As awful as COVID19 has been over the last year and a half one thing has continued to perplex myself and others. Why do babies whethe term or preterm so rarely acquire the virus? Numerous studies have been able to document placental changes and infection of these tissues. On rare occasions reports have come out with evidence of neonatal infection but fortunately most are mild.
These findings have in large part contributed to the Canadian Pediatric Society practice points on three topics.
In this post an argument was made that the reason these infants are resistant is due to low levels of ACE-2 receptors in the nasal mucosa of children. In this study children as young as 4 years of age were found to have very low levels of this receptor (portal of entry for SARS-CoV-2) into the host. I speculated at the time that if one carried forward the findings to younger children and infants you might find there were hardly any receptors at all.
Well, someone finally did the study and confirmed what I suspected. The study report is entitled Nasal expression of SARS-CoV-2 entry receptors in newborns by Heinonen S et al. It’s not a big study but the results are consistent across 28 newborns (17 term and 11 preterm) and 10 adults. In each newborn whether term or preterm a nasal mucosal scraping was performed at 24 hours of age and used to measure by reverse-transcription quantitative PCR mRNA expression of ACE2, transmembrane serine protease 2 (TMPRSS2), neuropilin 1 (NRP1) and neuropilin 2 (NRP2) and insulin-like growth factor 1 receptor (IGF1R).
What the results show you is that babies are not just small adults. They are different yet preterm do not seem to be that different than term infants in terms of receptors. While ACE2 has garnered most of the attention when it comes to receptors for SARS-CoV-2 the others also play a role and are in general expressed to a lesser degree in neonates than adults.
In the previous post I argued what was in your nose makes a difference to your risk of contracting SARS-CoV-2. Really the point is what is not in your nose. Thankfully neonates do not have good expression of these receptors and that may be the biggest reason for the general protection they have from this pandemic. It has certainly a good time to be in the “have not” group!
In the book Outliers by Malcolm Gladwell he talked about 10000 hours being the threshold at which if you practiced or gained that much experience with something you could become an expert. In Sweden the approach to 22 week pregnancies and above is to resuscitate all as a strategy. I wrote about this before in At 22 weeks of gestation does your faith matter most to outcome? The information gleaned from that paper was that if you have a policy of resuscitation at these gestational ages and you compare outcomes to a centre that is selective in who they resuscitate the outcomes are better when you believe all should be resuscitated.
New Study Expands Data
The same group has published this time around the results of the same cohort from 2006-2015 but this time with developmental outcome data. The paper is entitled Outcomes of a uniformly active approach to infants born at 22-24 weeks of gestation In this paper they discuss outcomes at 234 and 24 weeks respectively in addition to the findings for 22 weeks which they covered in the paper mentioned above. The reason for sharing this study is that if I asked you to imagine going into a room right now and talking to a family at 22 – 24 weeks and predicting the outcome of their infant, my hunch is that you would not provide as rosy a picture as the group in Uppsala, Sweden.
The authors looked at a group of infants with the following breakdown by gestational age.
Not surprisingly as gestational age declines the incidence of complications rise but looking at Table 3 even at 22 weeks there was no difference in rate of NEC or need for PDA surgery. Nor was there a difference in rates of severe IVH/PVL. Rates of BPD were higher and likely attributable to the longer durations of positive pressure ventilation. Are these rates for these complications terrible though when the other option is non-intervention which for certain means death?
What about outcome?
Looking at the outcome at 2.5 years, the rate of cerebral palsy is about 1:10 to 1:20 for all GA. Hearing impairment is almost non-existent and while developmental delay is detected in 50 percent of survivors at 22 weeks only about a quarter of the infants have severe impairment.
Deciding what to do
There is no question that many of you seeing what this post was about would simply say “NO WAY” but in the end isn’t it really about a shared decision with the family? It wasn’t that long ago that we had to have a real paradigm shift in thinking about resuscitating 23 week infants. The amount of mental energy spent for teams worldwide coming to this decision was tremendous and now if you were to suggest compassionate care at 24 weeks you get a look back like you are crazy! It wasn’t that long ago that 24 weeks was considered viability in many places and now that 23 is the new 24 this is the struggle some people have now. Should we go to 22 weeks everywhere as the Swedes have? Clearly this is a decision that institutions need to look at critically and determine if they have the space to accomodate. Each infant should they survive will occupy a bed for at least 6 months. This needs to be looked at before one can just say sure this is a good idea.
