dislike’ to show your point of view.
- Protect your community.
- Use the report tool to alert us when someone breaks the rules.
Thanks for reading our community guidelines. Please read the full list of posting rules found in our site's Terms of Service.
- Policy & Compliance
Research Misconduct
Learn what research misconduct is, how allegations are handled, and find resources to address misconduct.
NIH aims to enable scientific discovery while assuring honesty, transparency, integrity, fair merit-based competition, and protection of intellectual capital and proprietary information. As the largest public funder of biomedical research, NIH sets the standard for innovation and scientific discovery. We promote the highest levels of scientific integrity and public accountability in the conduct of science.
The scientific research enterprise is built on a deep foundation of trust and shared values. As the National Academies wrote in their 2019 On Being a Scientist report, "this trust will endure only if the scientific community devotes itself to exemplifying and transmitting the values associated with ethical scientific conduct" Falsifying, fabricating, or plagiarizing data—all forms of research misconduct—are contrary to these values and ethical conduct.
What is Research Integrity?
Failing to uphold research integrity undermines the public’s confidence and trust in the outcomes of NIH supported research. Research integrity includes:
- the use of honest and verifiable methods in proposing, performing, and evaluating research
- reporting research results with particular attention to adherence to rules, regulations, and guidelines
- following commonly accepted professional codes or norms
Shared values in scientific research
- Honesty: convey information truthfully and honoring commitments
- Accuracy: report findings precisely and take care to avoid errors
- Efficiency: use resources wisely and avoid waste
- Objectivity: let the facts speak for themselves and avoid bias
How does research integrity affect you?
- Researchers rely on trustworthy results of other researchers to make scientific progress.
- Researchers rely on public support, whether through public investments or their voluntary participation in research, to further science.
- The public relies on scientific progress to better the lives of everyone.
- The public could actually be harmed by researchers who are dishonest and act without regards to integrity
About Research Misconduct
Reporting a Concern
Process for Handling Allegations of Research Misconduct
NIH Expectations, Policies, and Requirements
NIH Actions and Oversight after a Finding of Research Misconduct
Notices, Statements and Reports
Responsible Conduct of Research (RCR)
Resources for NIH Staff
This page last updated on: July 15, 2024
- Bookmark & Share
- E-mail Updates
- Privacy Notice
- Accessibility
- National Institutes of Health (NIH), 9000 Rockville Pike, Bethesda, Maryland 20892
- NIH... Turning Discovery Into Health
ORIGINAL RESEARCH article
Regional cerebral oxygen saturation variability and brain injury in preterm infants.
- 1 Department of Pediatrics, School of Medicine University of Zagreb, University Hospital Centre Zagreb, Zagreb, Croatia
- 2 Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
- 3 Division of Neonatology, Department of Obstetrics and Gynecology, University Hospital Merkur, Zagreb, Croatia
- 4 Health Sciences Research, Division of Epidemiology, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
- 5 Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia
- 6 Center for Research on Perinatal Etiopathogenesis of Neurological and Cognitive Diseases, School of Medicine University of Zagreb, Zagreb, Croatia
Objective: To examine whether variation of regional cerebral oxygen saturation (rScO 2 ) within three days after delivery predicts development of brain injury (intraventricular/cerebellar hemorrhage or white matter injury) in preterm infants.
Study design: A prospective study of neonates <32 weeks gestational age with normal cranial ultrasound admitted between 2018 and 2022. All received rScO 2 monitoring with near-infrared spectroscopy at admission up to 72 h of life. To assess brain injury a magnetic resonance imaging was performed at term-equivalent age. We assessed the association between rScO 2 variability (short-term average real variability, rScO 2ARV , and standard deviation, rScO 2SD ), mean rScO 2 (rScO 2MEAN ), and percentage of time rScO 2 spent below 60% (rScO 2TIME<60% ) during the first 72 h of life and brain injury.
Results: The median [IQR] time from birth to brain imaging was 68 [59-79] days. Of 81 neonates, 49 had some form of brain injury. Compared to neonates without injury, in those with injury rScO 2ARV was higher during the first 24 h ( P = 0.026); rScO 2SD was higher at 24 and 72 h ( P = 0.029 and P = 0.030, respectively), rScO 2MEAN was lower at 48 h ( P = 0.042), and rScO 2TIME<60% was longer at 24, 48, and 72 h ( P = 0.050, P = 0.041, and P = 0.009, respectively). Similar results were observed in multivariable logistic regression. Although not all results were statistically significant, increased rScO 2 variability (rScO 2ARV and rScO 2SD ) and lower mean values of rScO2 were associated with increased likelihood of brain injury.
Conclusions: In preterm infants increased aberration of rScO 2 in early postdelivery period was associated with an increased likelihood of brain injury diagnosis at term-equivalent age.
1 Introduction
Brain injury in the preterm infant results from the combined developmental and destructive effects on the maturing nervous system due to multisystemic diseases and conditions from prenatal to postnatal life ( 1 ). Pre-conceptional maternal toxic stress and pregnancy-related illnesses affecting the maternal-placental-fetal triad can disrupt fetal brain development, contributing to preterm birth and/or increasing risks for peripartum brain injuries ( 1 , 2 ). Various postnatal injurious triggers such as respiratory insufficiency and hemodynamic instability secondary to severe respiratory disease, recurrent apneic spells, hemodynamically significant ductus arteriosus, late-onset sepsis or conditions such as necrotizing enterocolitis further increase the risk and promote subsequent brain injury ( 3 , 4 ).
