Tuesday, February 10, 2009

Impact of Postnatal Steroids...

Impact of Postnatal Corticosteroid Use On Neurodevelopment at 18 to 22 Months' Adjusted Age: Effects of Dose, Timing, and Risk of Bronchopulmonary Dysplasia in Extremely Low Birth Weight Infants


OBJECTIVE. Postnatal steroid use decreases lung inflammation but increases impairment. We hypothesized that increased dose is associated with increased neurodevelopmental impairment, lower postmenstrual age at exposure increases impairment, and risk of bronchopulmonary dysplasia modifies the effect of postnatal corticosteroid.


CONCLUSIONS. Higher steroid dose was associated with increased neurodevelopmental impairment. There is no "safe" window for steroid use in extremely low birth weight infants. Neonates with low bronchopulmonary dysplasia risk should not be exposed. A randomized trial of steroid use in infants at highest risk is warranted.

***I never know what I am allowed to post, legally. So I am only posting the objective and conclusion. If you click on the title it will take you to the abstract. I don't have access (can't afford-lol) to the entire article.

What I find interesting in the Conclusion is the statement, "There is no "safe" window for steroid use in extremely low birth weight infants."

47 comments:

Bec said...

Another reason why, if I had it to do again, I'd refuse the steroids.

Kristie said...

Wow, that is a very definitive (and scary for all the kids who've already been exosed) conclusion. I'm really glad we didn't end up needing to do steroids in the NICU. Thanks for posting this. I'm looking forward to reading the whole article tonight.

Sheila said...

The really "scary" thing in my mind is that we've known this for more than 15 years, and yet ... it's still being researched and published as "new" or "groundbreaking" data. I can think of at least a dozen researchers that have to be banging their heads into their keyboards when they see this kind of publishing getting the "this just in ... " treatment.

LOL

Bleh

Anonymous said...

I know everyone will jump all over this, but my kid had trouble getting off the vent, had the steroids, is now 4 and is fine. No bpd, lung issues, nothing wrong cognitively, etc....

Anonymous said...

Helen Harrison writes:

If anyone would like to see the entire study, contact me at
Helen1144@aol.com

I have articles/letters/studies dating back to the 1970s describing the harmful side-effects of steroids, and yet the *many* warnings over the decades were ignored, and even mocked, by many neonatalogists.

Why isn't the legal profession looking at this?

I spoke with a doc at SPR who presented research showing that even a single dose of prenatal steroids could reduce the brain size of babies born at term. This is very scary stuff, and I suspect it has something to do with the increased rate of autism.

Helen

terri w/2 said...

I have a full-term neice that is 16months old and is showing some signs of autism. Mom had a dose of steroids during pregnancy, so this study is indeed scarey. Relatives are voicing concern about her development, but being a first child, mom doesn't appear concerned yet, and I'm keeping quiet right now just in case it is not autism. .but, she is very flat looking, plays on the periphery, poor eye contact, etc. Guess time will tell.

Anonymous said...

"Why isn't the legal profession looking at this?"

Because any litigator who delves into brain development, NICU statistics and outcomes, quickly realizes that the opportunities for brain gorking are legion in a standard NICU stay. Even with studies like this, causation is almost impossible to prove. Each individual might have dozens of intervening factors. It would be impossible to form a class--big pharma's lawyers would point to all the severely impacted kids who never had a microgram of steroids and scream 'No commonality' among those who did.

Anonymous said...

Helen Harrison writes:

But PI lawyers are quick to pursue cases with eqaully nebulous causation in cases of heart and other problems purportedly resulting from various diet drugs,pain relievers, vaccines, implants, etc.

I think the elevation in risk of disability in preemies given postnatal steroids (51% had serious disability by age 2 in this study) compared to similar preemies (who had about half the incidence of handicap) is striking.

I want to make it clear that I don't suggest filing such suits -- parents who get into the legal system end up losing more than they gain, generally speaking -- but I'd think the lawyers would be interested.

Helen

Carrie said...

Helen, I know we have discussed prenatal steriods before, but I can't remember:) What kind of information is available about prenatal steroids? My son never received postnatal steroids, but I received the steroid shots. Interestly, I received them at 25 weeks and I didn't have my son until 28 weeks. My ob talked about repeating the treatment, but the peri said a resounding NO to repeat shots.
Carrie

ThePreemie Experiment said...

Carrie, if you google prenatal steroids, you'll come up with a bit of info.

Helen, I know you've posted the studies before on this blog. I have been bad about tagging them so they show up on my side bar. If anyone knows of a specific study, please let me know and I'll add it to the sidebar.

My water broke at 23.0 weeks. I had many rounds of shots (dex) before Paige was born at 25.5 weeks. She also had quite a bit of post natal steroids, none of which revolved around the vent. She was vented less than 24 hours.

Anonymous said...

Helen Harrison writes:

Below is the abstract of the study I referred to in my previous post. It was presented last May at SPR (Society for Pediatric Research) in Hawaii.

I should make clear that a small head circumference is often related to poor brain growth/abnormal brain development.

The results suggest that even a single dose of betamethasone prenatally can adversely affect head (brain) growth in term born human infants. (And this is *definitely* the case in test animals.)

This sort of effect on growth is hard to detect reliably in preterm infants because of all the other problems and confounding variables that surround their births.

In addition, autism is often related to some sort of interruption in brain growth and development, so this finding could be of great significance in possibly helping to explain the current increasing rate of autism.

I have to wonder how many term babies who've been diagnosed with autism were also exposed to steroids in utero?

The rate of autism has risen in tandem with the escalation in NICU care for micropreemies and the associated use of steroids both pre- and postnatally.

Along with the acceleration in NICU care, OB-GYNs have become more aggressive in managing possible preterm labor. As a result, countless term-born babies have been unnecessarily exposed to steroids.

I'll try to get some more studies on steroids of various sorts, used in various ways, and the dangers they seem to pose to developing human infants preterm and term.

