The analysis by Yates and Newell points out the need for new trials to determine if there is a safe and effective way to give postnatal steroids for preterm infants. A conclusion that I can only agree with. However their article is limited by one major error, and by the failure to describe one of the serious limitations of the available evidence.
The Major error is contained in the section "CLD severity and CP risk". The authors s...
The analysis by Yates and Newell points out the need for new trials to determine if there is a safe and effective way to give postnatal steroids for preterm infants. A conclusion that I can only agree with. However their article is limited by one major error, and by the failure to describe one of the serious limitations of the available evidence.
The Major error is contained in the section "CLD severity and CP risk". The authors state that the meta-analysis of Doyle et al "found in babies at high risk of CLD that steroid treatment reduces the risk of CP". This is untrue. It would indeed have been a remarkable result as there is not one single individual trial in their review which has shown a reduction in CP with postnatal steroids.
The meta-regression which these authors are referring to was a comparison of control group CLD frequency to the COMBINED OUTCOME OF DEATH OR CP. This has clearly very different implications. If we examine the data used by Doyle et al for that meta-analysis, the studies with a greater than 50% rate of CLD among controls, CP frequency INCREASED among the steroid treated babies by 36%, while mortality decreased. The combined outcome of death or CP among this subgroup of trials is in fact 65/206 steroid treated, and 69/197 controls.
The serious limitation of all the current evidence that was not discussed is the very high frequency of contamination (treatment of control babies with steroids) in the majority of the studies. Many of the studies having over 50% (and up to 75%)rates of contamination. Such an enormous exposure of controls to steroids, has been one of the major hindrances to understanding the effects on long term outcomes. This rate of contamination also affects meta-regression discussed above, as the studies with higher rates of control group CLD also had high rates of contamination.
The multiple systematic reviews of steroid therapy do show certain circumstances where mortality appears to be reduced, and under certain circumstances the reduction in mortality may be greater than the increase in CP. Future studies of postnatal steroids should target such circumstances and should severely limit the use of steroids among controls, as far as ethically appropriate.
The author has read with great interest the report of Leow and Ward
Platt (1), who accurately studied the incidence of sudden, unexpected and
unexplained early neonatal deaths in the North of England giving an
overall rate of 0.35/10,000 live births.
While several works have stressed the importance of post-mortem
examination in every case of suspected sudden infant death syndrome
(SIDS), little, if any, attention has bee...
The author has read with great interest the report of Leow and Ward
Platt (1), who accurately studied the incidence of sudden, unexpected and
unexplained early neonatal deaths in the North of England giving an
overall rate of 0.35/10,000 live births.
While several works have stressed the importance of post-mortem
examination in every case of suspected sudden infant death syndrome
(SIDS), little, if any, attention has been given to the mandatory need to
apply the same investigational protocol also in all cases of sudden
perinatal unexplained death, i.e., sudden neonatal unexplained death
(SNUD) and sudden intrauterine unexplained death (SIUD) (2-5).
First of all, it should be underlined that there is a clear continuum
between unexplained perinatal death and SIDS, as developmental
abnormalities have been detected to be common to both, particularly in the
cardiac conduction system and in the brainstem centers regulating vital
functions. From the analysis of the conducting tissue, the following
pathological findings emerged: accessory atrio-ventricular pathways,
mostly Mahaim fibers, cartilaginous hypermetaplasia, abnormal resorptive
degeneration, junctional islands, persistent fetal dispersion, hypoplasia
of the cardiac conduction system or of the central fibrous body, splitting
of the atrio-ventricular node or of the His bundle, and the Zahn node. All
of these cardiac conduction findings may be isolated incidents, but they
are frequently associated with autonomic nervous system alterations of the
brainstem (2-5).
There is evidence to hypothesize the presence of a preexisting damage
in the cardiac conduction system and brainstem of vulnerable subjects, not
only in infants - newborns 0-1 month-old and infants 1-12 month-old - but
also, and at a greater frequency, in fetuses(2-5). This preexisting
vulnerability, if associated to a supervening pathology, such as a
bronchus-pneumonic or a placental infection act as triggering phenomenon
in particularly vulnerable infants and fetuses. The SIUD/SNUD/SIDS event
would occur, in subjects with preexisting still quiescent and undetected
abnormality in the conducting tissue and/or brainstem, when a new
pathological event, itself not deadly, concurs.