Intracranial hemorrhage and white matter injury (WMI) are frequent pathologies (20%–30%) in preterm infants ( 5 – 8 ). Intraventricular hemorrhage (IVH) usually originates in the subependymal germinal matrix, a richly vascularized collection of neuronal-glial precursor cells in the developing brain ( 9 ). The risk of hemorrhage is inversely proportional to gestational age (GA), with most of IVH occurring in infants less than 32 weeks of gestation ( 10 ). Factors primarily related to dysregulation of cerebral blood flow and pressure in the microvascular bed of the germinal matrix play a major contributory pathogenic role ( 9 , 11 , 12 ). Most IVH events occur within the first week of delivery, and in the majority (90%) can be detected within the first 72 h of life ( 13 ). Cerebellar hemorrhage is also a common form of brain injury in preterm infants. Detection of these injuries by magnetic resonance imaging (MRI) has been reported in up to 37% of infants less than 33 weeks GA ( 14 ). WMI represents a spectrum of disease that ranges from focal necrotic lesions deep in the white matter, with or without subsequent cyst formation, to the more common, diffuse, and nondestructive WMI ( 15 ). The injury is believed to be induced by cerebral ischemia, infection and/or inflammation ( 16 ). Several fundamental physiological factors related to cerebral blood flow, including oxygenation, hypocarbia, levels of glucose and its metabolites, and a variety of inflammatory factors, likely influence the severity of WMI ( 17 ).
Considering that prevalent types of brain injury among preterm infants often coincide with hypoxic, ischemic, and reperfusion events in the early postdelivery period, it is of utmost importance to be able to assess adequacy of cerebral blood flow to improve managements designed to mitigate the risk for injury. Near-infrared spectroscopy ( N IRS) monitors regional cerebral oxygen saturation (rScO 2 ), provides non-invasive information on hemodynamics, real time brain oxygen delivery ( 18 ), and is considered to be a surrogate marker for cerebral blood flow ( 19 – 21 ). NIRS uses multiple wavelengths of near-infrared light and relies on the absorption spectra of oxygenated and deoxygenated hemoglobin to calculate relative concentrations of each, which are then used to calculate rScO 2 . Since NIRS makes no distinction between brain blood compartments, rScO 2 estimates hemoglobin oxygen saturation in a mixed arterial, capillary, and venous compartments ( 22 ). The association between rScO 2 measurements and development of brain injury is not well explored. In the current study we hypothesize that variability in rScO 2 recorded from NIRS in the early postdelivery period may predict brain injury assessed from MRI at term-equivalent age (TEA). We especially focus on short-term average real variability (ARV) of rScO 2 during early postdelivery period as a potential culprit for brain injury. This hypothesis was tested on preterm infants by rScO 2 monitoring with NIRS for the first 72 h after birth. An improved understanding of the relationship between altered rScO 2 and development of brain injury may be used in future management strategies designed to improve neonatal outcomes.
2.1 Settings
This study was conducted in the University Hospital Centre (UHC) and the Croatian Institute for Brain Research, Zagreb, Croatia as a part of a multidisciplinary, longitudinal research project. The UHC is the largest Croatian tertiary referral center for neonatal care and does not have a maternity ward. The hospital admits preterm infants from hospitals that do have maternity wards but do not have the capacity to manage high-risk neonates. Therefore, all neonates in the current study are outborns.
2.2 Patient population, inclusion/exclusion criteria
This is a prospective study of all consecutive newborn admissions to the Neonatal Intensive Care Unit (NICU) at the UHC Zagreb between May 1st, 2018, and June 31st, 2022. The infants were eligible for enrollment if they were less than 32 weeks’ GA at birth and had a normal cranial ultrasound (cUS) on admission. Preterm infants with chromosomal or congenital anomalies, and those with delayed transfer (>12 h) from outside institutions were excluded.
2.3 Study design, NIRS monitoring and study aims
Upon NICU admission cUS was performed to exclude the presence of brain injury. All qualified infants (i.e., no brain injury on cUS) received rScO 2 monitoring using NIRS immediately on admission for up to 72 h of life. A 72-hour period has been accepted as a suitable time frame for NIRS monitoring in premature infants ( 23 ), as majority of IVH in premature infants happens within the first 3 days of life ( 24 ). In our study a two wavelength (730 and 810 nm) near-infrared spectrometer (INVOS 5100, Covidien, Mansfeld, MA) was used by firmly attaching a small neonatal sensor (Covidien, Mansfield, MA) on the left side of the infant's forehead. Four rScO 2 summary statistics were considered: (1) short-term rScO 2 average real variability (rScO 2ARV ) using following equation:
(2) rScO 2 standard deviation (rScO 2SD ), (3) rScO 2 mean (rScO 2MEAN ), and 4) the percentage of time neonate spent with rScO 2 <60% (rScO 2TIME<60% ) all during 72 h after birth. The primary aim was to assess the association between variability of rScO 2 (rScO 2ARV and rScO 2SD ) and brain injury, and secondary aims were to assess the association between average rScO 2 , (rScO 2MEAN ) and percentage of time spent at oxygen saturation below 60% (rScO 2TIME<60% ) and brain injury.
2.4 Data collection
We reviewed obstetric, demographic and neonatal data from the hospital records: sex, GA, birth weight, type of delivery (natural delivery vs. Cesarean section), antenatal corticosteroid treatment, Apgar scores, age at hospital admission, Scores for Neonatal Acute Physiology Perinatal Extension II (SNAPPE-II); variables related to treatment: primary respiratory support, duration of mechanical ventilation, surfactant administration, transfusion of blood and blood products, use of inotropes; and prematurity related complications: pneumothorax, bronchopulmonary dysplasia, necrotizing enterocolitis, infection/sepsis, retinopathy of prematurity.
2.5 Grading of brain injuries
Brain imaging at TEA was done using a 3T MRI scanner (Magnetom, Prisma FIT , Siemens). MRI scanning was performed after regular feeding, infants were wrapped with linen diapers and a blanket. A neuroradiologist blinded to clinical data evaluated the MRI findings. WMI grades considered are: Grade I—punctate lesions; Grade II—small periventricular cysts; Grade III—extensive periventricular cysts; Grade IV—extensive subcortical cysts—also called multicystic encephalomalacia ( 25 – 27 ). IVH was classified according to Papile classification: Grade I—hemorrhage limited to germinal matrix; Grade II—extension into normal-sized ventricles; Grade III—extensive hemorrhage with dilatation of the ventricles; Grade IV—parenchymal involvement ( 28 , 29 ). Cerebellar hemorrhage was noted as present or absent.
