Neonatal Updates

Aly H, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol. 2015;35(3):186-91. Thirty asphyxiated infants undergoing hypothermia were randomized to melatonin or not, in a study from Egypt. The melatonin was given enterally, and serum concentrations rose in the treated group. There were some potential benefits in the melatonin infants, with less seizures and improved MRI appearance. But this was a very small unblinded study, so a high risk of bias, but very interesting, suggestive results.

Livingston MH, et al. Glycerin Enemas and Suppositories in Premature Infants: A Meta-analysis. Pediatrics. 2015;135(6):1093-106. I must say I have never ordered a glycerin enema for a baby (or for anyone else for that matter), but I have occasionally given a suppository for a baby who has not stooled for a couple of days and appears distended. The three trials included in this meta-analysis are all of routine use of glycerine suppos or enemas. The trials all have some significant limitations, but they show, in general, that there may be a minor effect on the stool pattern, but no other clinical benefits, and there may be an increase in Necrotizing Enterocolitis. The relative risk for NEC was very high at 2.72, but with wide 95% confidence intervals which include the possibility of no effect.

I don’t really understand the rationale behind doing further trials of this subject, even though the authors of this review note that there are 3 that have been or are being done. With the data already in the literature, including the potential for an increase in NEC, I think that routine glycerine suppositories should be avoided, and even occasional intermittent use should be reconsidered or abandoned.

van Pul C, et al. Safe patient monitoring is challenging but still feasible in a neonatal intensive care unit with single family rooms. Acta Paediatrica. 2015;104(6):e247-e54. As many of us are moving toward single patient rooms, a common concern is how to provide alarm surveillance. If a nurse has two patients, as is usual in most places around the world for the more stable NICU patient, and is in a room suctioning a baby, for example, what happens when the other babies ventilator circuit comes apart? The problem is obviously compounded at break times. Many centers have adopted technological solutions which lead to distributed alarms, so the caregivers are supplied with wireless devices that receive alarms, with the primary nurse receiving alarms immediately for her/his patients, and a second nurse receiving the alarm if the first is not able to respond. One thing that I don’t see in the publication is how long it takes on a daily basis to log each primary or secondary nurse or other caregiver to their patient(s). We are expecting a substantial time commitment for that process when we move to our new unit, in about 18 months. This study is reassuring that a workable system can be developed which does not increase the alarm fatigue of the nurses. A system which includes important equipment alarms including the ventilator would be an improvement.


Posted in Neonatal Research | Leave a comment

What is a perfect baby?

With the recent publication from the NICHD network concerning survival rates of the most immature infants, there has been a lot of discussion. Including a strange article in “the Daily Beast”, by Jeff Perlman. Why he would publish something there I don’t know, but his argument is weird. He basically doesn’t believe babies can be viable before 23 weeks (he says that at his hospital they have decided that viability is at 24 weeks), and notes that there are uncertainties in gestational age assessment. But he is extremely inconsistent and then argues that we should use that same uncertain assessed gestational age to decide whether a baby should be given a chance of survival, using completely arbitrary cutoffs that reflect the traditional gestational age mantra. If gestational age assessment is so problematic (which I agree with entirely) how can we use that as the over-riding consideration in whether an extremely immature baby is offered intensive care or not?

He goes on to suggest that the data are biased because they are observational; which is also a strange argument. They are supposed to be observational. The data show that, among babies who are born in centers where almost all “22 weekers” are resuscitated, 23% survive, in centers where they are more selective the average survival among infants getting intensive care is 28% but the overall survival is much less, depending on the proportion getting intensive care. In centers where 0% are resuscitated, then 0% survive. I don’t understand where the bias is there. The data are clear and irrefutable, there is huge variation in the approach between centers, and huge variation in survival as a result. Sure, some of the babies who survived who were called 22 weekers might have been 23 weekers, but some of the 22 week babies who were not offered intensive care, and therefore died, might also have been 23 weekers (or even 24 weekers).

Dr Perlman’s article ends by saying that, based on his decision that viability starts at 24 weeks, they will not offer intervention before 23 weeks at his hospital, nowhere does he suggest that parents have been involved in making that decision; I guess the doctors know best.