REFERENCES
1. Leow JY, Ward Platt MP. Sudden, unexpected and unexplained early
neonatal deaths in the North of England. Arch Dis Child Fetal Neonatal Ed
2011 Mar 11. [Epub ahead of print]
2. Matturri L, Ottaviani G, Lavezzi AM. Guidelines for neuropathologic
diagnostics of perinatal unexpected loss and sudden infant death syndrome
(SIDS): a technical protocol. Virchows Arch 2008;452:19-25.
3. Ottaviani G. Crib death. Sudden unexplained death of infants: the
pathologist's viewpoint, Springer-Verlag, Berlin Heidelberg, Germany 2007.
4. Matturri L, Ottaviani G, Ramos SG, Rossi L. Sudden Infant Death
Syndrome (SIDS): a study of cardiac conduction system. Cardiovasc Pathol
2000;9:137-45.
5. Ottaviani G, Matturri L. Histopathology of the cardiac conduction
system in sudden intrauterine unexplained death. Cardiovasc Pathol
2008;17:146-55.
The article "Global Burden of Rh hemolytic disease" is an excellent
article, highlighting the problem, statistics of the problem and
preventive aspect. No doubt rh hemolytic disease is preventable as
examplified in developing countires by antenatal rh group testing of
mothers,use of anti-d and iv immunoglobulin in affceted neonates, along
with effective phototherapy .
In developing countries and in India, data from inst...
The article "Global Burden of Rh hemolytic disease" is an excellent
article, highlighting the problem, statistics of the problem and
preventive aspect. No doubt rh hemolytic disease is preventable as
examplified in developing countires by antenatal rh group testing of
mothers,use of anti-d and iv immunoglobulin in affceted neonates, along
with effective phototherapy .
In developing countries and in India, data from instituional deliveries
from neonatal units shows a high incidence of hyperbilirubinemia (hbil)
,almost 0ne fourth to one third of nursery admissions need phototherapy.
With a high burden of low birth weight babies ,problem of hbil is further
increased. A study from Northern India (Narang et al 2001 Ind Pediatr)
noted that 76.6% of vlbw babies devloped hbil in nicu,37%of them required
exchange transfusion. They further noted that hbil incidence increased
with decreasing birth weight and 12.8% of vlbw had g6pd deficiency .Nnf
Database 2002-2003,showed incidence of hbil 3.3%in a large multi
institutinal study of nearly 1.5 lac neonates. Pathological hbil was
noted by Murki etal(2009 jour neonatology) in 2-10% of nicu babies and
1/3rd of total needed phototherapy . Similar observations were made by
Timan et al from pakistan(Tropical and International health 2010).
Although neonatal hbil is a problem, rh hemolytic disease is not a
major factor in hospital studies . Among 1060 inborn nicu admissions in a
govt hospital in Delhi, 24% had serum bilirubin >12.0 mg/dl, only 12
babies developed bilirubin level>20.0mg/dl. Etiology of hbil was
prematurity in 65%, abo incompatibility in 11% ,rh in 2.2% of cases. A
recent observation from NICU with intramural and extramural births among
1852 neonates, 22.0 % had hbil, of these rh hemolytic diseae was noted in
6.0% of cases only and of 34 babies who needed exchange transfusion, only
6 were due to rh incompatibility. Incidence of pathological hbil is noted
to be higher in extramural births , almost 20-30 cases of bilirubin
encephalopathy were noted in a nicu with only extramural admissions.
