Every parent the world over waits for that moment after birth when they first hear the cry of their child. The cry is a sign of health, of vigour and a relief that all should be ok. I had never questioned when the infant cry develops but one thing is for sure, it doesn’t matter whether you are born at 25 , 30 or 37 weeks, the babies all seem to make it after delivery. Much like suck, rooting and swallowing which we know begin in utero as we can see fetal swallowing movements the question is does cry begin in utero.
Evidence for an In-Utero Start
Before I get into the answer to this let me address the title question. A cry is produced as a baby exhales and moves air in a turbulent fashion across the vocal cords. Since a fetus is not breathing air it would seem impossible for a cry to be produced by a fetus. It doesn’t mean though that a fetus can’t try to at least practice and get ready for birth.
Back in 2005, a research team from New Zealand sought to answer this question in their paper Fetal homologue of infant crying. The authors described a case of a 33 week infant who was exposed to an artificial larynx generating a sound on the maternal abdomen while she was undergoing an ultrasound. The artificial larynx produced a vibroacoustic stimulation (VAS) after first keeping monitoring the fetus with ultrasound for a period of 20 minutes. The duration of the VAS was for 40 seconds and during this time the fetus was found to turn its head upon hearing the VAS and appeared to startle.
As per the authors the fetus underwent the following steps after the stimulation.
“There is a brief expiration that is followed by a deep inspiratory phase with a subsequent pronounced expiratory phase. This expiration is associated with jaw opening, taut tongue, and chest depression (fig 2). It is immediately followed by three augmented breaths with progressive increase in chest rise and head tilt (fig 3).”
At the end of this episode the chin was found to be quivering. This as I see it is the best and first description of fetal crying. While it doesn’t make a sound I believe at least that this is the beginning of an important step in development that will prepare the infant after birth to clear its lungs and inflate them with air.
The question now I ask is when does this develop? As I mentioned earlier the ability to cry is definitely present in preterm infants at pretty much any gestational age I have seen all the way down to 22 weeks. Much like other reflexes present at birth and the swallowing function mentioned earlier this must develop for a reason and I am hopeful that future work will uncover when this first appears and eventually add an explanation of what function this in-utero crying movements serve!
For commentary on this including a video of the first and second cry for this infant have a look at the full video below
I couldn’t think of a better topic for World Prematurity Day 2021 than what constitutes the edge of viability. Thinking back over my career, when I was a resident and fellow infants born at 25 and 26 weeks were deemed about as low as “we should” go but we certainly resuscitated infants at 24 weeks but this was considered heroic. Jump ahead to the last decade and we began caring for infants at birth at 23 weeks so commonly that the thought of offering comfort care only to infants at 24 weeks became almost unthinkable for many health care providers. Before I get jumped on, let me say that I am not saying I agree or disagree with that sentiment but it is something that is felt by many.
The Shared Decision Model
In the last few years a rethink again has occurred whereby the concept of the treating team knowing best has been replaced by the “shared decision model”. In this line of thinking, it is not up to us as health care providers to “tell the parents” what to do but rather come to a shared decision based on an assessment of the wishes and values of the parents in conjunction with hearing about both short and long term problems their infants may face if resuscitated. This concept was central to the statement by the Canadian Pediatric Society that I am proud to have been part of with respect to its development. The statement for those that are interested is Counselling and management for anticipated extremely preterm birth
What’s next? Going below 22 weeks?
The challenge of the shared decision model is that there comes a point where the answer is simply “no”. If for example a family at 19 weeks gestation demanded an attempt at resuscitation I would have to inform them that survival is not possible (assuming ultrasound confirmed anthropometric measurements consistent with that age). The question though becomes a little more difficult to answer at 21 weeks and was the subject of a recent article in the New York Times about a survivor at 21 weeks gestation.
Even with the best gestational age dating the estimate can be off by up to 5 days so it’s possible that the infant in this story was closer to 22 weeks or even midpoint between 22 and 23 weeks in reality. Regardless it does raise the question about what to do at 21 weeks and I suspect we will begin to see more stories about this now that the glass ceiling of 22 weeks has been breached. What about below 21 weeks? Sounds impossible I know but with research that remains at the stage of animal studies this may become possible. Maybe not in the next 5-10 years but it could happen in my lifetime in this chosen field.