Helen

***
In the meantime here's the study abstract from SPR. It is interesting to me that the school of psychiatry at UC Irvine is involved with this research.

Prenatal Exposure to Glucocorticoids Affects Growth in Full Term Infants

Elysia P. Davis, Feizal Waffarn, Cherry Uy, Calvin J. Hobel, Laura M. Glynn, Curt A. Sandman. Psychiatry Human Behavior and Pediatrics, University of California, Irvine, Orange, CA; Maternal Fetal Medicine, Cedars Sinai, Los Angeles, CA.

BACKGROUND: Prenatal glucocorticoid (GC) therapy is the standard of care for women at risk for preterm delivery. Because the clinical diagnosis of preterm labor (PTL) is imprecise and because preterm delivery may be prevented with clinical interventions, over one third of women diagnosed as being in PTL deliver at term, thus leading to the exposure of fetuses subsequently born at term to prenatal GC treatment. Animal models have demonstrated that prenatal GC exposure results in restricted fetal growth. Studies evaluating the impact of prenatal GC therapy on somatic growth among human infants have focused on preterm infants and yielded conflicting results. Consideration of the consequences of prenatal GC treatment on term infants is important because 1) preterm infants are already at risk for delayed development and 2) for many infants born preterm there is only a short time interval between GC treatment and delivery that may limit the ability to observe effects on fetal growth.
OBJECTIVE: The objectives of this study were to determine if 1) prenatal treatment with a single course of the GC betamethasone affects size at birth at term gestation; and 2) if this effect is independent of fetal size prior to GC administration or exposure to PTL.
DESIGN/METHODS: Participants included 105 term infants (GAB = 39.1, SD =1.1) recruited into three groups (30 GC treated with a single course of betamethasone; 60 controls without GC treatment or PTL matched for GA and sex; 15 PTL controls without GC exposure). Fetal size (biparietal diameter, head circumference, femur length, abdominal circumference) and estimated fetal weight were obtained prior to GC treatment using 3D ultrasound; and neonatal length, weight and head circumference were measured at birth.
RESULTS: Analysis of Covariance (ACNOVA) models demonstrated that length, weight, birth weight percentile and head circumference at birth were smaller among infants who received prenatal GC treatment as compared to matched controls (ps<.01). Importantly, the GC treatment and control groups did not differ in estimated fetal weight nor any of the other growth parameters prior to treatment (ps>.2). Furthermore, PTL alone did not account for this growth effect.
CONCLUSIONS: Prenatal treatment with a single course of betamethasone was associated with a reduction in size at birth among term infants. This effect cannot be explained by differences in fetal growth prior to treatment or exposure to PTL.

terri w/2 said...

Anonymous 1:20 writes:

"Even with studies like this, causation is almost impossible to prove."

And therein lies a huge problem with NICU care. The opportunities for brain damage are so immense, that this opens the door for research - both ethical and unethical to occur in this environment. It is extremely difficult to isolate beyond a reasonable doubt that experimental procedures, medicines, etc are responsible for a child's poor outcome when there are so many variables that can contribute to a child's poor outcome. Truly, the family and infant are victims in those units where experimental procedures are happening without the parent's knowledge.

Anonymous said...

Helen Harrison writes:

Terri is absolutely right on the undeclared perinatal and NICU "experimentation."

I hate even to dignify much of what goes on in the NICU by using the word "experiment" which implies that someone is actually gathering data, testing a well-thought-out hypothesis, conducting meaningful follow-up, or doing anything other than: "hey, guys, let's try this and see if it works, because even if it doesn't who will know the difference, given all the many sources of brain damage (and/or death) that are part of prematurity and NICU care?"

And if the therapy "works" in the short term -- say, by getting the baby off the vent -- what do the neos care about long term results like autism, and/or ROP, and/or cerebral palsy? The child will be long gone from the unit by the time the damage is revealed. And the parents won't try to sue because how will they ever figure out what did it to their child?

In one of Dr. Alan Jobe's papers on steroids, he quotes Tom Lehrer's lyrics about German rocket scientist Werner von Braun:
"Once the rockets go up, who cares where they come down? 'That's not by department!' says Werner von Braun."

With all the recklessness and confounding variables that plague preemie care, the study I just cited (in the post above Terri's) about the effects of steroids on fullterm "normal" infants is especially interesting and alarming.

Without the confounding variables of prematurity and NICU care, negative effects on fullterm infants from only one round of betamethasone were isolated. Scary stuff!

Again, it is extremely interesting to me that departments of psychiatry are pursuing research on prenatal steroids and their effects.

Helen

ThePreemie Experiment said...

Helen wrote: "And if the therapy "works" in the short term -- say, by getting the baby off the vent -- what do the neos care about long term results like autism, and/or ROP, and/or cerebral palsy?"

Not only do you have the doctors saying this, you also have many parents of infant preemies saying this too. They are overjoyed at the fact that their baby is off of the vent that they are not able (don't care to) think about the long term effects. I'm sure some of us can testify that some parents get brutal in defending the decisions of the NICU team, only to change their mind later down the road. Once the NICU dust settles we are left wondering what caused certain issues.

I think there should be an analytical team assigned to every NICU. They should be keeping track of meds used, dosage used and outcomes. Pair that with the follow up clinics that should be keeping track of kiddos until they are much older.

I know it's a dream but what is happening now is a nightmare.

Anonymous said...

Helen Harrison writes:

Here is a (partial) list of complications of steroid therapy taken from the first paragraph of most recent study in Pediatrics:

hyperglycemia, hypertension, gastrointestinal perforation, increased risk of infection -- particularly fungal sepsis, cardiac hypertrophy, severe retinopathy of prematurity, reduced head circumference, and neurodevelopmental impairment.

How many parents are told all this in the NICU? How many actually understand the longterm consequences?

I wish every parent reading this blog could come with me to neonatal medical conferences and hear the cavalier way in which these problems are discussed by docs who do not have to live with the aftermath.

I wish parents could understand from the outset the many uncertainties, controversies, and serious consequences that attend the irresponsible use of powerful drugs and medical techniques on our extremely preterm babies.