2.6 Statistical analysis
Raw rScO 2 NIRS measurements were recorded every 5–15 s. To exclude outliers, we aggregated raw rScO 2 data as a mean over 5-minute intervals for the four features of interest. The aggregated rScO 2 measurements were analyzed for 24-, 48-, and 72-hour intervals following birth. We examined the association between four rScO 2 features (time-weighted rScO 2ARV , rScO 2SD , rScO 2MEAN , and rScO 2TIME<60% ) and brain injury at TEA. The rScO 2ARV was calculated as the average of absolute differences between consecutive rScO 2 measurements during the observed time frame using a previously described equation ( 30 , 31 ). rScO 2ARV feature accounts for the order in which the respective rScO 2 measurements occurred and corrects for limitations of the commonly used measures of variability such as standard deviation, which accounts only for the dispersion of values around the mean, and not for the order of the respective readings ( 31 ). Patients with >50% missing rScO 2 values during the predetermined time intervals following admission were assigned a missing value for the respective feature. For calculating the rScO 2ARV and rScO 2SD , the rScO 2 ceiling-value of 95% was handled by excluding any of the aggregated 95% measurements, that were flanked on both sides by 95% measurements. For calculating the rScO 2MEAN and the rScO 2TIME<60% these 95%-measurements were not excluded.
For univariable analysis, rScO 2 features were compared between those with and without brain injury using the two-sample t -test or Mann Whitney U -test as appropriate. For the multivariable logistic regression analysis, our cohort size allows for two covariates aside from our feature of interest, for which we chose GA and birth weight. Results from the multivariable logistic regression model are summarized as odds ratio and 95% confidence interval for the given rScO 2 feature. There was no evidence of significant non-linearity of GA, birth weight, and all rScO 2 features, as tested by comparing a univariable linear and a univariable restricted cubic spline model (with knots at the 5th, 50th, and 95th or 15th, 50th, and 95th percentile) via the likelihood ratio test for each variable. A P -value <0.05 was determined statistically significant throughout. All statistical analyses were performed with Python v.3.9 (Python Software Foundation, Wilmington, Delaware, USA).
3.1 Cohort characteristics
Between May 1st, 2018, and June 31st, 2022, 81 neonates met criteria and were included in the study. The median [IQR] time from birth to initiation of NIRS monitoring was 2.5 [1.4–3.6] hours, and from birth to MRI at TEA 68 [59–79] days. MRI at TEA ruled out the presence of brain injury in 32 neonates, while 49 were diagnosed with single or multiple brain injuries (all were mild, grades I or II): 33 (40.7%) neonates had IVH, 28 (34.6%) had WMI, and 8 (10%) had cerebellar hemorrhage ( Figure 1 ). Table 1 shows neonatal characteristics, overall and according to the presence or absence of brain injury. There were no significant differences in characteristics between infants with and without injury: GA at delivery ( P = 0.555), Apgar scores at 1 and 5 min ( P = 0.673 and 0.899, respectively), and main comorbidities (sepsis, P > 0.99; need for respiratory support, P = 0.155; necrotizing enterocolitis, P = 0.462; bronchopulmonary dysplasia, P = 0.590; or retinopathy, P = 0.511).
Figure 1 Summary of 81 preterm infants according to MRI results at term-equivalent age. IVH, intraventricular hemorrhage; WMI, white matter injury.
Table 1 Demographic and clinical characteristics of preterm infants in our cohort.
3.2 Association of rScO 2 features with brain injury at TEA
Of the 81 neonates, 72, 77, and 80 had sufficient rScO 2 data (continuous NIRS monitoring for >50% of the timeframe) for the 24-, 48-, and 72-hours after birth, respectively. Compared to neonates without brain injury, rScO 2ARV was higher during the first 24 h in those diagnosed with brain injury, P = 0.026 ( Table 2 , Figure 2 ). Similarly, rScO 2SD was higher at 24 and 72 h ( P = 0.029 and P = 0.030, respectively) in those with injury. The rScO 2MEAN was lower at 48 h ( P = 0.042) in those with injury, and the percentage of time neonates spent at rScO 2TIME<60% was higher in those with injury ( P = 0.050, P = 0.041, and P = 0.009 at 24-, 48-, and 72-hours, respectively) ( Table 2 , Supplementary Figure S1 ). Similar results were observed from logistic regression analysis adjusted for GA and birth weight ( Table 2 ). Although not all results were significant, increased rScO 2 variability (rScO 2ARV, rScO 2SD ) was consistently associated with increased likelihood of brain injury at TEA. Also, lower values of rScO 2 (rScO 2MEAN and rScO 2TIME<60% ) were associated with increased likelihood of brain injury ( Table 2 and Figure 2 ).
Table 2 Comparison of four rScO 2 features during the first 72 h of life in infants with and without brain injury as seen on magnetic resonance imaging at term-equivalent age.
Figure 2 Results of logistic regression analysis showing the association between rScO 2 features (average real variability; rScO 2ARV ; standard deviation, rScO 2SD ; mean, rScO 2MEAN ; and percentage of time below 60%, rScO 2TIME<60% ) and brain injury at term-equivalent age. Values >1 indicate increased likelihood for brain injury at term-equivalent age.
4 Discussion
The most important findings of this study are that increased variability of regional cerebral oxygen saturation, lower mean saturation, and longer time neonates spent at saturation below 60% in the early postdelivery period were associated with an increased likelihood for being diagnosed with brain injury at TEA. Our results cannot distinguish if this association is consequential (rScO 2 pattern reflects presence of injury) or causative (rScO 2 pattern contributed to development of injury), therefore our study provides direction for future research.
