The Journey Behind our Groundbreaking Research on Cerebral Palsy

It all began during my pediatric ward rotations. One evening in early 2023, I encountered a 4-year-old boy with cerebral palsy. Witnessing his struggles and the emotional toll on his family left an impact on me. I then became deeply driven to understand cerebral palsy, dedicating weeks to reading everything I could find on the condition. During this time, I stumbled upon a few case-control studies conducted in Europe, which sparked an idea: What if we conducted a meta-analysis to identify antenatal biomarkers associated with cerebral palsy?

Fueled by this idea, I formed a team within my network ( Research Peer Network ) and we worked tirelessly for over a year to conduct the analysis. Unfortunately, our initial results didn't reveal anything significant. As a researcher, I found it hard to accept this outcome, especially since... it was quite counter-intuitive. All individual studies had reported skewed results. Night after night, I pored over the data, unable to sleep, until one night, my eyes caught something... we had mistakenly analyzed data for above the 95th percentile thresholds instead of below the 5th percentile. This error led us to incorrectly conclude there was no "increase" in biomarker levels, when in fact, there was a significant decrease. Once we corrected this, we found that PAPP-A significantly decreased in the first trimester among pregnant women who later gave birth to children with cerebral palsy. I was overwhelmed with emotion!!

But the journey didn’t end there. I was still nagged by counterintuitive thoughts. One night, I performed a sensitivity analysis, and discovered that Beta-HCG also significantly decreased during the 1st and 2nd trimesters! But as researchers, we cannot just exclude a study to suit our requirements. However, that study in particular, representing only 0.00064% of the total pooled sample size, made our results insignificant. I spent several sleepless nights reading this and every single study we had included, including their references!

Finally, I realized that the majority of participants in that study were primigravida, unlike the other studies, which mostly involved multigravida women. I hypothesized that primigravida status positively influenced Beta-HCG levels, leading to insignificant decreases in at-risk pregnancies. My hypothesis was supported not once, but twice! We performed a meta-regression, and the beta-coefficient values backed up my theory. Secondly, I also found several old papers that were published that claimed the same thing!

It was an incredible "researcher's moment" to see my hypothesis come to life and be validated!!

As we prepared the manuscript, I immersed myself in the literature, reading countless papers, trials, pre-clinical studies, and reviews on interventions that could help prevent cerebral palsy. This extensive reading allowed me to write a comprehensive introduction and discussion section for our paper, and I even synthesized a beautiful diagram on BioRender, that depicted the mechanisms involved.

However, we faced another challenge: determining how much the marker levels actually decreased during pregnancy. The studies didn’t report raw values; instead, they used various transformations like log transformations and multiple of medians (MoM). I remember having long meetings with professors and statistician colleagues to discuss how to back-transform these values. We spent many days and even delved into Higgins' original papers published decades ago, and tried multiple statistical techniques. Unfortunately, that didn't land us anywhere. However, we ultimately decided to analyze the marker level differences using MoM units, which are widely accepted in the literature.

Yet again, we hit a roadblock—one of the studies had a confidence interval of 1.04-1.04 (MoM), which meant it provided infinite evidence for meta-analysis, causing our R program to exclude it. I was determined to include this study, so I reached out to the study’s author, Dr. Mads Langager Larsen in Denmark. I honestly didn’t expect a response, especially given that I was still a medical student at the time, which sometimes left me feeling uncertain about myself. I sometimes wondered, "Vinay, are you stepping into forbidden territory? This is meant for experts in the field!" But despite those thoughts, I persisted, anyway. I reminded myself that it was all for the greater good of humanity. To my surprise, Dr. Larsen responded within 24 hours! He emailed the data with up to six decimal places!.. which allowed us to complete our analysis.

Another moment of euphoria came when, through a colleague ( Mainak Bardhan ), I managed to invite Dr. Sheffali Gulati, a legendary child neurologist from AIIMS Delhi, to contribute to our paper. Dr. Gulati had authored chapters in the O.P. Ghai textbook of pediatrics that I was studying at the time. In fact, it is read by medical students across the country. She had even written the chapter on cerebral palsy— making it a "dream come true moment" for me.

I also invited experts in the field, including my neurology professors and mentors (Dr. R.K. Garg and Prof. H.S. Malhotra) and our pediatric neurology specialist (Dr. Areesha Alam) for their critical input.

I can't thank everyone in the team enough for their contributions to this seminal paper.

I genuinely hope this research can bring about drastic changes in the field and improve the lives of millions of children who are going to be affected by cerebral palsy.

Other team members: Shiva Gupta , Yashita Khulbe , Muhammad Aaqib Shamim , Dr. Vaibhav Jain , Malavika Jayan , Madeeha, Neha Joe , Vivek Sanker , Aravind Gandhi P , Dr.Priyanka Roy , Mainak Bardhan

Now, many people ask, "So, we identify a risk during pregnancy—what next?" There are also many doubts about cerebral palsy. Here are a few key points I'd like to highlight:

• Understanding Cerebral Palsy: Cerebral palsy has a complex etiology. Contrary to popular belief, “birth asphyxia” is not the predominant cause of CP. Many factors contribute to its development, including antenatal factors during pregnancy. A comprehensive overview of this can be found in this Nature paper: https://www.nature.com/articles/s41582-018-0043-6

• Early Identification: Currently, CP is fully diagnosed only 1.5-2 years after birth through clinical assessment (abnormal motor function) and neuroimaging (MRI). Our study has pushed back the timeline for identifying CP risk to the 1st and 2nd trimesters (i.e MUCH BEFORE birth)!! Try fathoming the significance of that!
• Intervention: Once we identify the risk, what can be done? While there is no definitive cure for CP, there are interventions that can help. One such approach is therapeutic hypothermia, which involves cooling the brain shortly after birth to prevent further injury. Other interventions could include neurosteroids and even magnesium sulphate for neuroprotection (increased doses maybe? we need trials on this). There are treatments like creatine and allopurinol which are under investigation in ongoing trials. Most importantly, early intervention with physiotherapy is critical, as initiating it as soon as possible can significantly enhance developmental outcomes for the child. Also, providing parents with information about the risk of CP well before birth is crucial. This early communication allows families to prepare more effectively, plan for their child's future needs, and address the associated financial considerations.

I can't fully express how elated I am about this discovery. I hope it touches and improves the lives of millions for generations to come. I've always aspired to conduct impactful research, and I feel incredibly fortunate to have achieved this!

Here is the link to our paper: https://www.pedneur.com/article/S0887-8994(24)00280-7/abstract