Helen

Carrie said...

Helen Harrison said:

"Here is a (partial) list of complications of steroid therapy taken from the first paragraph of most recent study in Pediatrics:

hyperglycemia, hypertension, gastrointestinal perforation, increased risk of infection --"

And yet, the doctors can't seem to figure out how come my son has hypertension! I do think that the NICU team did a good job explaining the risks and long term effects of prematurity, but hypertension was never on my radar nor our pedi. We caught it at 1 years old because of a follow-up echo. Our pedi doesn't start reading blood pressures until 3 or 4 years old. I can't imagine the kind of damage to Max's heart or kidneys had his blood pressure not been regulated for 2 to 3 years.

Carrie

Anonymous said...

Helen Harrison writes to Carrie:

Whenever your son is seen by a pediatrician or pediatric specialist, be sure to mention not only the prematurity but also the steroid treatments. Have the docs, if skeptical, do a literature search on the long term side effects of steroid treatment in the perinatal period.

They might learn something important, and have a better idea of what is going on with your son.

Good luck with this,

Helen

mysweetmylovelymiraclebaby said...

I always wondered why my daughter Lilike had a high white cell count, on her day of birth and her levels never were high again and never reached the white cell count of a band neutrophil of 70% with toxic changes that she had on her day of birth, with no source of infection found. Toxic changes can be due to quite a few possibilities infection, inflammation, and severe physical or emotional stress. Rapid birth combined with AROM and told to push quick caused emotional distress on Lilike. The body would increase its white cell count when stressed to protect the body. And whilst she had been on antibiotics for 4 days alread daily heel sticks saying no infections she was on full 4 hourly bottle feedings, they fumbled around desperate to find a vein causing her pain just to administer antibiotics she had no need for considering they had no proof she was sick with an infection. She was still written down as pale at 8days old rooming in and was still discharged at 9 days old with no problems at all gaining weight at home. Her FBE full blood examination with the high white cell count was was done in the afternoon on her day of birth I only saw her breath a few breaths quickly while they gave her the very 1st heel stick done on her little foot as if it stressed her. And research indicates white cell counts are higher on a babies day of birth, higher in the afternoons and lower in the mornings. Lilike has always showed alot of stress to noises, even singing toys since she was a baby and even at 4 years old a singing doll really stressed her into fits of crying alot. And even with the the way she wore her socks. She became very stressed and screamed and thrashed at failed iv attempts, as a baby at four days old that a dummy stuck down her mouth would not keep her quiet. Poor little dear. Preemies, being so tiny, going through all those kinds of tests my term baby found distressing, tiny little miracles they are, I have admiration for these little battlers, who fight the odds brave the days in the NICU and overcome the battle of survival to come home to the comfort of love and peace at home with mom and dad. The mom who loves, nurtures and worries over what is best for the baby she is so happy to have

Anonymous said...

Regarding the dire need for hospital follow up studies beyond the 2 year follow along clinics, it should be interesting to note that Fairfax Hospital located outside of Washington DC is doing a major longitudinal study looking at outcomes at 3 and 6 years. It's one of the largest NICUs in the country and they routinely brag about having better outcomes than most. We'll see how my 1 year old 27 weeker twins fare.

Anonymous said...

Helen Harrison writes:

Here is an important study abstract that shows the importance of "longterm" follow-up, in this case by school age, of children exposed to post-natal steroids. Note, these are not children who were necessarily considered "impaired" in early childhood:

Outcomes at School Age after Postnatal Dexamethasone Therapy for Lung Disease of Prematurity

New England Journal of Medicine,
350;1304-13.March 25,2004.

Tsu F. Yeh, M.D., Yuh J. Lin, M.D., Hung C. Lin, M.D., Chao C. Huang, M.D., Wu S. Hsieh, M.D., Chyi H. Lin, M.D., and Cheng H. Tsai, M.D.

ABSTRACT

Background: We studied the outcomes at school age in children who had participated in a double-blind, placebo-controlled trial of early postnatal dexamethasone therapy (initiated within 12 hours after birth) for the prevention of chronic lung disease of prematurity.

Methods: Of the 262 children included in the initial study, 159 lived to school age. Of these children, 146 (72 in the dexamethasone group and 74 in the control group) were included in our study. All the infants had had severe respiratory distress syndrome requiring mechanical ventilation shortly after birth. In the dexamethasone group, 0.25 mg of dexamethasone per kilogram of body weight was given intravenously every 12 hours for one week, and then the dose was tapered. We evaluated the children's growth, neurologic and motor function, cognition, and school performance.

Results: Children in the dexamethasone group were significantly shorter than the controls (P=0.03 for boys, P=0.01 for girls, and P=0.03 for all children) and had a significantly smaller head circumference (P=0.04). Children in the dexamethasone group had significantly poorer motor skills (P<0.001), motor coordination (P<0.001), and visual–motor integration (P=0.02). As compared with the controls, children in the dexamethasone group also had significantly lower full IQ scores (mean [±SD], 78.2±15.0 vs. 84.4±12.6; P=0.008), verbal IQ scores (84.1±13.2 vs. 88.4±11.8, P=0.04), and performance IQ scores (76.5±14.6 vs. 84.5±12.7, P=0.001). The frequency of clinically significant disabilities was higher among children in the dexamethasone group than among controls (28 of 72 [39 percent] vs. 16 of 74 [22 percent], P=0.04).

Conclusions: Early postnatal dexamethasone therapy should not be recommended for the routine prevention or treatment of chronic lung disease, because it leads to substantial adverse effects on neuromotor and cognitive function at school age.

Anonymous said...

Helen Harrison writes on "what did they know and when did they know it"
***

"Many late [harmful] effects of [steroid] administration to fetal or newborn animals have been described and it might be naive to assume that none of these results would pertain during human development."

Taeusch HW. Glucocorticoid [steroid] prophylaxis for respiratory distress syndrome: A review of potential toxicity. J Ped 1975;87:617-623.

