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!
In NICU we are always vigilant for infections. Bacterial sepsis is not uncommon and in fact in the latest 2020 Canadian Neonatal Network annual report, 9.4% of all babies across Canada born at < 33 weeks gestation experienced an infection after 3 days of age. Looking at the rate of infections in those with central lines (Central Line Bloodstream Infection or CLABSI the rate was 2.9/1000 line days. Infections in NICU are not surprising given that these infants often have need for vascular access and needle pokes breaking the skin and have a somewhat fragile immune system associated with premature birth. There are many strategies to reduce infection risk in the NICU but one in particular that has been around a long time is cleansing of the skin before any skin breaking procedures are performed such as for blood draws. Options exist for cleaning in terms of solution and whether it contains alcohol or not. A common skin antiseptic used is chlorhexidine which comes available as a 2% or 1% solution and with or without alcohol. The babies in particular who are our smallest may be sensitive to the alcohol and may be left with skin burns so for the smallest of infants we often clean without the alcohol containing solutions. What we are going to talk about today though is the use of 2% vs 1% and whether one is any different than the other in terms of effectiveness.
The study was done in India by Sharma A et al and entitled Aqueous chlorhexidine 1% versus 2% for neonatal skin antisepsis: a randomised non-inferiority trial. The authors set out to determine a number of things. The primary outcome was the percentage of negative skin swabs after application of both but they also looked for evidence of harm in terms of skin rashes and chlorhexidine blood levels. The strategy employed was for the investigator to identify a 4cm2 skin area to obtain the pre-antisepsis skin swab from one of the following sites: cubital fossa, dorsum hand or dorsum foot. Each patient could be enrolled again after a 96 hour period of time had elapsed. An alternate site was selected at the time of repeat enrolment. Each patient had a swab of this area done in a specific and repeated way in terms of strokes of the skin and then in a randomized fashion each patient received either the 1% or 2% solution on a swab. The solution was tested by a pharmacist throughout the study to validate the concentration of chlorhexidine (swab was dipped in the tested solution) and then applied in a consistent manner to the skin area. The area was left to dry for 60 seconds and then a second swab taken to determine whether the skin had been cleared of the bacteria that would have been picked up by the swab pre-chlorhexidine. The study set a target of a 5% non-inferiority limit comparing the two concentrations with an expected efficacy of about 90% for a 2% chlorhexidine solution to sterilize an area. This meant that if the efficacy of the 1% solution fell below a 5% difference it would be deemed to not be equivalent to the 2%.
What did they find?
First of all the groups were comparable in baseline characteristics. The babies enrolled in the study ranged from 26 0/7 to 42 6/7 weeks at delivery. As planned the groups; 341 to 1% and 344 to 2% were stratified for analysis into 26 0/7 to 27 6/7, 28 0/7 to 34 6/7 and 35 0/7 to 42 6/7 groups. The means GA and BW for each overall group however were 2018 vs 2029 and 34 vs 35 weeks for 1 and 2% groups.
The table above has all the relevant information from the outcomes of interest. The efficacy of the antiseptics was a bit better than anticipated at 93% for the 1% vs 95.6% for the 2% group. On the surface you might be tempted to jump up and say “ah ha! They are equal”. However when you look at the 95% CI around the estimates you get a risk difference of -2.7% but the lower CI limit is -6.2% so as the authors concluded they are in fact not equal. Looking at the subgroups the number show some differences but only the middle group reached a statistical difference.
Importantly contact dermatitis which was scored by nursing using a standardized approach showed no difference at any time points. As expected some absorption did occur from application of the swabs but there was no difference between the two concentrations of significance although interestingly the higher concentration solution trended lower.
The authors do point out in this study that they did not get the 355 patients they wanted in each group although I have to say it was so close that I don’t believe adding a small percentage more of patients to the study would have been likely to change the conclusions.
Lesson from this study?
I suppose the first thing I take is that I am relieved that since our unit uses the 2% solution I don’t see any need for change. The second thing is that the rate of dermatitis from either solution is limited to about 1/10 babies after application but by 6 hours it is gone. Both have very high rates of successful skin antisepsis but if there is really no contraindication in terms of either skin irritation or high levels of drug in the blood my bias would be to grab onto the extra few percent successes at clearing the skin of bacteria. Even if it only a 3% gain, if we can maximize the cleaning of the skin before we poke a needle through it I think that is the way to go. If there are centres out there using the 1% though and plan on sticking to it I would be curious as to why?
If you work in Neonatology then you can’t help but see babies with jaundice. It is so common in the NICU that I would call it normal. While mild jaundice is part of neonatal life, sometimes levels increase to the point that it can be dangerous to the developing brain and in the short term cause acute bilirubin encephalopathy. Chronic injury can lead to hearing impairment and kernicterus with staining of the basal ganglia and cerebral palsy. Phototherapy has been the mainstay of treatment with exchange transfusion reserved for exceptionally high levels of bilirubin. In recent years people have utilized IVIG when hemolysis is present to reduce the risk of exchange transfusion. There hasn’t been much else that one could use but many years ago, proto-porphyrins (SnPP)were looked at as a class of drug that might help reduce the burden of bilirubin by blocking where the substance comes from. Bilirubin is liberated when heme is broken down by heme-oxygenase so an inhibitor of this enzyme (of which the metallo-porphyrins (Sn-MP)might be the right candidate for the job. While initial trials seemed to show benefit there was a side effect of studies in rats indicated that exposure to Sn-PP (but not Sn-MP) led to photosensitivity if exposed to UV light and phototherapy. Given that the Sn-MP class of drugs didn’t seem to have the same issues an interest in this class of drugs has experienced a resurgence.
Phase IIb clinical trial
In the development of drugs there are different phases of trials. In a phase IIb trial, researchers believing from previous research that there is a treatment effect, perform a larger study using different dosing to see if there is still a benefit. In the case of Sn-MP this was done by Rosenfeld WN et al in their recent trial Stannsoporfin with phototherapy to treat hyperbilirubinemia in newborn hemolytic disease. The trial design included infants with hemolytic disease with 91 patients divided into three groups; 31 controls, 30 receiving a 3 mg/kg IM dose and 30 receiving a 4.5 mg/kg IM dose of stannsoporfin along with phototherapy. The goal of the study was to see whether infants receiving such treatments would experience different trajectories in their levels of bilirubin. In order to standardize things as much as possible, all infants were enrolled once they reached a pre-specified level using the AAP phototherapy curves and underwent serial TsB measurements at 2,6,12,24,36 and 48 hours after study entry.
Phototherapy was standardized based on measurement of spectral irradiance at the skin surface with maintenance of 30 microW/cm2/nm to ensure that each infant received the same level of phototherapy.
I suppose it shouldn’t shock anyone that the drug works as the class of drug was found to work almost 40 years ago! Looking at the three groups over the 48 hour time frame shows a markedly different trajectory for the patients.
From a side effect standpoint, the following was noted:
Is this ready for prime time?
The purpose of sharing this information with you is not to promote it as a treatment that we should all jump on. I think this story is still early. What will be needed from here are larger studies with well designed follow-up targeting long term outcomes. This study will be following up patients to see how they did but larger numbers will no doubt be wanted before people embrace this wholeheartedly. A quick search of trials on clinicaltrials.gov shows that there are several trials completed and no doubt some to come. Having an exchange transfusion is no laughing matter as there are risks related to clotting, bleeding, platelets etc so having another tool in our toolkit to deal with this common issue in neonates is of interest to me. Maybe it is of interest to you as well.
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.