All these observations reveal that in our setup neonatal hbil is a
major issue and its anticipation and early managemant are the priority
issue. While rhhdn is an important and preventable issue, other causes are
also important specially prematurity, sepsis, birth asphyxia etc. Trends
in early discharge of neonates in hospital births with poor followup in
resource poor counties adds up to the problem. Incience of institutional
and supervised birhs is still less than 50%, the data is mostly among
hospital births, what about home births, majority in case of
illness or hbil either do not seek help or reach hospital too late for
intact survial. High bilirubin level can cause neurological damage and
later sequalae,. It was noted earlier that prolonged hbil is also harmful
with hearing problems later, and developmental dealy.(Ghosh et al ind
pediar 1971). In a study of 400 nicu graduates, among 90 with cerebral
palsy .50% had hbil,along with other risk factors.
Hence , efforts be made to create universal issue of yellow alert in
neonates ,by creating public awareness through media, educational
instituions and health education .Also to reduce burden of hbil and
intact survival later health professionals should try to deliver babies at
term as burden of late preterms is increasing and antenatal care for
managing complications of pregnancy is the pragmatic approach along with
making mother aware of danger signs in newborn at delivery,and attention
to feeding problems.
sudershan.kumari@gmail.com
We read the article by Jones et al with great interest describing
Ibuprofen may increase the risk of chronic lung disease (CLD) compared to
Indomethacin. We are unsure whether the data presented is fully supportive
of the conclusion that Ibuprofen poses a greater risk of CLD compared to
Indomethacin and whether this is clinically significant.
In Figure 4 the pooled risk ratio (RR) was 1.28 (95...
We read the article by Jones et al with great interest describing
Ibuprofen may increase the risk of chronic lung disease (CLD) compared to
Indomethacin. We are unsure whether the data presented is fully supportive
of the conclusion that Ibuprofen poses a greater risk of CLD compared to
Indomethacin and whether this is clinically significant.
In Figure 4 the pooled risk ratio (RR) was 1.28 (95% confidence
interval (95%CI) 1.03-1.60) and the p value p=0.03. However only 6 studies
were used, of these only 3 showed a higher risk ratio with Ibuprofen, with
the other 3 studies in fact showing a protective effect. The lower end of
the pooled RR 95% CI was also somewhat close to 1.0. In addition all the
studies' 95% confidence intervals of the RR include 1.0, further reducing
the statistical significance despite the p value being significant.
During the past five years, therapeutic hypothermia (TH) was shown to be effective and safe in improving neurodevelopmental outcome after hypoxic ischaemic encephalopathy (HIE) in newborns.(1) The use of this
therapy has been rapidly incorporated into clinical practice in many countries, even though many doubts related to clinical management and monitoring remain unanswered.(2) The lack of a national appro...
During the past five years, therapeutic hypothermia (TH) was shown to be effective and safe in improving neurodevelopmental outcome after hypoxic ischaemic encephalopathy (HIE) in newborns.(1) The use of this
therapy has been rapidly incorporated into clinical practice in many countries, even though many doubts related to clinical management and monitoring remain unanswered.(2) The lack of a national approach to TH, such as its inclusion in protocols shared among NICUs, is widely recognized.(3)
TH is employed in 1-3/1000 births in the north of the world and is 10-20
times more frequent in low resources settings. In such critical contexts, TH may be useful, but its utility needs to be proven. Wilkinson et al. addressed the difficulties in applying trial results from developed to developing countries and underlined the need for formal, randomized
controlled trials of TH in low- and middle income countries.(4)
The problem with transferring findings from an experimental context to clinical practice is one of the major challenges of modern evidence based medicine and TH is a fitting example. TH is effective if:
a) the management of multiorgan dysfunction is guaranteed;
b) appropriate interventions to confirm the diagnosis and routinely monitor cerebral function are carried out;
c) counseling and support to the family are provided. These are the essential responsibilities and rights that must be present when TH is employed, both in the North and South of the world.
Difficulties in generalizing TH are still present in the North and are amplified in the South, where priorities and resources are different.
There are low-cost interventions shown to be effective in reducing neonatal death and perinatal impairment outcomes in developing countries that must be implemented, diffused, and adequately monitored over the time.(5) According to the principles of equity, a global use of TH should be expected if and when other essential procedures are guaranteed. Thus, ethical and practical priorities, especially in settings in which HIE occurs more often (i.e. rural or isolated villages), suggest that, before focusing on randomized controlled trials of TH, more effective means to
provide and guarantee basic perinatal care over time in order to reduce HIE and the need for its treatment must be met.