There have been a lot of comments on parent blogs, including for example “life with Jack” and “they don’t cry“, many of which point out the stupidity of relying on inaccurate information to make life and death decisions, and the fact that survival with impairment is also a success, for many families.

Annie was interviewed about some of this recently on the radio, which reminded me of a recent radio program, in which I made a brief appearance, Radiolab, an NPR radio show that is generally very interesting and well made. When I was on the show, which was triggered by the experiences of a journalist who had an extremely preterm baby, I was asked to be there for my opinions about the story. Towards the end, I was not expecting a certain question, which was how Violette was doing.

I probably should have been ready with a glib answer, but I just stammered a little not knowing how best to answer, then I said simply, that she is ‘perfect’. After the show there were numerous comments, on the website, which implied that the producers of the show had selected families whose infants had unusually good outcomes. I am not going to give a lot of personal details about Violette, and how she is doing, because that is something that is actually irrelevant to this debate. I do want to try and answer the question, also addressed on “Life with Jack

“Does anyone have a ‘perfect’ baby?”

I have several

Or maybe I have none

We are extremely fortunate that Violette does not have a major neurological deficit. But even if she did, can a blind baby not be perfect? Is it impossible that a child with cerebral palsy is perfect?

My daughter will, in all likelihood, struggle more in school than if she had exactly the same genome, but been born at term. Does that make her less perfect as a result?

Not to me.

She is my gorgeous little girl, whom I love without limits, and who has a wonderful life ahead of her. To me she is perfect, despite her imperfections. Just as are my other children.

I am glad that I stammered and said she was “perfect”, I can’t think of a better description of her.

Today is her tenth birthday!

Posted in Neonatal Research | Tagged , | 4 Comments

Genetic variants and NEC risk

This post is out of my usual comfort zone, but I thought I’d write about it as it is fascinating, and might lead to something clinical. I don’t understand any of the lab methodology of this study, except to say that they examined bits of DNA. Sampath V, et al. SIGIRR Genetic Variants in Premature Infants With Necrotizing Enterocolitis. Pediatrics. 2015.

What they did was to look at bits of DNA that code for something called SIGIRR in preterm infants with NEC. Toll-like receptors are cell-surface receptors that are involved  in pathogen recognition and regulation of intestinal inflammation. SIGIRR is apparently the nom-de-guerre of a gene that inhibits TLR signaling, so when it doesn’t work properly you get exaggerated inflammation, and maybe NEC. The TLR which is most implicated is TLR4, which senses endotoxin from Gram-negatives, and it is this TLR which promotes inflammation when not regulated by SIGIRR (I think; someone can let me know if I am out to lunch). They tested this in an epithelial cell line to confirm the effect.

Basically a lot of the preterm babies with NEC had SIGIRR genes that were messed up. In the general population there are fewer than 400 potentially deleterious alleles in a database of 12,000 individuals. In 18 NEC cases there were 11 who had abnormal alleles. In 17 preterms without NEC they did not find any. The incidence is therefore dramatically associated with NEC and there is a strong mechanistic rationale.

The next question might be “Now what do we do about it?”

Well, not too much surprise here for regular followers of the blog, the answer is (or may be): Probiotics!

Bifidobacterial conditioned media increased mRNA levels of SIGIRR and other inflammatory regulators in this study :Ganguli K, et al. Probiotics Prevent Necrotizing Enterocolitis by Modulating Enterocyte Genes that Regulate Innate Immune-Mediated Inflammation. American Journal of Physiology – Gastrointestinal and Liver Physiology. 2012. This study and a couple of others show an effect of bifidobacteria in regulating the expression of SIGIRR, and therefore decreasing intestinal inflammation. Cool. Maybe even true.

Posted in Neonatal Research | Tagged , | Leave a comment

Cord milking/delayed clamping at the 2015 PAS-meeting

I have tried to go through the abstracts from PAS to find those that had new information, from controlled trials, about the efficacy and safety of cord milking and/or delayed clamping.

Mercer and the group from Rhode Island presented the 18-22 month follow-up of about 200 very preterm (<32 wks) babies randomized to immediate compared to delayed (30 to 45 s, combined with one milking of the cord) clamping. There was no effect on IVH in the groups they compared here, but there were fewer babies with Bayley motor scores under 85.