More to come...

Helen

Anonymous said...

Helen Harrison writes, again, on "what did they know and when did they know it"?
***

Follow-up of infants who received intravenous hydrocortisone for respiratory distress syndrome revealed an increased incidence of gross motor dysfunction and electrophysical abnormalities at 12 months corrected age.

Fitzhardinge et al. Sequelae of early steroid administration to the newborn infant. _Pediatrics_1974;53:877-883.

Anonymous said...

Please explain why my child got 3 doses, scores in the 95-99th range in cog. tests, and is not short, uncoordinated, etc. Seriously. How do you explain that?

Anonymous said...

Helen Harrison continues the discussion of "what did they know and when did they know it?"
***

The following excerpt comes from a study published in 1990. (Kazzi et al, "Dexamethasone effects on the hospital course of infants with bronchopulmonary dysplasia who are dependent on artificial ventilation" _Pediatrics_ 1990;86:722-727. t
The study itself showed that, despite bringing about a brief, short term improvement in pulmonary function, use of dexamethasone did not improve the infant's conditions overall or shorten their hospital stays.

What I am typing out here is a summation of the *previous* [before 1990] evidence on animal and human research concerning use of perinatal steroids cited in this study.

Comments and explanations in brackets are my own.

"Various serious sequelae [harmful side-effects] have been noted in newborn animals treated with glucocorticoids [steroids]. In studies [from 1989] of infant mice with chronic pulmonary oxygen toxicity it has been shown that administration of dexamethasone was associated with a significant decrease in lung wet weight, lung water, lung dry weight, and protein and DNA contents, as well as a significant reduction in growth of the body, thymus, and brain. These effects were observed with dexamethasone doses in the range used for preterm infants with bronchopulmonary dysplasia. In one animal study [from 1981] it was suggested that steroid therapy may increase the risk of retinopathy of prematurity.

With administration of ... [steroids] (comparable to those used in infants with bronchopulmonary dysplasia)to newborn experimental animals, [harmful]effects on brain cell division, differentiation, and myelination have been shown. [research from 1972 and 1974]

In addition, delayed effects including altered biogenic amine levels, altered response to stress, and changes in ultimate behavior have been reported. [in 1968 and 1975]

Weichsel [in 1977] warned that 'perinatal hormone therapy during critical periods of brain development is capable of exerting irreversible immediate effects on brain cell division and differentiation resulting in latent or longterm physiological and behavioral effects.'

Neuronal and DNA content has been shown to increase steadily with increasing gestational and postnatal age. The brains of human neonates, particularly those of premature infants, may be susceptible to inhibitory effect of effect of steroids on DNA synthesis and cellular proliferation...

Follow-up [in 1974] of infants who received intravenous hydrocortisone as therapy for respiratory distress syndrome revealed an increased incidence of gross motor dysfunction and electrophysical abnormalities at 12 months corrected age.

Growth failure associated with the prolonged use of dexamethasone (7 days) has also been reported in preterm infants. [in 1988 and 1989]

In addition to the immunosuppressive effects of [steroids] on leukocyte kinetics and function [proper functioning of white blood cells -- reported in 1975] results of follow-up studies done of 5-year-old children who received [steroids] in the neonatal period showed evidence of diminished percentage of T lymphocytes and increased number of infections compared with control infants.

Brief therapy with corticosteroids [steroids] in newborn infants may result in long-term neurologic and immunologic impairments."

23wktwinsmommy said...

Both of my 23 weekers received postnatal (and prenatal steroids.) Serena had very small and short dose to get her off of the vent. We had to consent to steroids given to our son at 3 weeks actual age because they did not routinely administer them that early (usually waited until at least 4 weeks...they said more risk earlier on? who knows...) Anyway, they assured us this was the ONLY way to get him off of the oscillator. The developmental worker came to talk to us and told us that VERY few (I can't remember the number) of children in follow-up who had received steroids had CP, and that there was MUCH greater risk keeping him vented. (I now know this to be false.) The steroids did get him off the oscillator enabling him to get his PDA ligated, which in turn enbabled him to get off the conventional vent. He was also given another course of steroids at about 2 months because he couldn't get off C-Pap. They had to consent with us for this as well because it was not typical to have multiple courses of steroids.
Come to find out, the stats from our NICU for 23 weekers is about 50% survival rate and 50% moderate to severe disabilities. (I just learned this from a lecture Thursday night given by a neonatologist from our NICU.) Assuming all 23 weekers get steroids, there was no way the developmentalist could say that only a small number of kids had CP from steroids. Who knows WHY they had CP, but more importantly, it's not a small number...it's half of them.
There was so much confusion, heart break, and desperation to see our children "get better" and survive, I can't even recall exactly everything we were told. I knew it wasn't good, but I seriously could not accept not trying what was medically available to help them.
Only now, 2 1/2 years later do I really understand the huge degree of unknowns and "experimentation" that went on even at our NICU that was relatively honest about how *crappy* their outcomes could be.

I know a lot could change but our daughter is testing within "normal" range, and yet not surprisingly our son has *moderate* hypotonic CP and is basically globally delayed. (He walks with a reverse walker, pulls to stand, sits up, self feeds, and says some words and signs.)
What is impossible to say is we regret our decisions because of how much we love and cherish out children, and the benefit we have that they are not suffering.
What *sucks* is there is a way to keep these tiny babies alive but yet so much damage that accompanies that survival. As much as I believe in parental consent, making the decision not to administer steroids would have probably meant sentencing my son to death, and because we believed that there was a liklihood this would help more than hurt, we thought we were doing what was right by him. (At the time of the steroids we made him a DNR and had a wean plan that was to be followed no matter what, if he improved great, keep weaning, if not, we'd take him off support.) If they know these drugs have harmful effects, why put a parent in a position to tell them this will help save their child's life? It puts parents, who have no experience of prematurity, in an impossible situation of heart breaking decisions.
Having been through micro prematurity, we are not sure we will have more children, and the last time I asked, DH said he would not want another preemie; and when I asked if that meant he wouldn't want to resuscitate, he basically said yes that's what he meant. Mind you he was more committed to "doing everything" than I.
When you cherish a pregnancy and the children you look forward to bring into the world, it is so difficult not to do everything medically possible. It is only after you have gone through it, or truly understand by the testimony of others do you understand what an incredibly difficult position you are in to make these types of decisions.
Understanding the risks, we are extremely lucky at our children's current *outcomes.* Only now do I realize just how much more we could be facing. But to think of life without the twins is simply impossible...I can't fathom it. Knowing my children how they are now, I would never wish to go back and make another decision.
But I still don't know where that leaves me as I navigate the feelings associated with micro prematurity and parental consent.
Thanks Stacy and others for sticking with me through my personal "process." And thank you for sharing information so others may have adequate information BEFORE they are thrown into this ethical decision making from hell.