The Artificial Placenta
This made headlines a few years ago with the news that the Children’s Hospital of Philadelphia had successfully kept a lamb alive for a period of 4 weeks using an artificial placenta and amniotic fluid.
You might think that this was a one-off experiment that will never see the light of day but similar work is being done in Toronto, Canada where they have been able to do similar work with preterm piglets in their paper Achieving sustained extrauterine life: Challenges of an artificial placenta in fetal pigs as a model of the preterm human fetus. Incidentally as my colleague Dr. Ayman Sheta worked on this project while in Toronto I am particularly pleased to share this research. Similar to the experience in CHOP the team in Toronto has been able to keep piglets alive for progressively longer durations. My understanding is that despite the best efforts infectious complications over arise limiting how long one can sustain such animals.
This leads me to my final thoughts on where we might be able to go. I see a future where we apply such technology to humans but not in the way that people might have thought. Keeping a fetus after delivery at 21 or 20 weeks on an artificial placenta for many weeks is not likely a realistic goal. What if we could get 1 or 2 weeks though and allow the fetus to be oxygenated without using positive pressure on their developing lungs and transition them at 23 or 24 weeks gestation? We may in this way be able to allow for postnatal maturation in a artificial uterine environment and give babies a chance who would otherwise never had the opportunity for a shared decision with medical staff.
Sound like science fiction? Well the beauty of the internet as my friend told me today is that once it’s out there it out there for good. Let’s see how this post stands the test of time and to all the babies out there in NICUs and to their families I wish you all a good and uneventful World Prematurity Day wherever you may be!
Before getting in to what they did it is important to understand how the mRNA vaccines work as the antibodies that one can look at in mothers and babies are of two types. The mRNA vaccines instruct the body to make anti-bodies against the spike protein (S antibodies) which forms the basis of how the vaccine helps our bodies identify the virus and then destroy it. For those who have actually been exposed to the virus and are not vaccinated, they develop a second antibody to the nucelocapsid protein (N antibody) which is within the viral core so this type will only be present in people who have been infected with the virus and their immune systems have dealt with it on their own. This is an important distinction as it allows you to create pure samples of people who have had the virus as a true infection and those who have been vaccinated and finally those who are neither.
Comparing Three Groups
So the authors here decided to compare three groups of women. Eighty three cord blood samples were divided into three groups (from the paper quoted) based on IgG antibody titres.
Group 1 included 29 samples (37%) from women who were infected with SARS-CoV-2 during pregnancy. Twelve had RT-PCR confirmed Covid-19 infection: three were infected in the first trimester, three in the second trimester and six in the third trimester. The other 17 had no clinical signs of SARS-CoV-2 infection during pregnancy and had a positive serologic test on admission. None of the 17 women had active SARS-CoV-2 infection at the time of delivery. Group 2 included 29 samples (37%) from women who were vaccinated against SARS-CoV-2 in the 3rd trimester.
Group 3 included 21 women (34%) and served as controls.
Looking at antibody levels in Group 1&2, 100% were positive for S antibodies. Interestingly, in group 1, 4 women did not test positive for the N antibody (3 were asymptomatic and one infected in the 1st trimester). In group 3 none of the women tested positive for any antibodies confirming they were neither vaccinated or had the infection previously.
Looking at mean antibody S titres there was a significant difference found in that Group 1 had a mean of 83.7 U/mL vs 225.5 U/mL for the newborns whose mothers were vaccinated. Also notable was the relationship (not surprisingly between antibody levels in the mother at the time of delivery and newborn cord blood titres.
There was a linear correlation between the level in the mother and the level found in the newborn with higher levels presumably better for protecting the infant. Having said that, no infants in this study had neonatal COVID infection. Detractors would be quick to point out that this indicates it doesn’t matter if you get the vaccine since all babies were ok but remember although this may be the biggest study looking at antibodies in cord blood it remains a very small sample and neonatal infection although reported, remains a very rare occurrence.