In the end what the study demonstrates I believe is that the outcome at 22 and 23 weeks for that matter need not be universally dismal. There certainly is a good chance that a surviving infant will have one or more deficits but in the end I would advocate this is a conversation all units need to be having and critically look at whether each institution has the capactity to consider.
My bet is that five years from now this discussion will be moot as we will be mostly in that direction but at this time I think we are still in evolution.
Private room vs open bay for the NICU. Can always get a quote from a parent saying it is great but….? At what cost? Impact on staff? Is parent time in those NICUs greater now? Other alternatives?
Included in the post was an article discussing the benefits of such a design. Below I will look at the benefits and risks and conclude with an answer to his last question.
The NICUs of the 1970s through late 1990s have been described as “barn like” or “open concept” but in recent years the belief that single patient rooms (SPR) would offer greater benefit to infants led to the adoption of such a unit design across North America. The imagined benefits would be related to improved parent comfort, creating a desire for families to spend more time with their children. As we move to a “family centred” approach to care, a key goal of all units should be to make their families as comfortable and stress free as possible in order to have a positive experience.
Detractors meanwhile, speak of concern regarding isolation of such infants when families do not visit and moreover a risk that such infants deprived of sensory experience will have impaired development. Last year a paper was published that did not help quell such fears; Alterations in Brain Structure and Neurodevelopmental Outcome in Preterm Infants Hospitalized in Different Neonatal Intensive Care Unit Environments (full article in link). This study which compared infants cared for in SPR to an open unit (the hospital in this study had a mixture of both in their NICU) found a worrisome finding at 2 year follow-up in that the infants in SPR had lower scores on language and a trend towards lower motor scores as well. Additionally, partly explaining such findings may have been differences noted at term equivalent age in both the structure and activity of the children’s brains compared to those cared for in an open environment. We were starting construction on a new NICU at the time this paper was published and I can tell you the findings sent shockwaves through our hospital as many wondered whether this was the right decision.
Devil Is in The Details
Looking further into this study, the urban population bore little resemblance to our own. In our hospital all women are taught how to perform skin to skin care and the majority of our mothers spend a great deal of time with their infants. To see how successful have a look at our recent Kangaroo Care drive results! The families in this study however the average hours per week of parent visitation over the length of stay ranged from 1.8-104 hours with a mean of 19+/- 19 hours. The average number of days held per week over the length of stay was 0-6 days with a mean of 2.4 +/-1.5 days. The average number of days held skin-to-skin over the length of stay ranged from 0-4 days, with a mean of 0.7 +/- 0.9 days. In short they were hardly there.
Statistically significant results (all Ps ≤.05) showed that infants in the SPR NICU weighed more at discharge, had a greater rate of weight gain, required fewer medical procedures, had a lower gestational age at full enteral feed and less sepsis, showed better attention, less physiologic stress, less hypertonicity, less lethargy, and less pain.Nurses reported a more positive work environment and attitudes in the SPR NICU.
This study in fact demonstrated greater maternal involvement in a SPR with improvement in outcomes across the board. It would seem then that in a SPR environment, provided there is enough family visitation and involvement this model truly is superior to the open concept. Furthermore despite concerns by some nurses that the loss of line of sight to their patients will make for a more stressful working environment this does not seem to be the case.
What About Families Who Cannot or Simply Aren’t Visiting Frequently?