Side note...I have also been doing a lot of online reading about traumatic brain injury in children (near drowning, choking, etc.) What is known about outcomes in an anoxic event is pretty devastating, and yet EMTs and then ICUs resuscitate and provide treatment. I do not wish to even get into this, but my point for bringing it up is that I can't imagine much will change in NICUs if PICUs are resuscitating and treating children who will 100% have significant to severe brain injury given what can be determined by acid levels, MRIs, and EEGs. Sorry for the tangent.

Anonymous said...

I had an interesting conversation with the physiatrist who follows my twins today regarding research studies with preemies. He is an extremely candid physician who sugarcoats nothing and is very forthcoming about the risks of prematurity. Part of his job involves going to the NICU three times per week and subsequently tracking "micropreemies" defined as those under 26 weeks and/or 1000 kg. He typically follows them for months and in some cases, years. When I mentioned enrolling my daughter in a study (since she's the only one of the two who meets the criteria), he looked at me a moment and remarked that she would one of the healthier ones participating. In his experience of many years with a number of premature patients as well as significant research, he simply said that most kids enrolled in these studies are typically "not those that are doing well. Most, certainly not all, of those with decent to good outcomes are not commonly in these study groups. When I asked why not, he said that when the parents are contacted, they're usually too "busy", i.e their kids are either doing well and/or they want to put the NICU experience behind them. Interesting perspective. Interesting perspective.

Anonymous said...

Helen Harrison, continuing on the issue of "what did they know and when did they know it":

In my previous post, I quoted from a 1990 study by Kazzi et al, which showed a short-term respiratory "benefit" of steroids followed by *no* sustained benefit.

In response, an interesting letter to the editor was published in Pediatrics from pulmonologist Lee Frank MD, PhD.

Here are some quotes from his letter written *18* years ago!

"The distressingly high incidence of bronchopulmonary dysplasia (BPD) in today's very low birth weight premature infant population and the prolonged morbidity and tumultuous clinical problems associated with BPD in these tiny infants have led to a trial usage of dexamethasone treatment to try to assuage these problems in this patient population. The report by Kazzi et al is noteworthy because the authors not only indicate in clear fashion the failure of relatively prolonged dexamethasone treatment to ameliorate the hospital course of infants with BPD (in a randomized prospective double-blind study) but they also clearly identify potential risk factors associated with dexamethasone treatment that are of concern to them as clinical investigators, risk factors based both on clinical [human] and experimental animal studies. The investigators emphasize possible neurological sequelae of glucocorticoid treatment in neonates, but they also refer to potential growth inhibitory effects, and abnormal immunologic system function secondary to hormonal treatment.

"As one who is also concerned and uneasy about the continued use of dexamethasone in clinical trials ...especially when nearly all the clinical trails to date [in 1991!] have *not* demonstrated a meaningful sustained beneficial effect of dexamethasone treatment -- I feel it necessary to emphasize two major points about the detrimental effects of glucocorticoids in oxygen-requiring newborns...that may not be as well known to clinical neonatologists as the neurological and ...growth effects cited by Kazzi et al."

[And now I will paraphrase]:

1) evidence, from a variety of animal studies, consistently shows that oxygen toxicity is *worsened* by concurrent treatment with steroids. Steroids also prevent proper lung healing from injury induced by oxygen toxicity.

2) Exposure to excess oxygen [and no one knows for sure what "excess" is] is all it takes to shut down normal lung growth and development, so that survivors of BPD may have only 1/3 to 1/2 the amount of normal usuable lung tissue when all is said and done.

In animals, adding steroids to the developmental derangement of the lungs that oxygen causes, makes the shutdown of development much worse than it would be otherwise. This is particularly worrisome when you consider that the lungs of a 25-28 weeker would normally be entering a phase of accelerated growth and development of the alveoli.

Dr. Frank concludes:

"Faced with a series of well-conducted clinical trials which have mostly failed... to demonstrate any substantial sustained benefit of dexamethasone for either preventing of BPD, or for short-terming the morbid course of BPD, and faced also with many possible serious contraindications to such therapy...it is hoped that neonatal caretakers carefully consider whether the continued use of long-term [7 days!] dexamethasone treatment in this clinical setting can be justified."

Let me repeat ...this was published in 1991 --18 years ago!!!

Helen

Anonymous said...

I've got to reply to the last anon. That's our family for sure! We don't go back for studies, but when I read things like I do here, I feel guilty. We would skew the results as everything is fine despite 3 steroids, etc. I DO use the excuse of being to busy!

It just seems weird to drag myself back. To compensate, I do post at places like this so that its not so one sided.

BTW, at kid's preschool, there is a set of micropreemie twins. 27 weekers, 2.2 pounds and 1.1. They were born early because the 1.1 had NO HEARTBEAT, was "dead" and had to c-section to save the other.

The 1.1 pounder came out shocking everyone AND today he skateboards, skis, also cog. normal, no delays etc. (He is short). They are also both fine. The mom and I compare notes. They ALSO got the shots.

Anonymous said...