The Other Side
If you have followed my coverage of the COVID saga from the start you would know that I am in favour of vaccination and in pregnancy as well. The results of this study are encouraging but we need to compare apples to apples. This study compared women who were vaccinated in the 3rd trimester to women who were infected at earlier time points and may have been sick or asymptomatic. The lower antibody levels found in group 1 could represent declining titres as the infection becomes more remote. What we also don’t know is what they antibody levels would have looked like in group 2 if the mothers were vaccinated in the 1st or 2nd trimester as this is now happening. Would the levels be similar? They just might be as the antibody levels do decline with time. We rely on memory cells to reactivate our antibody producing cells if the virus comes along again.
I am not saying this study is meaningless but be prepared if you quote this study for vaccine hesitant to point out that you are comparing recent vaccination to potentially mild cases or remote infections. What is clear and hopeful though is that your newborn is protected by antibodies you make in pregnancy from vaccination at very good levels and until we can vaccinate babies this is the greatest protection we can offer.
Extubation is a regular occurrence in the NICU. We do our best to predict who will succeed and who will fail but it isn’t always easy to figure out who they are in advance. We use techniques such as looking at oxygenation histograms and using thresholds for PIP, PEEP or MAP but in the end sometimes it works and other times it doesn’t. In an effort to improve on intubation success, some creative researchers in Switzerland employed a technique called end-expiratory lung impedance or EELI to measure lung volume before, during and after the extubation process. The use of EELI is based on the impendance of the lung changing with the distribution of tissue and air and by placing electrodes one can generate a cross sectional volume that has been shown in neonates to be representative of total lung volume. The EELI technique creates an image like this which is use to generate the estimate of lung volume.
The researchers in this study were seeking to do a quality improvement project and use EELI to estimate lung volume at different time points in an extubation. The time points were all 30 seconds including, immediately before first handling of the infant (baseline), tracheal suctioning (suction), start and end of adhesive tape removal (adhesive tape begin and adhesive tape end), pulling the endotracheal tube (extubation), initiation of non-invasive ventilation (NIV), immediately before and after turning the infant to prone position (supine and prone, respectively), and 10 min after turning to prone position (prone10). As per unit policy all babies were ventilated with Draeger VN500 ventilators and if <28 weeks went on to NIPPV when extubated or if 28 weeks or more straight CPAP. The purpose of this quality initiative was to determine using EELI at what point in the extubation process infants might be losing lung volume and then based on the information see if they could ultimately use this to improve the chances of successful extubation in the future.
What makes this study interesting is that the infants were found to lose volume but at a time when I would not have expected it.
Below is a graphical depiction of EELI and estimates of FRC during the different time points. The changes in electrical impedance by EELI were converted on the right Y axis to an FRC in mL/kg.
What is surprising at least to me here is the loss of volume occurs not with extubation but rather when the tape removal process happens. With the placement of the prongs on the infant at extubation the FRC gradually rises and recovery occurs. Moreover as shown in the 12 patients included in this study, the recovery once non-invasive ventilation is provided is quite rapid and evident within 1-2 breaths.
A couple other things to note. The loss of FRC during tape removal was about 10 mL/kg and if typical FRC in a preterm infant is 20-25 mL/kg you can see the impact this would have on lung volume and reserve. As this was a small study it could not detect a threshold at which extubation would fail but one infant who developed a pneumothorax and required reintubation did not get back to their baseline FRC.
What is this signaling?
Yes this is a small study but it did look at about 3000 breaths so there is a fair amount of data to look at. What the paper demonstrates I think is that there is a vulnerable time during tape removal where likely due to the fact that we use uncuffed ETTs in neonatology it is possible for these infants to lose lung volume. It may be that as they strain and bear down the ventilator may not be as effective at delivering volume to them. Measures that might help during this time could be skin to skin care, breastmilk drops or scent, sucrose or a variety of other non-pharmacologic measures to keep them calm. This might help to minimize such volume loss. Secondly, knowing the significant risk of volume loss it underlines the importance of placing nasal prongs on as quickly as possible during the transition from invasive to non-invasive ventilation as recovery of lung volume is possible. It think it also suggests that if we are “peepaphobic” and use an insufficient amount of support at extubation these infants may be vulnerable to experience significant volume loss as well.