Hosono was the first author of the paper about cord milking from a few years ago. This time he led a multi-center RCT which compared cord milking in a new way that they described in another of the articles I just briefly reviewed, that is cutting the cord very long, then a one time milking of the cord. There were 100 patients in each group when they stopped the study, but they only present data in the abstract from 77 per group. Don’t know why. They say that there were fewer severe IVH (no data but they write p<0.04) and less mortality in the one time cord milking group.

The APTS study echocardiographic sub-study (Popat et al) reported cardiac function findings after delayed cord clamping (at least 60 seconds) compared with immediate clamping in about 260 babies of less than 30 weeks gestation. They found very little difference in cardiac function, BP was unaffected, SVC flow was the same, and right ventricular output was a little lower.

Anup Katheria from San Diego led a 2 center trial looking at hemodynamics after cord milking in very preterm babies delivered by C-Section. They showed higher BP and higher RVO in the cord milking group.

Most of the other abstracts were either before/after reports, or concentrated on hemoglobin, as far as I can see.

Posted in Neonatal Research | Tagged , , , , | Leave a comment

Does gestational age matter?

Gagliardi L. On the importance – and unimportance – of gestational age. Acta Paediatrica. 2015;104(6):544-6.

This article by Luigi Gagliardi discusses the incidence of white matter injury on head ultrasound across extremely low gestational ages. He was intrigued by Bree Andrews article from Chicago, showing no significant effect of gestational age on developmental outcomes among surviving infants.

The data he discusses shows a relatively constant incidence of  white matter injury, despite major changes in mortality.

He notes the systematic review by Gregory Moore and others that shows a modest gradient in moderate and severe impairment at 4 to 8 years of age in former extremely preterm infants.

What he does not note is that, when Moore limited their analysis to severe impairment, there was no difference by gestational age groups. To remind everyone the definition of severe impairment that they used in their review of the published data was

an IQ score more than 3 SDs below the mean, nonambulant cerebral palsy (Gross Motor Functional Classification System, 4-5), no useful vision (worse than 20/200), or no useful hearing despite amplification

Other data are also consistent with this, when you look at large groups, and if you concentrate on scores on developmental screening tests at around 2 years, there is a modest gradient in outcomes by week of gestational age between 22 and 25 weeks. Once you get to an age at which developmental/intellectual evaluation is more stable and more likely to reflect later function, there is little or no evidence of a gestational age effect. Of course there are very few infants less than 23 weeks best-guess gestational age in these data sets.

Being smaller and more immature certainly affects survival, but once you get out of the NICU, there is little evidence that gestational age has a major impact on important functional outcomes.

Posted in Neonatal Research | Tagged , | Leave a comment

Delayed cord clamping or cord milking for the very preterm newborn… or both?

What should we be doing, given the current state of the evidence, for the very preterm neonate?

I think the evidence is now pretty clear that full-term babies have benefits, and no significant harm, from delayed cord clamping, which has been for a defined period of time (1 minute, 2 minutes, or 3 minutes) or until after a defined clinical event, such as when the cord stops pulsating (sometimes with a maximum duration, of for example 5 minutes) or when the baby is breathing well, or after placental descent, in the various studies. The major benefit in the term baby is an improved (more physiologically normal?) iron status and hemoglobin. **this paragraph has been updated, see note after post**

In larger preterm babies the same is probably true. Studies confined to this group have been positive.

In the very preterm baby the evidence as summarized in the latest Cochrane review was still lacking. This group of babies, with of course, the highest risk of complications, must be investigated as a separate group. Potential benefits and possible harms may well be different.

The latest Cochrane review suggests there may be a reduction in all grades of IVH, but not clearly an effect on severe IVH, there may be a reduction in NEC but the confidence intervals are wide, and surgical NEC is not clearly affected, there may be “better circulatory stability” but what this means for outcomes is not certain.

There have been no significant harms shown from either delayed clamping or cord milking, but of course the precise way in which the practice is performed in the studies, and the proportion of randomized infants who actually receive the intervention, and the reasons for, and outcomes of, not following through with the randomized intervention will be different between studies, and have to be understood before we can figure out what to do.

There is a lot going on in this field right now, so its difficult to stay up with everything, at the PAS-meeting this year there were many studies, ancillary studies and physiologic investigations that were relevant. I haven’t had time to digest them all.