TO Anon 2:06
The studies don't show that 100% of the kids that got the shots have significant problems.
It shows:
The frequency of clinically significant disabilities was higher among children in the dexamethasone group than among controls (28 of 72 [39 percent] vs. 16 of 74 [22 percent], P=0.04).
I would think the bad outcomes outweight the good when the disparity is this huge. You mention the results are skewed because the good cases don't get followed up, in that I disagree. These studies start when the babies are born and certain controls are put into play. They are followed and the results are what they are.
I always advocate for more studies but I don't know why since the information from previous studies gets ignored. My son is 7 and he has only been in 1 study. Naturally, a study on RSV shots since RX companies have the money to fund them.
Very glad to hear your child's good fortune. Enjoy him or her.

Anonymous said...

Helen Harrison writes:

There seems to be some misunderstanding about the way children are followed for the purposes of scientific studies versus purposes of general intervention and services.

Children who had especially rocky NICU courses are often followed selectively (for non-scientific purposes) because they are *expected* to have serious problems that will need long term management and intervention. This seems to have been the case with the parent who was discouraged from coming to follow-up because her child was doing well. There is only so much funding to go around in this case, and you want to focus on the most serious cases.

Scientific studies have a different purpose and different methodology. Scientific studies define a cohort of children to study *from the outset* (birth, survival), when outcomes are unknown and cannot be predicted. *All* children are followed (to the extent that the parents co-operate). Children with severe problems are not selectively followed, children developing well are not excluded -- *everyone* is followed.

There is, of course, some loss to follow-up -- some parents move, are "too busy," some children die after leaving the hospital, some parents just don't want anything more to do with the hospital -- if they can avoid it.

And, in fact, when children whose parents do *not* voluntarily return for follow-up are aggressively tracked, they almost always turn out to be the *most* impaired. Their absence from follow-up, in fact, skews many follow-up studies toward optimism.

A huge body of research has shown this to be true.

So whether you feel your prematurely-born child is doing well or whether you suspect they *aren't* doing so well, please, please take them to follow-up if you are part of an actual *formal* scientific study, and if you are worried about "skewed" results.

It has been found, however, that the higher the percentage of "return to follow-up," the worse the outcomes of preemies appear to be -- think of the EPICure study.

Helen

ThePreemie Experiment said...

I think the biggest problem that I have with the NICU follow up is that the kiddos are only tracked until age 2 (or 3 in some NICU's). Many of the long term issues related to prematurity do not rear their ugly head until much later. The results are not accurate in my opinion.

Paige was discharged from the follow up study with the only issues being constipation, speech delay, fine motor delay and I think a minor large motor delay.

That doesn't even begin to tell her full story.

Anonymous said...

Helen Harrison adds:

Yes, TPE, the *duration* of follow-up is extremely important!

Those studies which last only a year or two are much more optimistic than those that last into late childhood, adolescence, or adulthood.

Preemies' brains (and other organs) change over time, and not in a good way, as a study in the same most recent issue of Pediatrics shows. The damage incurred as a result of prematurity and NICU care continues to disrupt development in new ways throughout life.

See: Ment et al. "Longitudinal brain volume changes in preterm and control subjects during late childhood and adolescence." _Pediatrics_ 2009;
123: 503-511.

Only the most obvious, severe disabilities can be diagnosed at age 2.

Our son, for example, was given a fairly clean bill of developmental health at the age of 3. The developmental psych said he was "socially and intellectually precocious," despite some "mild" motor delays. He even did fairly "well" in preschool.

Fast forward 32 years. Edward has an IQ of 59, a diagnosis of autism, CP -- he is ambulatory, but still significantly impaired by it, and needs one-on-one care. And that's only the beginning...I won't even get into the longterm health issues.

Short term studies yield falsely optimistic data. And preschool is too soon to make definitive statements about outcome.

Helen

future of hope said...

Helen wrote:
"Our son, for example, was given a fairly clean bill of developmental health at the age of 3. The developmental psych said he was "socially and intellectually precocious," despite some "mild" motor delays. He even did fairly "well" in preschool.

Fast forward 32 years. Edward has an IQ of 59, a diagnosis of autism, CP -- he is ambulatory, but still significantly impaired by it, and needs one-on-one care. And that's only the beginning...I won't even get into the longterm health issues."

I have wanted to ask a question everytime I have heard a recap of your story, but have hesitated because I didn't want it to be taken as a flame. I have worked with infants/toddlers/preschoolers for 20 years - many neuro-typical, and many not, to various degrees. What I find odd is that your son was considered "socially and intellectually precocious," at age three. Looking back, do you agree with that assessment, or was the developmental psych a flake? Especially on the "Social" part. A "socially and intellectually precocious" 3 year old should be meaningfully verbally, physically, and emotionally interacting with his environment, parents, and peers. How do you go from that to a measured IQ of 59? Do you feel that the current IQ assessment is accurate, or is it more of a result of him being untestable? How much of his current level of functioning is a result of additional damage that has occurred as he has grown due to shunt malfunctions, etc.?

Anonymous said...

I also have a question for Helen pertaining to her son. Not meant to be inflammatory either but I seem to recall you saying that Ed was "....walking (sort of) and talking (sort of) by age 2. Although these delays may not be significant red flags, how does a child clearly at risk make that big of a leap in a year only to fall tragically behind?

Anonymous said...

Also, what effect does a listeria infection during pregnancy have on in-utero development?

Anonymous said...

Helen Harrison in response to future of hope and anonymous 12:54:

Ed's early development was always on schedule for his corrected age (at least the very far side of the spectrum for his corrected age).

For example he began walking (usually toe walking) at about 18 months corrected age. (Our full term daughter by comparison was walking quite normally by 9-10 months.)

Ed's walking was soon followed by running (on tip toe), climbing, standing on his head, etc. Sounds good. But the walking never really looked quite normal. Ed would often hold his hands out for balance, toe walk, and his steps had an unnatural stiff and springy quality to them. (This was a manifestation of CP, we now know, as were signs of "precocious" head control, early flipping himself over, that were actually the result of spasticity).

