A new publication and an editorial address some of the issues around whether we can predict outcomes in preterm infants.
This was a large cohort study from the NICHD network, the usual multi-multi-multi-author paper, 34 authors wrote this paper apparently, Hintz SR et al: Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants. Pediatrics 2014. There were 480 infants of less than 28 weeks who were enrolled in the SUPPORT trial (from 16 of the 20 SUPPORT centers), they had early head ultrasounds, late head ultrasound near term, and MRIs close to term. Then followed up with standardized neurodevelopmental testing. 10% had major anomalies on early ultrasound, 6% on late ultrasound. 20% had MRI white matter injury defined as moderate or severe, and 16% had cerebellar lesions seen on MRI.
The authors showed that if you have imaging brain abnormalities you are more likely to have adverse outcomes. There are many p-values less than 0.001.
Which is hardly surprising.
They show that early head ultrasounds are of little value when you take into account clinical factors and late findings. They also show that
a substantial proportion of children with adverse late Cerebral US or MRI findings in our cohort did not have severe adverse outcomes at 18 to 22 months, emphasizing that neuroimaging must not be used in isolation to predict outcomes.
To me this is the most important finding of this study.
But first lets look at early ultrasound findings: of those without a major finding on a 4 to 14 day ultrasound, there were 6% with “neurodevelopmental impairment”; of those with a serious hemorrhage or cystic PVL there were 28%. If we make that a ‘glass half-full’ statement, that means that if you have serious early ultrasound findings there is a 72% probability that you will not have “impairment”.
Late imaging findings were more strongly associated with “impairment”, but only the 18 babies who had severe MRI white matter injury were really any different in terms of outcomes (the babies with moderate abnormalities don’t seem much different to those with ‘normal MRI’), and among those babies, half had serious cerebral palsy and 22% had Bayley 3 cognitive scores below 70, (in other words, 78% of infants with severe white matter abnormality on late MRI did not have low cognitive scores on Bayley 3 testing).
The positive predictive value of cerbellar lesions was also very poor, 10% of infants with cerebellar lesions had moderate to severe cerebral palsy, and 15% had cognitive scores below 70.
Late head ultrasounds, (scored as abnormal in the presence of a shunt, moderate to severe ventricular enlargement, cystic PVL or a porencephalic cyst), were to my eyes, just about as good (or bad) as an MRI; with PPVs ranging from 23 to 50%.
What does all this mean in clinical practice? I think we should, as the authors of this study state “re-evaluate the practice of early head imaging” in very preterm infants. I think the data also suggest that we should “re-evaluate the practice of late head imaging”! We should continue to examine closely why we are doing such studies, what we want to get out of them, and how we inform parents, both for prior consent and after we have the result.
An editorial accompanying the study asks many of the same questions, as Eric Eichenwald states, “we need to understand the potential impact of of our predictive uncertainty on the parents of these vulnerable infants. …neuroimaging techniques.. cannot yet be used to determine follow-up strategies or target interventions after discharge and thus may be of little or no benefit to many parents.” (and he references the article by Annie and me!)
I think an objective evaluation of the usefulness of these tests for predicting outcomes in individual babies would lead to the inescapable conclusion that they are close to useless. Sometimes worse than useless, as they give false reassurance, or create false anxieties.
Both early and late head imaging fail to satisfy any of the criteria for a useful screening test. We should consider limiting early head ultrsound to use for detection of treatable lesions, and later imaging for research purposes only, with extensive informed consent to ensure that parents are well aware of the limitations of both MRI and near term head ultrasound.
Neonatal Research 
So, as a non-neonatologist, I’m curious about the current “standard of care” or, if you will, “conventional practice” in most NICUs today. Is it the case that ultrasounds are ordered on all babies, by an implicit or explicit protocol? Or are they ordered based on a clinical judgment that the baby has some problems that might be explained by the finding of a brain bleed. To put it another way, are the “screening” tests (quotes, there, because it isn’t clear what, exactly, is being screened for.)? Or are they diagnostic tests? And how much practice variation is there in the use of US in different NICUs?
In most NICUs the standard is to follow the American Academy of Neurology guidelines (endorse by th AAP), which recommend a head ultrasound between 7 and 14 days for all infants less than 30 weeks gestation. They specifically state ‘for VLBW preterm infants ultrasounds should be used to predict long term neurodevelopmental outcomes.’ I really don’t understand what they mean by that phrase, what are you exactly supposed to do? The data to support it have similar positive predictive values to the NICHD NRN data.
Many (I think most, but there is some variability) also perform earlier ultrasounds around 3 to 5 days, and they are usually done as screening rather than diagnostic tests. Occasionally a baby with a rapid fall in hemoglobin, or unusual neurological signs will have an ultrasound for more diagnostic reasons, but most often they are done as a screen.
I think people are screening for ultrasound indices of brain injury, without clearly analyzing the PPV of the abnormalities that might be found.
I find this topic intriguing. My 790 g baby born at 26 w 0 day gestation had only a grade 1 IVH on her initial head ultrasound. Another ultrasound was performed before discharge (three months later) and the IVH resolved. It was predicted that we were one of “the lucky ones”. Our baby was going to catch up quickly and easily by two. We were even connected with another family of a twenty six weeker that did.
A few months home, a nightmare slowly unfolded. Our baby missed all of her motor milestones. She had torticolis, her hands were fisted longer than most babies, and she hardly moved. No one had talked to us about CP or neuro issues in the NICU. I had no idea what was wrong but I knew it was something. I asked that other preemie family and they said, “I know it’s hard not to worry but she will be fine.” I thought I was going crazy.
I searched in a neonatalogy textbook for ideas of what could possibly be wrong. It looked like CP. But, I’m not an expert and I didn’t want to get ahead of myself. I decided to bring it up at the next peds appointment. The pediatrician was testing my baby’s reflexes and had a perplexed expression as she looked at her. I blurted out, “Do you think it could be CP?” She breathed a sigh of relief and nodded. She added, “But, it’s not my specialty. So let’s wait to see what the specialist says.”
Anyhow, long story short. At eighteen months, my baby received her CP diagnosis. It wasn’t a big shock. I knew it was coming from the moment I asked the pediatrician. I think the most difficult part, for me, was being ill prepared for it. The surprise was like experiencing another loss again (first lost being having a micropreemie). I don’t think it would have been that way had we been prepared for it.
Most recently, my baby (now toddler) had an MRI at 31 months. The developmental pediatrician suspected and expected to find PVL due to the motor issues. Her MRI found no abnormalities. It’s a mystery to me. When we go back to the NICU reunions, we see babies who were sicker than my baby who are further along in “catching up”.
I apologize for the long rambling comment. She’s doing well. She will get there in her own time. It has just taken and will take significant time and effort. I still consider us one of “the lucky ones”. Just not in the way the NICU doctors intended.
Thanks for the comment, it is stories like yours that emphasize how poor we are at predicting motor delay, and cerebral palsy in individual babies. And we are even worse at predicting cognitive delay, or intellectual disability.
I think that most parents feel, like you, that they are lucky to have their lovely children with them, even when they face extra challenges in their lives. Facing and, hopefully, overcoming such challenges can be a source of joy as well as heartache.