While EELI may not be perfect, this study is the first of its kind and may shed some light into why some infants fail after extubation. While usually I say less is more, I do wonder if in the case of extubation, this study gives some evidence to support starting with a higher PEEP than you think you need non-invasively and then backing off after one has successfully extubated. This may be the first study I have seen on this but I am certain it won’t be the last.
I have written a lot over the years on the topic of BPD. It isn’t by chance as it is a condition that Neonatologists have put a lot of weight on. In many ways it is a benchmark that is often the go to condition when comparing one unit to another. When two Neonatologists get together their first question isn’t what’s your rate of ROP or severe developmental delay but more often comparing rates of BPD. We like to compare this as a metric as it’s something we can see as compared to say rates of late onset sepsis. You can see a patient on a ventilator or on CPAP at 36 weeks but you can’t see bacteria coursing through veins.
Not all BPD is the same though. in 2000 the NIH produced a new consensus definition of BPD as shown below.
What stands out for the babies <32 weeks is how severe BPD is defined. Babies who are ventilated are classified in the same severity group as those who are on CPAP. Somehow that doesn’t seem quite right intuitively but alas that is what they decided at the time.
Type 1 sBPD: patients on nasal cannula or noninvasive positive pressure support (i.e., high flow nasal cannula (HFNC), nasal continuous positive airway pressure (nCPAP), noninvasive intermittent positive pressure ventilation (nIPPV)) Type 2 sBPD: infants receiving iMV
The authors then looked at a sample of 564 patients from 2015-2019 in the BPD collaborative registry and subdivided them into 429 (76%) Type 1 vs 135 (24%) Type 2 sBPD and compared outcomes between the two. The differences between the two types of BPD are quite significant and shown in Table I. Babies who went on to develop sBPD as Type 2 were younger and smaller than those with Type 1. Medication use within the NICU and after discharge was markedly different as were the total ventilator days which is likely not surprising since by definition they were still intubated at 36 weeks. Importantly if you were still intubated at 36 weeks PMA almost one quarter of the patients went on to receive a tracheostomy.
Looking at it another way using relative risks the signifance of having Type 2 sBPD is impactful.
Taking Meaning From This
You might be quick to say, Michael this is absolutely no surprise. On the other hand if you have read this blog for some time you may remember this piece The New BPD That Matters. This study looked at what gestational age really mattered when looking at long term pulmonary outcomes in a Canadian cohort. When you take all comers it was 40 weeks and not 36 weeks that really mattered. The likely differernce here though is that by selecting out only the severe patients in this current study it is indeed the 36 week mark that still has relevance. I actually think the two papers together are not contradictory but rather additive.
What I think one takes away from the current study is that failure to extubate by 36 weeks does in fact carry with it significant long term risk to the patient. It would be easy enough to say that these babies should be extubated but as you see from table I it isn’t that they didn’t try. From a medication standpoint it would appear that they ” threw the kitchen sink” at these babies. The only thing I find a little surprising is that only 47% of babies in the collaborative with type 2 sBPD received systemic steroids. If they were that sick I would have expected it to be higher although that also may just be a reflection of my own practice.
One thing that I think will be a hot topic moving forward is the use of higher levels of CPAP than what many units are accustomed to. This has also been recently discussed in High CPAP vs NIPPV. Is there a winner? There may be a reluctance by some units to use CPAP levels in the +9-12 cm H2O range but when looking at these downstream complications for patients who remain ventilated at 36 weeks I think people need to seriously consider their biases and whether they are based on science or what they were taught. I can’t help but think of the oft used expression absence of evidence is not evidence of absence and think that if we can all be a little humble who knows what we may discover that can help this population.