Variations in cerebral perfusion and oxygenation are considered to be the key risk factors for brain injury in preterm infants ( 9 , 11 , 12 ). Continuous assessment of rScO 2 can identify infants with altered cerebral oxygenation ( 32 ). Although NIRS is increasingly used by neonatologists for rScO 2 monitoring, there are no reports that consistently establish the rScO 2 references or cut-off values for adverse outcomes related to altered brain oxygenation ( 23 , 33 ). Alderliesten et al. ( 23 ) published reference values of rScO 2 during the first three days of life in 999 preterm infants (GA <32 weeks) and found that at NICU admission the average rScO 2 was ∼65% and continued to increase with GA at a mean rate of 1% per week, following a parabolic curve in relation to postnatal age with a peak at −36 h. It is important to note, Alderliesten et al. ( 23 ) references were obtained mostly from measurements using small adult sensors (983 small adult sensors and 16 neonatal sensors). In order to convert neonatal sensor readings to the small adult sensor equivalent, the obtained rScO 2 values were interpolated using statistical modelling tools ( 23 ). It is well established that rScO 2 values depend on the type of NIRS sensor used (e.g., adult, neonatal, pediatric) ( 23 , 34 ). In comparison to adult sensors, neonatal rScO 2 sensor readings are consistently higher, but the difference is not fixed and is less at the threshold indicative of cerebral hypoxia; the neonatal sensor difference is approximately 10% when adult sensors read 85%, but nearly similar (58.8%) when adult sensors read 55% ( 35 ). The SafeBoosC-III study evaluating the benefit of an interventional strategy to reduce cerebral hypoxia using NIRS-derived rScO 2 monitoring demonstrate no significant difference between group in rates of death or severe brain injury at 36 weeks post-menstrual age ( 36 ). The study used at least 5 different device and sensor combinations with varying hypoxia thresholds based on linear transformations obtained in an in vitro model. Although the trial did not show evidence of decreased mortality or severe brain injury, concerns remain that the selected thresholds were not equivalent across devices due to proprietary algorithms and the nonlinear nature of human physiology ( 37 ). Therefore, in order to properly interpret rScO 2 cut-off values, it is of utmost importance to specify the type of sensor when comparing the data between studies.
Because low brain blood flow is associated with reduced oxygenation it poses a risk for development of brain injury. Specifically, Alderliesten et al. ( 34 ) found that a rScO 2 <55% (using a small adult sensor) increased risk for grade III/IV IVH with an odds ratio of 1.017 per one percent (95%CI 1.007–1.026, GA corrected) of time spent below 55%, as well as in neonates who spent at least 20% of time below 55% in the first 72 h following delivery. Furthermore, Alderliesten et al. ( 34 ) found that a rScO 2 <55% was associated with unfavorable cognitive outcomes at 24 months with an OR of 1.4 (CI 1.1–1.7) for neonates who spent at least 20% of time below that threshold during the first 3 days after delivery. Chock et al. ( 38 ) measured rScO 2 with neonatal sensors and reported that infants with adverse outcomes had significantly lower mean rScO 2 (67 ± 9%) compared with those without adverse outcomes (72 ± 7%), and that rScO 2 below 50% could be identified as a cut-off point for identifying infants with adverse outcome with an area under the curve of 0.76. Verhagen et al. ( 39 ), using pediatric sensors, demonstrated that preterm infants with IVH, compared to those without IVH, had lower median rScO 2 during the first two weeks following birth, suggesting that lower cerebral blood flow in those with injuries remains present for a longer period than just the first few hours after birth. However, it remains unknown whether this lower blood flow and oxygenation contributed to injury or rather reflects the presence of hemorrhage. In our cohort few infants had rScO 2 below 50%, therefore we examined the time spent with rScO 2 below 60% during 72 postdelivery hours. Using this cut-off point in unadjusted analysis we found a positive association between rScO 2TIME<60% and brain injury, however after adjusting for weight and GA the significance was lost, but the trend towards positive association remained.
A short-term ARV represents measurement-to-measurement, within-subject variability in the parameter (in our study parameter of interest was rScO 2 ) that accounts for the order in which measurements has occurred ( 31 ). In cardiovascular research short-term ARV was shown to be an independent risk factor for severity of organ damage ( 40 , 41 ), cardiovascular morbidity and mortality ( 30 , 42 ). The precision of estimates from ARV is dependent on frequency of sequential readings (measurements), and in the current study data were recorded every 5–15 s, and ARV was aggregated over 5-minute intervals during 72-hours after delivery. Therefore, our frequency of measurements provides a reliable assessment of rScO 2ARV features in regard to the outcome sought. It is well known that inadequate or fluctuating cerebral perfusion and oxygenation contribute to IVH and WMI ( 10 , 12 , 38 , 43 – 47 ). Preterm infants are at high risk for early hemodynamic instability and many factors may contribute to fluctuations in systemic blood pressure in the first few days of life. Moreover, cerebral autoregulation has limited capacity and is thought to be particularly fragile in the immature brain ( 48 ). A number of factors that influence vascular reactivity are likely to promote the pressure passive state (hypoxia, hypocarbia, hypercarbia), significantly perturb cerebral blood flow and increase the risk for WMI and intracranial hemorrhage ( 49 – 52 ). The proportion of infants with impaired cerebral autoregulation and increased periods of pressure-passive cerebral circulation appear to be substantial ( 53 , 54 ). As the pressure-passive state can fluctuate over time and can occur without markedly low blood pressures, it could be readily overlooked with routine monitoring ( 54 ). On the other side, increases in systemic blood pressure, especially abrupt increases, could lead to cerebral hyperperfusion and hemorrhagic complications. Since oscillations of systemic blood pressure create variations in regional blood flow which can be assessed with NIRS ( 55 ), rScO 2 ARV emerges as an attractive approach to assess the adequacy of regional brain perfusion and oxygenation. To the best of our knowledge rScO 2ARV using NIRS has never been examined in assessing the association between rScO 2 and brain injury. Our study suggests that increased short-term rScO 2ARV , early following delivery of preterm infants may be either a predictor or a marker for increased likelihood of brain injury.