The reality is that there are many reasons for parents to be absent for long periods during their newborns stay. Having a home outside of the city with other children to care for, work obligations, or loss of custody and abandonment due to apprehension are just some of these reasons. In our hospital, at least 15-20% of all patients admitted are from outside Winnipeg. The evidence as I see it supports the move to a SPR but what do we do for those children who need more visitation? The solution is a cuddler program. In our new hospital we are grateful for the generosity of our Children’s Hospital Foundation who secured a donor to pay for a coordinator of such a program. The veteran parent who is leading this program ensures that no infant goes beyond a set period of time without feeling the touch or hearing the sound of a voice. Such a program is in fact already in place at our other tertiary hospital and was featured in a lovely article attached here. Taking all the information together that is out there I think that if we can provide the necessary stimulation from both touch and auditory stimuli as well we can provide these infants with the developmental needs that each of them requires.
The SPR is the right design in my mind for families with many benefits that spring forth in such an environment. This need not be a win-lose scenario for your hospital. Do not underestimate the power of a cuddler and don’t hesitate to seek support to initiate such a program. It could mean the difference from going from good to great!
We have all been there. After an uneventful pregnancy a mother presents to the labour floor in active labour. The families world is turned upside down and she goes on to deliver an infant at 27 weeks. If the infant is well and receives minimal resuscitation and is on CPAP we provide reassurance and have an optimistic tone. If however their infant is born apneic and bradycardic and goes on to receive chest compressions +/- epinephrine what do we tell them? This infant obviously is much sicker after delivery and when the family asks you “will my baby be ok?” what do you tell them? It is a human tendency to want to reassure and support but if they ask you what the chances are of a good outcome it has always been hard to estimate. What many of us would default to is making an assumption that the need for CPR at a time when the brain is so fragile may lead to bleeding or ischemia would lead to worse outcomes. You would mostly be right. One study by Finer et al entitled Intact survival in extremely low birth weight infants after delivery room resuscitation.demonstrated that survival for infants under 750g was better if they had a history of CPR after delivery. The thought here is that more aggressive resusctiation might be responsible for the better outcome by I would presume establishing adequate circulation sooner even if the neonates did not appear to need it immediately.
The Canadian Neonatal Network
In Canada we are fortunate to have a wonderful network called the Canadian Neonatal Network. So many questions have been answered by examining this rich database of NICUs across the county. Using this database the following paper was just published by Dr. A. Lodha and others; Extensive cardiopulmonary resuscitation of preterm neonates at birth and mortality and developmental outcomes. The paper asked a very specific and answerable question from the database. For infants born at <29 weeks gestational age who require extensive resuscitation (chest compressions, epinephrine or both) what is the likelihood of survival and/or neurodevelopmental impairment (NDI) at 18-24 months of age vs those that did not undergo such resuscitation? For NDI, the authors used a fairly standard definition as “any cerebral palsy (GMFCS1), Bayley-III score <85 on one or more of the cognitive, motor or language composite scores, sensorineural or mixed hearing impairment or unilateral or bilateral visual impairment.” Their secondary outcomes were significant neurodevelopmental impairment (sNDI), mortality, a Bayley-III score of <85 on any one of the components (cognitive, language, motor), sensorineural or mixed hearing loss,or visual impairment.sNDI was defined as the presence of one or more of the following: cerebral palsy with GMFCS 3, Bayley-III cognitive, language or motor composite score <70, hearing impairment requiring hearing aids or cochlear implant, or bilateral visual impairment”
What did they discover?
It is a fortunate thing that the database is so large as when you are looking at something like this the number of infants requiring extensive resuscitation is expected to be small. The authors collected data from January 1, 2010 and September 30, 2011 and had a total number of infants born at less than 29 weeks of 2760. After excluding those with congenital anomalies and those who were born moribund they were left with 2587. From these 80% had follow-up data and when applying the final filter of extensive resuscitation they were left with 190 (9.2%) who received delivery room CPR (DR-CPR) vs 1545 who did not receive this.
Before delving into the actual outcomes it is important to note that neonates who did not receive DR-CPR were more likely to be born to mothers with hypertension and to have received antenatal steroids (89 vs 75%). With these caveats it is pretty clear that as opposed to the earlier study showing better outcomes after DR-CPR this was not the case here.