Reference
1. Azzopardi D. Clinical management of the baby with hypoxic ischaemic encephalopathy. Early Human Develp 2010; 86:345-50.
2. Barks JD. Current controversies in hypothermic neuroprotection. Semin Fetal Neonatal Med 2008; 13:30-4.
3. Allen NM, Foran A, O'Donovan DJ. Neonatal therapeutic hypothermia: practice and opinions in the Republic of Irealand. Arch Dis Child Fetal Neonatal Ed doi:10.1136/adc.2010.195354.
4. Wilkinson DJ, Thayyil S, Robertson NJ. Ethical and practical issues relating to the global use of therapeutic hypothermia for perinatal asphyxia encephalopathy. Arch Dis Child Fetal Neonatal Ed 2011;96 F75-F78.
5. Waldemar CA et al. Newborn-care training and perinatal mortality in developing countries. N Engl J Med 2010; 362:614-23.
We read this paper with interest and would like to comment. The
authors have concluded that there is little evidence that early postnatal
hypotension indicators are associated with developmental delay at 24
months corrected in their large cohort of extremely low gestational age
newborns.
We agree with their conclusion as our recent study in 11 asphyxiated
term infants demonstrated the simila...
We read this paper with interest and would like to comment. The
authors have concluded that there is little evidence that early postnatal
hypotension indicators are associated with developmental delay at 24
months corrected in their large cohort of extremely low gestational age
newborns.
We agree with their conclusion as our recent study in 11 asphyxiated
term infants demonstrated the similar results (1): there were no
significant differences in mean arterial blood pressure (ABP) nor mean
cerebral blood flow (CBF) during the first 4 days of life between 5
infants with delayed development and 6 infants with normal development at
20 months of age. Interestingly enough, however, significant difference
(p=0.04) was found in an average stability index during the first 48 hours
of life (SI), arbitrarily defined as a coefficient of variation of CBF
monitored by a newly developed laser doppler flowmeter system (CDF Trend,
LIBMECH Inc. Tokyo, Japan) (2).
Cerebral blood passivity develops when changes in blood pressure
exceed the capacity of the intact cerebral autoregulatory system or the
system is impaired by illness such as HIE. In such a situation, ABP may
directly affect and are expected to correlate with CBF. Contrary to our
expectation, however, there was no significant relationship between the
mean ABP and CBF even in the 5 infants with HIE in the present study.
Thus, function of cerebral autoregulatory system, which is expected
to be a good predictor for neurological prognosis, cannot be assessed by
simple measurements of ABP. Serial monitoring of CBF stability during
early neonatal period assessed as SI by a novel laser doppler flowmeter
can be sensitive indicator for cerebral autoregulatory system as it
reflects instability of CBF in the vulnerable period. Further study will
be worthwhile.
References
1. Ohashi A, Kuroyanagi Y, Kitamura N, Kinoshita Y, Kaneko K, Yabuta K.
Cerebral blood flow monitoring using a novel laser Doppler flowmeter in
asphyxiated infants. Pediatr Int. 2009; 51: 715-719
2. Niwayama J, Sanaka Y. Development of a new method for monitoring blood
purification: the blood flow analysis of the head and foot by laser
Doppler blood flowmeter during hemodialysis. Hemodial Int. 2005; 9: 56-62
The article by Prendergast et al describes an important outcome following
a very common antenatal complication. However, there is no description of
the proportion of infants surviving in the two groups which may overshadow
any lack of difference in BPD development between the two groups.
In the statistical methods no assessment appears to have been made in the
regression model between duration of membrane...
The article by Prendergast et al describes an important outcome following
a very common antenatal complication. However, there is no description of
the proportion of infants surviving in the two groups which may overshadow
any lack of difference in BPD development between the two groups.