Ed began talking even earlier than his fullterm sister and had quite a vocabulary by the age of two. He was even reading about 50 to 100words that he learned from flash cards by ages 2-3.

His normal sister, by contrast, was not at all interested in flash cards, and prefered to play with other children, toys, dolls and dress up clothes and listen to me read imaginative stories. She found the alphabet boring.

Ed was interested in memorization and rote learning -- and in a few obsessions he developed such as stickers, sliding boards, collecting and arranging little toys in rows, and marble rolls (red flags for autism, but no one knew or told us.)

Ed's development did indeed have many big red flags, but the experts who tested him were impressed by the fact that he was a whiz with a shape sorter, that he knew a trapezoid from a parallelogram (and was using these words at age 2), that he could count to 100, knew the alphabet, etc. He was also fairly good at making toddler type interactions with adults -- not so much with other children, but still not so unengaged with them as to be worrisome to the follow-up people.

It was to us, however, especially when we tried to take him to birthday parties and he would freak out from the sensory input of the noise (another big red flag).

As with many preemies who are later diagnosed with autism spectrum disorders, he was, in early childhood, hyperlexic and "advanced." and he did indeed leave the NICU follow-up clinic at age 3, having been declared cognitively and socially advanced, by a group of experts (who were either deceiving us or who should have known better).

But... as children grow they need the intellectual and emotional flexibility to handle an expanding social, physical, and cognitive world.

Ed couldn't manage this, and by age 6 it was obvious to us that he needed to be in a special education program or a special school.

He had not, at this time, been officially declared to have any problems other than hydrocephalus and vision problems, although he was receiving OT and PT.

And, BTW, we have never noticed any disintegration in his function due to hydrocephalus.(In fact, to this day he continues to make slow progress he is expressing himself a little better at age 32 years, using pronouns and tenses more accurately, playing more challenging music on his keyboards).

But as Ed aged from early to mid childhood, he became progressively further and further behind.

He had reached most of his potential very early -- he was our first child and we gave him *a lot* of attention.

His walking has became more labored and difficult as he got older and gained weight(CP was officially diagnosed at age 8 when he was referred for heel cord surgery).

Despite a great deal of exercise he continues to lose physical function with age (and this is typical in preemies with CP -- I know some who lose the ability to walk as they get older.)

Ed still walks slowly and with a bit of a limp, but doesn't run or stand on his head anymore.

His IQ was first measured when he was 18 and the psychologist was amazed that it was as "high" as it was, given Ed's lack of ability to function independently.

Ed, like other preemies, tends to test higher than his actual functioning would suggest because of his "splinter skills" such as the hyperlexia and math abilities (and calendar and music skills) typical of autism.

So, to sum up, compared with normal children, Ed usually reached early milestones within acceptable limits, but the "quality" of his walking and talking (though it sometimes seemed precocious, and certainly fooled the experts) was far from normal.

I have previously stated that preemies seem to manifest more brain damage as they age because the complexity of what they are expected to do changes with time. Many preemies, for example, excel at rote learning and memorization, and this gets them through the early years, but when more complex social skills and abstract thinking come into play, they are lost and fall behind.

Recent research, such as the MRI study I cited yesterday also seems to show that it the loss of function with age has a physical basis. Theses studies indicate that early damage continues to exert novel effects as the brain changes and remodels itself with age. So I can't rule out something like this having happened with Ed.

Overall, he seemed to hit a developmental wall at about
ages 4-6, and any progress he's made since then has been too slow to make much of a difference in his ability to live independently or in the level of care he still requires.

Helen

Anonymous said...

Helen Harrison to anon 1:45 who asked about listeria:

It all depends. I know children who were born at term infected with listeria who are normal. Other children die in utero.

It is a dangerous organism, but I'm not sure it is any worse in the long term effects it has on survivors than any of the other infectious organisms that cause preterm birth and subsequent damage (and most very preterm births are the cause of infection).

Ed is not considered especially handicapped for a preemie.

He is *only* *mildly* retarded, has *only* *mild* CP, which wouldn't even count in some studies since he is ambulatory without assistive devices. He is not totally blind, and in fact is able to read. His hearing is fine. So he would not be considered to be severely impacted by many neonatal follow-up studies, and yet he will never live independently or even semi-independently.

Helen

Anonymous said...

Helen Harrison amends previous comment:

most very early preterm births are caused by infection

ThePreemie Experiment said...

Helen wrote: "I have previously stated that preemies seem to manifest more brain damage as they age because the complexity of what they are expected to do changes with time. Many preemies, for example, excel at rote learning and memorization, and this gets them through the early years, but when more complex social skills and abstract thinking come into play, they are lost and fall behind."

Although Paige was delayed in expressive language until the age of 3 1/2 (when her language exploded and she tested on 7 year old level), she was always ahead of her peers in rote learning and memorization also. It wasn't until she became of an age where socialization was important that her differences started showing, to outsiders. (we could always see it)

Now that she is 10 I can see how critical thinking skills are hard for her. We homeschool so we've made it a priority to work on those skills. We have a bonus board on one of our doors where we put up a new riddle weekly. We also constantly work with her with regard to hypothetical situations. She is a literal person so these are difficult for her.

One of Paige's MRI's showed that she has right brain atrophy. I often wonder how much of that will affect her in the future.

terri w/2 said...

My daughter was diagnosed with Non-verbal learning disorder and aspergers at age 16. We had concerns about her development from about age 15 months or so.

She was very very very verbal - to the point of being scarey smart. She couldn't walk, but boy could she talk. Everyone thought she was gifted - even her grandma who was an administrator for a gifted and talented program in a large public school system.

Doctors who saw her were so impressed. I saw a child who while yes she could speak everything that was spoken to her, and had an incredible memory, there were huge gaps in her intellect. I am reminded of a beautiful Monet painting with a large chunk out of the center with a connect the dots picture - and the dots aren't connected.