The results are interesting in that it is pretty clear that receiving DR-CPR is not without consequence (higher rate of seizures, severe neurological injury, BPD). Looking at the longer term outcomes though is where things get a little more interesting. Mortality and mortality or neurodevelopmental impairment are statistically significant with respect to increased risk. When you take out NDI alone however the CI crosses one and is no longer significant. Neither is CP for that matter with the only statistically significant difference being the Bayley-III Motor composite score <85. The fact that only this one finding came out as significant at least to me raises the possibility that this could have been brought about by chance. It would seem that while these infants are at risk of some serious issues their brains in the long run may be benefiting for the neurological plasticity that we know these infants have.
The study is remarkable to me in that an infant can have such a difficult start to life yet hope may remain even after dealing with some of the trials and tribulations of the NICU. Parents may need to wade through the troubling times of seizures, long term ventilation and CPAP and then onto a diagosis of BPD but their brains may be ok after all. This is one of the reasons I love what I do!
As the saying goes, sometimes less is more. In recent years there has been a move towards this in NICUs as the benefits of family centred care have been shown time and time again. Hi tech and new pharmaceutical products continue to develop but getting back to the basics of skin to skin care for many hours and presence of families as an integral team member have become promoted for their benefits. The fetus is a captive audience and hears the mother’s heart beat and voice after the development of hearing sometime between 24-26 weeks gestational age. This is a normal part of development so it would stand to reason that there could be a benefit to hearing this voice especially after hearing has developed and the fetus has grown accustomed to it. Hospital including my own have developed reading programs for our patients and some companies have developed speakers in isolettes designed to limit the maximum decibel to 45 but allowing parents to make recordings of their voices. Music may be played through these speakers as well but today we will focus on the benefit of voice.
Could reading to your baby reduce apnea of prematurity?
This is the question that Scala M et al sought to answer in their paper Effect of reading to preterm infants on measures of cardiorespiratory stability in the neonatal intensive care unit. This was a small prospective study of the impact of parental reading on cardiorespiratory stability in preterm NICU infants. Eighteen patients were enrolled who were born between 23-31 weeks gestation. The study was carried out when the babies were between 8-56 days old at a mean postnatal age of 30 weeks. Each patient served as their own control by comparing episodes of oxygen desaturation to <85% during pre-reading periods (3 hours and 1 hour before) to during reading and then 1 hour post reading. Parents were asked to read or create a recording lasting a minimum of 15 min but up to 60 min of recorded reading. The parents were offered a standard set of books that had a certain rhythm to the text or could choose their own. Recorded reading was played for infants up to twice per day by the bedside nurse. While it was small in number of patients the authors point out that the total exposure was large with 1934 min of parental bedside reading analyzed (range 30–270 min per infant, mean 123, median 94 min). Patients could be on respiratory support ranging from ventilators to nasal cannulae.
Was it effective?
It certainly was. I should mention though that the authors excluded one patient in the end when it was found that they failed their hearing screen. Arguably, since the infant could not have benefited from the intervention effect this makes sense to me. As shown from table 3 there was a statistical reduction in desaturation events during the reading period which was sustained in terms of a downward trend for one hour after the intervention was completed. In case you are asking was the difference related to oxygen use the answer is no. There was no difference in the amount of oxygen provided to patients. While the events were not eliminated they were certainly reduced. The other point worth mentioning is that there appears to be a difference between live (through open portholes) vs prerecorded reading (through a speaker in the isolette).
Now for a little controversy
Does source of the reading matter? The authors found that maternal had a greater effect than paternal voice. As a father who has read countless books to his children I found this a little off-putting. As a more objective critic though I suppose I can buy the biologic plausibility here. I suspect there is an independent effect of voice having a positive impact on development. If we buy the argument though that the voice that the fetus has most been accustomed to is the mothers, then the findings of an augmented effect of the maternal voice over fathers makes some sense. I will have to put my ego aside for a moment and acknowledge that the effect here could be real.
There will no doubt need to be larger studies done to drill down a number of questions such as what is the ideal type of reading, duration, rhythmic or non etc but this is a great start. I also think this falls into the category of “could this really be a bad thing?”. Even if in the end no benefit is shown to this type of intervention, the potential for family bonding with their preterm infant alone I think is cause for embracing this intervention.