In the statistical methods no assessment appears to have been made in the
regression model between duration of membrane rupture and BPD risk. An
interaction could also have also been tested within the regression model
to assess whether any effect modification exists between duration of
membrane rupture and presence of chorioamnionitis.
This additional information would be of use for counselling parents
following delivery in the presence of chorioamnionitis.
Vallabhaneni et al. describe a preterm infant developing obstruction secondary to bezoar formation. This is a rare but important occurence. The relationship with gaviscon (an un-licensed and un-proven treatment for gastro-oesophageal reflux) has been previously reported in this journal and is an alternative explanation. Should this be reported using the yellow card system to the BNF?
Vallabhaneni et al. describe a preterm infant developing obstruction secondary to bezoar formation. This is a rare but important occurence. The relationship with gaviscon (an un-licensed and un-proven treatment for gastro-oesophageal reflux) has been previously reported in this journal and is an alternative explanation. Should this be reported using the yellow card system to the BNF?
Dr. Millar raises the point that an alternative broader-spectrum (and
more expensive) antibiotic combination could be considered for empirical
therapy of neonates with suspected early-onset sepsis in preference to
penicillin and gentamicin which (based on our data) he estimated to be
ineffective for 6% of cases.
We support Dr Millar's view on the importance of appropriate
empirical antibiotic treatment for septi...
Dr. Millar raises the point that an alternative broader-spectrum (and
more expensive) antibiotic combination could be considered for empirical
therapy of neonates with suspected early-onset sepsis in preference to
penicillin and gentamicin which (based on our data) he estimated to be
ineffective for 6% of cases.
We support Dr Millar's view on the importance of appropriate
empirical antibiotic treatment for septic neonates and the need to discuss
acceptable thresholds for antibiotic resistance. However, extrapolating
the number of neonates experiencing clinical failure of treatment and
subsequent adverse effects from the proportion of pathogens resistant to
the empiric antimicrobials used for treatment should be treated with
caution since in vitro resistance does not necessarily equate to treatment
failure in vivo. We were unable to address this important issue in our
published study due to the lack of clinical information and outcome data
in the laboratory surveillance data analysed. Our recommendation was based
on a value judgement where we weighed poorly quantified but serious risk
and costs of increased antibiotic resistance for future patients against a
potentially serious adverse effect of using less effective antibiotics in
a small number of patients.
Avoiding selection pressure, particularly for carbapenem resistance
in Gram-negative bacteria, should be paramount in Neonatal Intensive Care
Units. Furthermore, clinical experience suggests that although antibiotics
should be stopped by 48 hours when cultures are found to be negative, this
will not always be the case. Further research is needed to evaluate
outcomes for neonates receiving empirical antibiotic treatment in order to
define appropriate therapy and subsequently identify 'high risk' patients
for whom guidelines might need to be amended. The National Institute for
Health and Clinical Excellence (NICE) is currently reviewing the
management of neonatal infections and this could perhaps be one of the key
areas of future research.
Black women produce more testosterone than white women and, I
suggest, this is directly involved in problematic birth weights of
offspring which occur more often in black women. Additionally, I think
testosterone is increasing in women of different races and may account for
ongoing changes in birth weight of offspring as well as a group of other
negative pregnancy outcomes and problems in these offspring in later life....
Black women produce more testosterone than white women and, I
suggest, this is directly involved in problematic birth weights of
offspring which occur more often in black women. Additionally, I think
testosterone is increasing in women of different races and may account for
ongoing changes in birth weight of offspring as well as a group of other
negative pregnancy outcomes and problems in these offspring in later life.
A syndrome is occurring in America and other countries, the cause of
which is often attributed to one part or another of the syndrome and more
often attributed to the environment or life style. I suggest a single
cause may be involved that is biological and evidence of ongoing
evolution.