Today at 23, she is neither gifted nor particularly talented, she is however, very disabled. She will never live independently. She has very big problems with social skills and problem-solving. She is in college and doing well scholastically, but can't figure out that if she parks in a "no parking" place, she's going to get parking tickets. . she seems to think that the school "knows her car" and knows that she has CP, therefore, they should give her a break when it snows. I have to tell her - and no one should be explaining this to a 23 year old. .that the campus is huge, the parking people do not know you or your car, and if you continue to park there (without a handicapped sticker) you're going to get a ticket.

This is just one of many, many, many daily issues that come up. On some level, she is very bright, on common sense issues, it is exasperating, exhausting, mind-numbing.

And yes, I have heard recently also that as the brain ages - particularly around puberty, that the growth can actually cause damaged areas to become more pronounced, causing the child to lose skills they once had.

MasterpieceMom said...

So what would be the alternative? Nephew born at 25 weeks--they are getting ready to do a 10 day round of steriods on him for his lungs. Right now he's fighting pneumonia.

Anonymous said...

And yes, I have heard recently also that as the brain ages - particularly around puberty, that the growth can actually cause damaged areas to become more pronounced, causing the child to lose skills they once had.

Anonymous said...

And yes, I have heard recently also that as the brain ages - particularly around puberty, that the growth can actually cause damaged areas to become more pronounced, causing the child to lose skills they once had.

Roberta said...

Please, Moms, there is so much more to neonatal care than the occasional reading of an article. First of all, the 2 doses of betametahsone given to Mom in preterm labor have prevented so much pain and sufefring it's hard to list them all. The AnteNatalSteroids (ANS) have been proven for 30 years to be safe and effective. As to the PostNatal: for many years in the past the dosing and the length of treatment were HIGH and LONG. As in 6 weeks at high dose, full milligrams per unit of body weight. Those were certainly associated with long term neurodevelopmental effects, such as preventing the grey matter from growing. But both the dose and the length have been dramatically decreased: different steroids, since they each have a different power, as well as tiny doses - tenths of milligram, 0.05, 0.01..., and the duration: 3 to 10 days. We are not anywhere near the same effects. But steroids are precious medications. They will be given to the former preemie or full term kid who develop asthma, they are very effective in quenching inflammation, they are frequently used inhaled, with applciations such as allergic rhinitis - hay fever - etc. But the prolonged ventilator use, high oxygen, frequent drops in oxygenation are so bad for the preterm infant! Very little to do with legal actions against unconscionable use of toxic drugs by mindless neonatologists. Please. We are in this line of work because we truly care about these fragile babies, not because we EXPERIMENT on them.

Roberta said...

And this comment by a highly respected and truly compassionate neonatologist may illustarte our perspective better.

PEDIATRICS Vol. 111 No. 1 January 2003, pp. 221-222

Postnatal Steroids to Treat or Prevent Chronic Lung Disease in Preterm Infants
To the Editor.—
The recommendations from the American Academy of Pediatrics Committee on Fetus and Newborn concerning use of postnatal steroids to prevent chronic lung disease in premature infants1 is a wonderful review and synopsis of the literature. In general, I applaud the spirit of the recommendation that, in essence, we restrict the use of this drug to a population of infants much sicker than those treated historically. However, I feel that, as was done in the past, we as neonatologists may be taking this to another extreme and may cause more harm by not administering steroids than we presently do.

I concur that neonatologists jumped on the dexamethasone bandwagon with both feet and without thinking through the potential complications clearly. I attended a Neonatal Pharmacology Conference in 1995 where a leader in the field stated, "If you are going to use steroids, use them early." Obviously, many infants who were only moderately ill received steroids, and we need to curtail this practice. However, steroids have probably been life-saving in some infants and should be strongly considered for patients with severe pulmonary disease. For instance, in the study by Kothadia et al,2 at first glance one would assume that the enrolled patients were quite ill, with an average oxygen requirement at entry of F2 (fraction of inspired oxygen) of 0.60. However, the range went as low as F2 (fraction of inspired oxygen) of 0.30, a concentration that many would agree should not lead to use of a potentially dangerous medication. More importantly, their data shows a strong trend favoring survival, with only 7 of 57 dexamethasone-treated infants dying compared with 16 of 61 controls (P = .07). Is this a random finding that 9 more infants died who did not get steroids?

This leads me to my major disagreement with the statement—parental consent before use. Does anyone feel that the parents are in a better position to make the judgment about steroid use than the practicing neonatologist? I don’t, just as I don’t feel they are in a better position to choose when, which, and how often to use surfactant, if nitric oxide should be used, or if a cephalosporin should be used instead of an aminoglycoside. Are these important topics that we do not have the ultimate correct answer for at this time? Absolutely. But, to me, it just means that educated, informed physicians should come together and decide when these therapies should be applied using the best data available at that time. I believe that within the group of neonatologists at our institution, we can establish criteria for dexamethasone use in our neonatal intensive care unit, reserving it for patients that are at high risk for death or severe chronic lung disease. Our training and experience have given us more information and knowledge concerning this issue than we could ever impart on the parents. Finally, we have the best interests for the health of children in mind as we make guidelines for dexamethasone use, as is our responsibility.

Roberta said...

Continued:
I do not feel that we should abdicate our decision-making responsibilities to the families for these issues. How many other medications do we use in the neonatal intensive care unit that have been subjected to far less scrutiny than glucocorticoids that also have detrimental side effects? It’s a slippery slope—today, dexamethasone; tomorrow, ampicillin? I do not feel that this is a decision that parents should be forced to make because of the potential guilt that they will be carrying for life. As with all of our critical care therapies that have potentially detrimental as well as beneficial consequences, we should be communicating with the parents and making them aware of the seriousness of the situation. The issue of informed consent for much of the practice of neonatology is an important issue; however, in my opinion, the use of glucocorticoids is not a decision that should require parental consent.

David J. Burchfield, MD
Professor and Chief, Neonatology
University of Florida
Gainesville, FL 32610, USA

Lenett said...

I know everyone will jump all over this, but my kid had trouble getting off the vent, had the steroids, is now 4 and is fine.