4.1 Strengths and limitations
A strength of this study is prospective enrollment of consecutive neonates who fulfilled the research criteria. To examine more precisely the relationship between rScO 2 and brain injury only neonates with a normal cUS on admission were included. Another strength of our study is the use of MRI over cUS to detect the severity and extension of brain injury. Compared with cUS, MRI is more sensitive for detection of low grade IVH, non-cystic WMI, especially punctate white matter lesions which correspond to small periventricular necroses of apparent ischemic or hemorrhagic nature, as well as cerebellar hemorrhage, particularly small punctate hemorrhages ( 56 , 57 ).
Our study must be interpreted in the context of several limitations. First, we focused on rScO 2 monitoring in the first 3 days following birth. While most brain injuries (70%) are expected to occur within the first 72 h following birth ( 13 ), this monitoring window may not be adequate to capture injuries that occur later (of note, it is estimated that 95% of brain injuries occur by day 7, with a very small additional percentage between days 7 and 10) ( 24 ). Our study assumes that the majority of injuries occurred during 72-hour time frame after birth, as well that these injuries may be associated with altered rScO 2 . Second, our study assumes that early occurring brain injuries remain detectable with MRI at TEA, and ignores the possibility that some may have resolved in interim. Third, there was a substantial variability in measured rScO 2 values which limits the statistical power of consistently detecting differences. Although we found evidence that rScO 2 in early postdelivery period is associated with brain injury at TEA, as well that the time spent below 60% saturation is associated with increased risk for brain injury, our study is not large enough to provide the exact cut-off point for critical rScO 2 levels. Therefore, future studies are needed to define critical rScO 2 values and examine whether interventions designed to optimize rScO 2 can prevent brain injury in infants.
5 Conclusion
In conclusion, our results suggest that features of increased rScO 2 variability in preterm infants, as well as lower rScO 2MEAN and increased percentage of time spent <60% within the first three days following delivery may be associated with increased likelihood for brain injury at TEA. Our study design does not allow to discern whether the observed association between rScO 2 and brain injury is causative or is rather a marker of its presence. Therefore, our study opens an intriguing question and provides direction for future research.
Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics statement
The studies involving humans were approved by Institutional Ethics Committee of the University Hospital Centre Zagreb and Institutional Ethics Committee of the School of Medicine University of Zagreb. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.
Author contributions
TĆ: Investigation, Methodology, Writing – original draft. MR: Data curation, Writing – review & editing, Formal Analysis, Validation. KB: Writing – review & editing. ND: Writing – review & editing, Investigation. DS: Data curation, Writing – review & editing, Formal Analysis, Validation. JS: Writing – review & editing, Data curation, Methodology, Supervision. TW: Writing – review & editing. MR: Investigation, Writing – review & editing, Funding acquisition. IK: Investigation, Writing – review & editing. RG: Investigation, Methodology, Project administration, Supervision, Writing – review & editing.
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article.
This publication was supported by Croatian Science Foundation projects IP-2020-02-7166; co-financed by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience project "Experimental and clinical research of hypoxic-ischemic damage in perinatal and adult brain"; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2024.1426874/full#supplementary-material
Abbreviations
ARV, average real variability; cUS, cranial ultrasound; GA, gestational age; IQR, interquartile range; IVH, intraventricular hemorrhage; MRI, magnetic resonance imaging; NICU, Neonatal Intensive Care Unit; NIRS, near infrared spectroscopy; rScO 2 , Regional cerebral oxygen saturation; rScO 2ARV , rScO 2 average real variability; rScO 2MEAN , Mean rScO 2 ; rScO 2SD , rScO 2 standard deviation; rScO 2TIME<60% , percentage of time neonate had rScO 2 below 60%; SD, standard deviation; TEA, term-equivalent age; WMI, white matter injury.
1. Scher MS. “The first thousand days” define a fetal/neonatal neurology program. Front Pediatr . (2021) 9:683138. doi: 10.3389/fped.2021.683138
PubMed Abstract | Crossref Full Text | Google Scholar
2. Scher MS. Interdisciplinary fetal-neonatal neurology training applies neural exposome perspectives to neurology principles and practice. Front Neurol . (2024) 14:1321674. doi: 10.3389/fneur.2023.1321674
3. Kartam M, Embaireeg A, Albalool S, Almesafer A, Hammoud M, Al-Hathal M, et al. Late-onset sepsis in preterm neonates is associated with higher risks of cerebellar hemorrhage and lower motor scores at three years of age. Oman Med J . (2022) 37(2):e368. doi: 10.5001/omj.2022.41
4. Lu J, Martin CR, Claud EC. Neurodevelopmental outcome of infants who develop necrotizing enterocolitis: the gut-brain axis. Semin. Perinatol . (2023) 47(1):151694. doi: 10.1016/j.semperi.2022.151694
5. Kusters CD, Chen ML, Follett PL, Dammann O. “Intraventricular” hemorrhage and cystic periventricular leukomalacia in preterm infants: how are they related? J Child Neurol . (2009) 24(9):1158–70. doi: 10.1177/0883073809338064
6. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD neonatal research network. Pediatrics . (2010) 126(3):443–56. doi: 10.1542/peds.2009-2959
7. Arulkumaran S, Tusor N, Chew A, Falconer S, Kennea N, Nongena P, et al. MRI findings at term-corrected age and neurodevelopmental outcomes in a large cohort of very preterm infants. AJNR Am J Neuroradiol . (2020) 41(8):1509–16. doi: 10.3174/ajnr.A6666
8. Kostović I, Kostović-Srzentić M, Benjak V, Jovanov-Milošević N, Radoš M. Developmental dynamics of radial vulnerability in the cerebral compartments in preterm infants and neonates. Front Neurol . (2014) 5:139. doi: 10.3389/fneur.2014.00139
9. Ballabh P, de Vries LS. White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies. Nat Rev Neurol . (2021) 17(4):199–214. doi: 10.1038/s41582-020-00447-8
10. Lou HC, Lassen NA, Friis-Hansen B. Impaired autoregulation of cerebral blood flow in the distressed newborn infant. J Pediatr . (1979) 94(1):118–21. doi: 10.1016/s0022-3476(79)80373-x
11. Inder TE, Perlman JM, Volpe JJ. Preterm intraventricular hemorrhage/posthemorrhagic hydrocephalus. In: Volpe JJ, editor. Neurology of the Newborn . Philadelphia: Elsevier (2018). p. 637–98.