One important factor to consider is that the physiologic benefits demonstrated, in animal models, of delaying cord clamping are not due solely (or even mostly) to transfusion effects. Cardiovascular adaptation around birth is different when the cord is clamped after the onset of breathing, I am not sure if there is a similar study of the effects of cord milking, but I would guess that the effects would be quite different. I don’t think we should assume that the two procedures are equivalent, even if the same amount of extra blood is delivered.

Let’s look at some of the studies published since the last Cochrane review.

Elimian A, et al. Immediate compared with delayed cord clamping in the preterm neonate: a randomized controlled trial. Obstetrics and gynecology. 2014;124(6):1075-9. This study randomized 200 mothers of 24 to 34 weeks gestation to either immediate or delayed (30 seconds) clamping. The delayed clamping group were also allowed to get cord milking (2 to 3 times). The primary outcome was the need for transfusion. Which personally I don’t care about, on the other hand I understand the need to sometimes use intermediate outcomes, especially in modestly sized single center trials. Anyway in this trial they found no differences of any importance between the groups, but the average gestational age in the two groups was 31 weeks, so most of the babies would be expected to do well. What I found most surprising in this study was a rate of about 25% of transfusions (at least one transfusion) in babies who were relatively mature. There was also a surprisingly high rate of intraventricular hemorrhage, 20% of the immediate clamping group, and 11% of the delayed (most of course being grade 1 or 2). Overall, no substantial improvements in clinical outcomes, but all in the direction of benefit of delayed clamping for 30 seconds in association with cord milking. For example there was 1 NEC in the delayed group, and 3 in the immediate group.

Krueger MS, et al. Delayed cord clamping with and without cord stripping: a prospective randomized trial of preterm neonates. Am J Obstet Gynecol. 2015;212(3):394 e1-5. Compared 67 babies, 22 weeks to 32 weeks gestation, randomized to either 30 seconds of delayed clamping, or delayed clamping combined with cord milking. They found no added benefit of the milking, specifically no improvement in hemoglobin.

Alan S, et al. Effects of umbilical cord milking on the need for packed red blood cell transfusions and early neonatal hemodynamic adaptation in preterm infants born <!–=1500 g: a prospective, randomized, controlled trial. J Pediatr Hematol Oncol. 2014;36(8):e493-8. Forty-eight VLBW infants of under 32 weeks randomized, to either immediate clamping, or milking, performed 3 times, before the cord was clamped. The primary outcome was the number of the transfusions required, which was not affected, it is hard to make much sense of the other results, due to how they are reported.

March MI, et al. The effects of umbilical cord milking in extremely preterm infants: a randomized controlled trial. J Perinatol. 2013. Seventy preterm infants 24 to 28 weeks gestation were randomized to milking twice before cord clamping, or immediate clamping. Primary outcome was need for transfusion. There were significantly fewer IVHs, and fewer NEC cases (not statistically significant). I can’t understand the severe IVH numbers, as there seem to be more serious IVH than the total numbers of IVH.

Patel S, et al. Effect of Umbilical Cord Milking on Morbidity and Survival in Extremely Low Gestational Age Neonates. Am J Obstet Gynecol. 2014. This is the largest of these studies, with over 300 babies in a before and after study, the cord milking period included the usual 30 second delayed clamping with 3 episodes of milking. Survival, IVH, severe IVH and NEC were all improved in the milking period compared to the previous period.

Katheria AC, et al. The Effects of Umbilical Cord Milking on Hemodynamics and Neonatal Outcomes in Premature Neonates. The Journal of pediatrics. 2014. Anup Katheria has published a couple of papers from this study, this is the one with the clinical outcomes, 60 babies under 32 weeks were randomized, the milking group had the cord milked twice by the obstetricians before clamping, compared to immediate clamping. The primary outcome was the SVC flow, which was around 20% higher in the umbilical milking group. There seemed to be fewer severe IVH and less BPD with cord milking, and no NEC results are given.

Hosono S, et al. One-time umbilical cord milking after cord cutting has same effectiveness as multiple-time umbilical cord milking in infants born at <29 weeks of gestation: a retrospective study. J Perinatol. 2015. In this paper from the group who first reported an RCT of cord milking, they compared a practice of milking the cord after clamping (from 2007 to 2008) to the practice as described before, milking by the obstetrician before clamping, (2001-2002) I don’t know about all the other missing years, and there were only 20 babies in each group. There was similar effects of the 2 procedures in terms of cardiovascular adaptation and hemoglobins.