It is my hypothesis that the "secular trend," the increase in size and
earlier puberty occurring in children, is caused by an increase in the
percentage of individuals of higher testosterone. More specifically, I
suggest this is due to an increase in the percentage of mothers of higher
testosterone with time within the population. This exposes more fetuses to
increased maternal testosterone with time within the population. This
causes permanent effects in the fetus which persist throughout the life
span. I suggest this is the cause of the parallel increases in morbidity
occurring within the population, such as obesity, cancer, breast cancer,
diabetes, etc., including prematurity, small for gestational age, etc.,
including less obvious gross effects which later contribute to "failing
schools" and other adverse behavioral outcomes in children.
I have come to the conclusion that the "increase in testosterone" may
partially be due to a reduction in "sex hormone binding globulin (SHBG)"
as a number of phenomena explained by the secular trend may be based on
changes in SHBG. A decrease in SHBG increases free testosterone levels.
Low SHBG has been found in obese children who do not produce excessive
testosterone. A number of negative phenomena which may be caused by
increased testosterone are found with low SHBG and a number of positive
effects of reduced SHBG exist.
It is my hypothesis that human evolution is driven by increases in
testosterone ("Androgens in Human Evolution," Rivista di Biologia /
Biology Forum 2001; 94: 345-362). This was directly supported by research
in 2003; see the chart of testosterone levels in humans and related great
apes, upper left at www.anthropogeny.com . I suggest that periodically
testosterone increases excessively and the exposure to excessive maternal
testosterone causes negative and evolutionarily consequential changes to
the human population. We may be experiencing this effect at this time.
The author has read with great interest the report of Leow and Ward Platt (1), who accurately studied the incidence of sudden, unexpected and unexplained early neonatal deaths in the North of England giving an overall rate of 0.35/10,000 live births. While several works have stressed the importance of post-mortem examination in every case of suspected sudden infant death syndrome (SIDS), little, if any, attention has bee...
The article "Global Burden of Rh hemolytic disease" is an excellent article, highlighting the problem, statistics of the problem and preventive aspect. No doubt rh hemolytic disease is preventable as examplified in developing countires by antenatal rh group testing of mothers,use of anti-d and iv immunoglobulin in affceted neonates, along with effective phototherapy . In developing countries and in India, data from inst...
Dear Sir,
We read the article by Jones et al with great interest describing Ibuprofen may increase the risk of chronic lung disease (CLD) compared to Indomethacin. We are unsure whether the data presented is fully supportive of the conclusion that Ibuprofen poses a greater risk of CLD compared to Indomethacin and whether this is clinically significant.
In Figure 4 the pooled risk ratio (RR) was 1.28 (95...
Dear Editor,
During the past five years, therapeutic hypothermia (TH) was shown to be effective and safe in improving neurodevelopmental outcome after hypoxic ischaemic encephalopathy (HIE) in newborns.(1) The use of this therapy has been rapidly incorporated into clinical practice in many countries, even though many doubts related to clinical management and monitoring remain unanswered.(2) The lack of a national appro...
Dear Sir,
We read this paper with interest and would like to comment. The authors have concluded that there is little evidence that early postnatal hypotension indicators are associated with developmental delay at 24 months corrected in their large cohort of extremely low gestational age newborns.
We agree with their conclusion as our recent study in 11 asphyxiated term infants demonstrated the simila...
Dear Sir,
The article by Prendergast et al describes an important outcome following a very common antenatal complication. However, there is no description of the proportion of infants surviving in the two groups which may overshadow any lack of difference in BPD development between the two groups. In the statistical methods no assessment appears to have been made in the regression model between duration of membrane...
Reference
(1) Sorbie AL, Symon DN,...
Dr. Millar raises the point that an alternative broader-spectrum (and more expensive) antibiotic combination could be considered for empirical therapy of neonates with suspected early-onset sepsis in preference to penicillin and gentamicin which (based on our data) he estimated to be ineffective for 6% of cases.
We support Dr Millar's view on the importance of appropriate empirical antibiotic treatment for septi...
Black women produce more testosterone than white women and, I suggest, this is directly involved in problematic birth weights of offspring which occur more often in black women. Additionally, I think testosterone is increasing in women of different races and may account for ongoing changes in birth weight of offspring as well as a group of other negative pregnancy outcomes and problems in these offspring in later life....
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