Google Scholar
12. Lu H, Wang Q, Lu J, Zhang Q, Kumar P. Risk factors for intraventricular hemorrhage in preterm infants born at 34 weeks of gestation or less following preterm premature rupture of membranes. J Stroke Cerebrovasc Dis . (2016) 25(4):807–12. doi: 10.1016/j.jstrokecerebrovasdis.2015.12.011
13. McCrea HJ, Ment LR. The diagnosis, management, and postnatal prevention of intraventricular hemorrhage in the preterm neonate. Clin Perinatol . (2008) 35(4):777–92. doi: 10.1016/j.clp.2008.07.014
14. Gano D, Ho ML, Partridge JC, Glass HC, Xu D, Barkovich AJ, et al. Antenatal exposure to magnesium sulfate is associated with reduced cerebellar hemorrhage in preterm newborns. J Pediatr . (2016) 178:68–74. doi: 10.1016/j.jpeds.2016.06.053
15. Inder TE, Anderson NJ, Spencer C, Wells S, Volpe JJ. White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term. AJNR Am J Neuroradiol . (2003) 24(5):805–9. PMID: 12748075; PMCID: PMC7975772.12748075
PubMed Abstract | Google Scholar
16. Back SA. White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol . (2017) 134(3):331–49. doi: 10.1007/s00401-017-1718-6
17. Back SA, Volpe JJ. Encephalopathy of prematurity: pathophysiology. In: Volpe JJ, editor. Neurology of the Newborn . Philadelphia: Elsevier (2018). p. 405–24.
18. Zhang Y, Liu D, Mao Y, Gao Q, Xiong T. Cerebral near-infrared spectroscopy monitoring to predict periventricular-intraventricular haemorrhage and neurodevelopmental outcomes in preterm infants: a protocol for a systematic review and meta-analysis. BMJ Paediatr Open . (2023) 7(1):e001859. doi: 10.1136/bmjpo-2023-001859
19. Zweifel C, Castellani G, Czosnyka M, Helmy A, Manktelow A, Carrera E, et al. Noninvasive monitoring of cerebrovascular reactivity with near infrared spectroscopy in head-injured patients. J Neurotrauma . (2010) 27(11):1951–8. doi: 10.1089/neu.2010.1388
20. Brady K, Joshi B, Zweifel C, Smielewski P, Czosnyka M, Easley RB, et al. Real-time continuous monitoring of cerebral blood flow autoregulation using near-infrared spectroscopy in patients undergoing cardiopulmonary bypass. Stroke . (2010) 41(9):1951–6. doi: 10.1161/STROKEAHA.109.575159
21. Caicedo A, De Smet D, Naulaers G, Ameye L, Vanderhaegen J, Lemmers P, et al. Cerebral tissue oxygenation and regional oxygen saturation can be used to study cerebral autoregulation in prematurely born infants. Pediatr Res . (2011) 69(6):548–53. doi: 10.1203/PDR.0b013e3182176d85
22. Watzman HM, Kurth CD, Montenegro LM, Rome J, Steven JM, Nicolson SC. Arterial and venous contributions to near-infrared cerebral oximetry. Anesthesiology . (2000) 93(4):947–53. doi: 10.1097/00000542-200010000-00012
23. Alderliesten T, Dix L, Baerts W, Caicedo A, van Huffel S, Naulaers G, et al. Reference values of regional cerebral oxygen saturation during the first 3 days of life in preterm neonates. Pediatr Res . (2016) 79(1-1):55–64. doi: 10.1038/pr.2015.186
24. Hand IL, Shellhaas RA, Milla SS, Committee on Fetus and Newborn, Section on Neurology, Section on Radiology. Routine neuroimaging of the preterm brain. Pediatrics . (2020) 146(5):e2020029082. doi: 10.1542/peds.2020-029082
25. de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res . (1992) 49(1):1–6. doi: 10.1016/s0166-4328(05)80189-5
26. Dorner RA, Burton VJ, Allen MC, Robinson S, Soares BP. Preterm neuroimaging and neurodevelopmental outcome: a focus on intraventricular hemorrhage, post-hemorrhagic hydrocephalus, and associated brain injury. J Perinatol . (2018) 38(11):1431–43. doi: 10.1038/s41372-018-0209-5
27. Agut T, Alarcon A, Cabañas F, Bartocci M, Martinez-Biarge M, Horsch S, et al. Preterm white matter injury: ultrasound diagnosis and classification. Pediatr Res . (2020) 87(Suppl 1):37–49. doi: 10.1038/s41390-020-0781-1
28. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr . (1978) 92(4):529–34. doi: 10.1016/s0022-3476(78)80282-0
29. Starr R, De Jesus O, Shah SD, Borger J. Periventricular and Intraventricular Hemorrhage. in StatPearls . Treasure Island, FL: StatPearls Publishing (2023). Available online at: https://www.ncbi.nlm.nih.gov/books/NBK538310/ (accessed April 21, 2024).