I think we still need to remember that multiple small trials may inflate the size of any benefit, and the APTS trial, and other large trials, are needed to be sure that the benefits are real, but it looks quite unlikely that delaying cord clamping or cord milking are harmful. I guess the next stage will have to be trials comparing delayed clamping (probably for 1 to 2 minutes) to cord milking (combined with 30 seconds maximum of delayed clamping), to perhaps milking after clamping.


**In response to the comment by Ola Andersson below, I corrected the paragraph about delayed cord clamping in the term baby, and I have also added a link to the Cochrane Review. Previously the paragraph implied that the maximum duration of cord clamping studies was 2 minutes, as I had in my head a couple of large studies, but other large studies have had longer durations, which might possibly be needed to get the full benefit**

Posted in Neonatal Research | Tagged , , , , | 4 Comments

A letter from a mother to neonatologists

From the blogger Alison Epps, a mother of an extremely preterm boy, who writes at the blog 22w6d. Below the letter on her blog there are before and after photos of her son James at the age of 4 1/2.

Dear NICU Doctor,

I’m writing to you with utmost respect and admiration for what you do.  In my eyes you are a hero. Doctors like you saved the life of my son against seemingly insurmountable odds. I hope you will take a moment to read this letter and look over the information included. It is important.

I am writing to you as a mom; A mom of a very special little boy born at 22 weeks 6 days gestation. My son James weighed 44o grams and was 10.5 inches long when he was born. Doctors attempted life-saving measures on James because of an error made by my OBGYN when I was admitted to the hospital, five days prior to his birth. A simple error that stated on Monday, August 2 he would be 23 weeks gestation. I was to receive my first steroid shot and first 20 minute heart rate monitoring, thankfully, one day early. James was delivered due to severe heart rate decelerations that became worse as the day progressed.  Had his heart rate not been monitored one day early, he likely would have passed during the night.

Like most hospitals, Baylor University Medical Center, where James was born, has policies in place regarding when life saving measures are attempted with micro-preemies. At the time of James’ birth they did not attempt life saving measure prior to 23 weeks gestation. Between 23 and 25 weeks gestation they attempt life saving measures only at the family’s request. At 25 weeks gestation they always attempt life saving measures.

James did not fit their policies. Had they known his actual gestational age, that one day would have made the difference between a chance at life and certain death. One day.

A friend of mine has said, quite often, “I think he was 23 weeks, or even 23 weeks and a few days.” She might be right. As you know, gestational age is not an exact science.  Errors exist on both sides, but very few hospitals take that in to account when determining, what they believe to be, viability.

James will be five this summer. He is an amazing little boy who spreads joy everywhere he goes. He is smart, really smart! He can count higher than 800 and knows his alphabet forward and backward. He even knows how to read quite a few words. He is full of energy and runs everywhere he goes. James loves life, and we cannot imagine our lives without him.

I write about James and tell his story to anyone who will listen. I do that because I’ve met too many families who were in our exact situation, but no life saving measures were attempted. I’ve met families who wonder, “What if?” What if their baby was given the chance James was given.

I know we are biased. We have a good outcome. I can’t imagine the agony you’ve witnessed and the pain some babies go through only to lose their lives anyway. I know that exists. I’m asking you to remember that the other side exists too. Please consider the fact that babies born under 23 weeks gestation have survived and thrived. When making decisions about a chance at life or certain death, please be mindful that gestational age is not an exact science. I’m respectfully asking you to take all of this into consideration, as well as the wishes of the family, when you’re making life and death decisions.

This is important to me.  I’m only writing to you after much thought and discussion about this issue. I am certain you have thought about this before, and I truly hope you will consider it again. I’ve included a brief medical history of my son for your review. I am very willing to provide additional medical documents at your request. I’ve also included a brief medical history written by a mom whose baby wasn’t given life saving measures. These are the moms who contact me and want to know more about James.

I will be glad to answer any questions you might have or provide further information. Thank you for your time and for your thoughtful consideration of viability under 23 weeks gestation.


Alison Epps

Posted in Neonatal Research | Tagged , | 6 Comments