30. Mena L, Pintos S, Queipo NV, Aizpúrua JA, Maestre G, Sulbarán T. A reliable index for the prognostic significance of blood pressure variability. J Hypertens . (2005) 23(3):505–11. doi: 10.1097/01.hjh.0000160205.81652.5a
31. Mena LJ, Maestre GE, Hansen TW, Thijs L, Liu Y, Boggia J, et al. How many measurements are needed to estimate blood pressure variability without loss of prognostic information? Am J Hypertens . (2014) 27(1):46–55. doi: 10.1093/ajh/hpt142
32. Alderliesten T, Lemmers PM, Smarius JJ, van de Vosse RE, Baerts W, van Bel F. Cerebral oxygenation, extraction, and autoregulation in very preterm infants who develop peri-intraventricular hemorrhage. J Pediatr . (2013) 162(4):698–704.e2. doi: 10.1016/j.jpeds.2012.09.038
33. Hyttel-Sorensen S, Pellicer A, Alderliesten T, Austin T, van Bel F, Benders M, et al. Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial. Br Med J . (2015) 350:g7635. doi: 10.1136/bmj.g7635
34. Alderliesten T, van Bel F, van der Aa NE, Steendijk P, van Haastert IC, de Vries LS, et al. Low cerebral oxygenation in preterm infants is associated with adverse neurodevelopmental outcome. J Pediatr . (2019) 207:109–116.e2. doi: 10.1016/j.jpeds.2018.11.038
35. Variane GFT, Dahlen A, Noh CY, Zeng J, Yan ES, Kaneko JS, et al. Cerebral oxygen saturation in neonates: a bedside comparison between neonatal and adult NIRS sensors. Pediatr Res . (2023) 94(5):1810–6. doi: 10.1038/s41390-023-02705-z
36. Hansen ML, Pellicer A, Hyttel-Sørensen S, Ergenekon E, Szczapa T, Hagmann C, et al. Cerebral oximetry monitoring in extremely preterm infants. N Engl J Med . (2023) 388(16):1501–11. doi: 10.1056/NEJMoa2207554
37. Chock VY, Vesoulis ZA, El-Dib M, Austin T, van Bel F. The future of neonatal cerebral oxygenation monitoring: directions after the SafeBoosC-III trial. J Pediatr . (2024) 270:114016. doi: 10.1016/j.jpeds.2024.114016
38. Chock VY, Kwon SH, Ambalavanan N, Batton B, Nelin LD, Chalak LF, et al. Cerebral oxygenation and autoregulation in preterm infants (early NIRS study). J Pediatr . (2020) 227:94–100.e1. doi: 10.1016/j.jpeds.2020.08.036
39. Verhagen EA, Ter Horst HJ, Keating P, Martijn A, Van Braeckel KN, Bos AF. Cerebral oxygenation in preterm infants with germinal matrix-intraventricular hemorrhages. Stroke . (2010) 41(12):2901–7. doi: 10.1161/STROKEAHA.110.597229
40. Sega R, Corrao G, Bombelli M, Beltrame L, Facchetti R, Grassi G, et al. Blood pressure variability and organ damage in a general population: results from the PAMELA study (pressioni arteriose monitorate E loro associazioni). Hypertension . (2002) 39(2 Pt 2):710–4. doi: 10.1161/hy0202.104376
41. Li CL, Liu R, Wang JR, Yang J. Relationship between blood pressure variability and target organ damage in elderly patients. Eur Rev Med Pharmacol Sci . (2017) 21(23):5451–5. doi: 10.26355/eurrev_201712_13934
42. Del Giorno R, Balestra L, Heiniger PS, Gabutti L. Blood pressure variability with different measurement methods: reliability and predictors. A proof of concept cross sectional study in elderly hypertensive hospitalized patients. Medicine (Baltimore) . (2019) 98(28):e16347. doi: 10.1097/MD.0000000000016347
43. Aspide R. Relationship between brain tissue oxygen and near-infrared spectroscopy in patients with nontraumatic subarachnoid hemorrhage: invited commentary. Neurocrit Care . (2022) 37(3):616–7. doi: 10.1007/s12028-022-01566-4
44. Ballabh P. Pathogenesis and prevention of intraventricular hemorrhage. Clin Perinatol . (2014) 41(1):47–67. doi: 10.1016/j.clp.2013.09.007
45. Noori S, McCoy M, Anderson MP, Ramji F, Seri I. Changes in cardiac function and cerebral blood flow in relation to peri/intraventricular hemorrhage in extremely preterm infants. J Pediatr . (2014) 164(2):264–70.e703. doi: 10.1016/j.jpeds.2013.09.045
46. Sorensen LC, Maroun LL, Borch K, Lou HC, Greisen G. Neonatal cerebral oxygenation is not linked to foetal vasculitis and predicts intraventricular haemorrhage in preterm infants. Acta Paediatr . (2008) 97(11):1529–34. doi: 10.1111/j.1651-2227.2008.00970.x
47. Vesoulis ZA, Whitehead HV, Liao SM, Mathur AM. The hidden consequence of intraventricular hemorrhage: persistent cerebral desaturation after IVH in preterm infants. Pediatr. Res . (2021) 89(4):869–77. doi: 10.1038/s41390-020-01189-5
48. Volpe JJ. Brain injury in the premature infant: neuropathology, clinical aspects, and pathogenesis. Ment. Retard Dev Disabil Res Rev . (1997) 5(3):3–12. doi: 10.1002/(SICI)1098-2779(1997)3:1%3C3::AID-MRDD2%3E3.0.CO;2-U
49. Fabres J, Carlo WA, Phillips V, Howard G, Ambalavanan N. Both extremes of arterial carbon dioxide pressure and the magnitude of fluctuations in arterial carbon dioxide pressure are associated with severe intraventricular hemorrhage in preterm infants. Pediatrics . (2007) 119(2):299–305. doi: 10.1542/peds.2006-2434
50. Erickson SJ, Grauaug A, Gurrin L, Swaminathan M. Hypocarbia in the ventilated preterm infant and its effect on intraventricular haemorrhage and bronchopulmonary dysplasia. J Paediatr Child Health . (2002) 38(6):560–2. doi: 10.1046/j.1440-1754.2002.00041.x
51. Greisen G, Vannucci RC. Is periventricular leucomalacia a result of hypoxic-ischaemic injury? Hypocapnia and the preterm brain. Biol Neonate . (2001) 79(3-4):194–200. doi: 10.1159/000047090
52. Pryds O. Control of cerebral circulation in the high-risk neonate. Ann Neurol . (1991) 30(3):321–9. doi: 10.1002/ana.410300302
53. Tsuji M, Saul JP, du Plessis A, Eichenwald E, Sobh J, Crocker R, et al. Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics . (2000) 106(4):625–32. doi: 10.1542/peds.106.4.625
54. Soul JS, Hammer PE, Tsuji M, Saul JP, Bassan H, Limperopoulos C, et al. Fluctuating pressure-passivity is common in the cerebral circulation of sick premature infants. Pediatr Res . (2007) 61(4):467–73. doi: 10.1203/pdr.0b013e31803237f6
55. Alderliesten T, Lemmers PM, van Haastert IC, de Vries LS, Bonestroo HJ, Baerts W, et al. Hypotension in preterm neonates: low blood pressure alone does not affect neurodevelopmental outcome. J Pediatr . (2014) 164(5):986–91. doi: 10.1016/j.jpeds.2013.12.042
56. Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med . (2006) 355(7):685–94. doi: 10.1056/NEJMoa053792
57. Inder TE, de Vries LS, Ferriero DM, Grant PE, Ment LR, Miller SP, et al. Neuroimaging of the preterm brain: review and recommendations. J Pediatr . (2021) 237:276–287.e4. doi: 10.1016/j.jpeds.2021.06.014
Keywords: neonates, preterm infants, magnetic resonance imaging, intraventricular hemorrhage, white matter injury, near-infrared spectroscopy, regional cerebral oxygen saturation
Citation: Ćaleta T, Ryll MJ, Bojanić K, Dessardo NS, Schroeder DR, Sprung J, Weingarten TN, Radoš M, Kostović I and Grizelj R (2024) Regional cerebral oxygen saturation variability and brain injury in preterm infants. Front. Pediatr. 12 : 1426874. doi: 10.3389/fped.2024.1426874
Received: 15 May 2024; Accepted: 9 July 2024; Published: 22 July 2024.
Reviewed by:
© 2024 Ćaleta, Ryll, Bojanić, Dessardo, Schroeder, Sprung, Weingarten, Radoš, Kostović and Grizelj. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ruža Grizelj, [email protected]
† These authors have contributed equally to this work and share first authorship
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
IMAGES
VIDEO
COMMENTS
Learn Research Methodology, earn certificates with paid and free online courses from Stanford, MIT, University of Michigan, Johns Hopkins and other top universities around the world. Read reviews to decide if a class is right for you.
We explain how to formulate a research problem, design research methods, select samples and write a research proposal. The course then demonstrates how to collect, process, analyze and present data before taking you through the steps required to write a clear and compelling research report. COURSE PUBLISHER -.
edX | Build new skills. Advance your career. | edX
Course layout. Week 1: Philosophy of Science (subjective versus objective, materialism versus idealism, causality, etc.) Week 2: Logical Reasoning (inductive logic, deductive logix, syllogistic logic) Week 3: History of development of science and the influence of philosophy. Week 4: What Scientists Actually Do.
This MOOC draws on a wealth of existing course material developed to support research training across SOAS, University of London and particularly drawing from the Centre for International Studies and Diplomacy (CISD). In 2015, the course was nominated for the prestigious Guardian University Award for its innovative approach to online learning.
Good knowledge of research methodology is a precondition for a successful PhD thesis. However, not all PhD students have access to methodology courses as part of their PhD programme. Fortunately, there are good options online, such as the following 10 powerful methodology online courses for PhD students provided via Coursera. Disclosure: This post contains affiliate
The Research Methods, Measurement & Evaluation online master's degree program is designed for educators and various practitioners ranging from corporate training & learning designers through sales force management seeking program evaluation expertise. Further, it is an ideal option for recent college graduates currently in or entering the ...
The Certificate in Mixed Methods Research (MMR) is designed for researchers and practitioners in social work, nursing, psychology, public health, anthropology, political science, sociology, education, and other applied fields who are interested in: ways to integrate qualitative and quantitative research methods and data.
10 Best Research Methodology Online Course. Proper research methods can ensure that research is conducted in a systematic, and objective manner. Thus, minimizing any chance of bias and increasing the credibility of the findings. Here is a list of the 10 best research methodology online courses.
A short course that will teach you how to analyze qualitative data. This short course is adapted from a semester length graduate level course taught at MIT covering Qualitative Research Methods. The first half of the course is covered in 21A.819.1x, and covers an introduction to qualitative research and conducting interviews.
This free online course offers a general introduction to understanding different research methodologies and various approaches. Development research methods combine rigorous academic study with practical skills. You will learn the significance of linking the gap between theory and practice, where knowing how to write a persuasive proposal or ...
Postgraduate Online Training: Research Methodologies. This guide provides step-by-step training, working through the various stages of the research cycle, to develop and improve the necessary skills to complete your research. ... For more recommended sources and tips on Research Methodologies, see our Research Methods tab. << Previous ...
The Introduction to the Principles and Practice of Clinical Research (IPPCR) course trains registrants on how to effectively and safely conduct clinical research. The course focuses on the spectrum of clinical research and the research process by highlighting biostatistical and epidemiologic methods, study design, protocol preparation, patient ...
According to research and analysis by Statista, the global e-learning market is projected to reach a value of $400 billion by 2026, with thousands of established and newer providers (including ...
Research integrity includes: the use of honest and verifiable methods in proposing, performing, and evaluating research reporting research results with particular attention to adherence to rules, regulations, and guidelines following commonly accepted professional codes or norms; Shared values in scientific research
Online programs might offer software and virtual tools, but the tactile experience is limited. Networking: Being on-campus can make it easier to network with local artists and attend gallery openings and exhibitions in the city. Online students might miss out on these spontaneousopportunities but can still build connections through virtual events.
For example, research by James et al. (2017) observed that landing strikes on the ground and completing takedowns was a successful strategy to winning bouts in MMA. While such methods provide important information on overall winningness in combat sports, there are certain areas that remain relatively unexplored.
2 Methods 2.1 Settings. This study was conducted in the University Hospital Centre (UHC) and the Croatian Institute for Brain Research, Zagreb, Croatia as a part of a multidisciplinary, longitudinal research project. The UHC is the largest Croatian tertiary referral center for neonatal care and does not have a maternity ward.