July 2010 Fact Sheet

Drs. Sylvie Girard and Guillaume Sébire, recently published a study in the April 2010 issue of the Journal of Immunology examining the role of maternal bacterial infection and inflammation occurring at the end of gestation. Although it is recognized as an independent risk factor for neuro-developmental disorders such as cerebral palsy, mental deficiency, and autism, it remains unclear whether the inflammation is causal or simply associated with these conditions. The two authors prepared the following literature review regarding maternal infection, inflammation and perinatal brain damage.

The mechanism linking maternal inflammation and fetal brain anomalies is still a controversial matter. In this study, we injected lipopolysaccharide (LPS, also known as endotoxin) from E. coli into the peritoneal space of gravid rats and showed that placental inflammation and the expression of pro-inflammatory cytokines, mainly IL-1beta, can be implicated in perinatal brain damage. The causal link between IL-1 and the altered brain development was documented when an IL-1 receptor antagonist, (L-1Ra) given to the gravida protected her pups (increased survival rate, decreased microglial activation, and preservation of motor functions). Perhaps, the use of IL-1Ra could be a therapeutic strategy to protect against perinatal brain damage arising from pathogen-induced gestational inflammation in humans.

Strength and limitations of the rat model?
An important strength of our animal model is the clinical relevance of the experimental design. We triggered inflammation by exposing the pups prenatally to a relatively low amount of bacterial component (LPS) at the end of the gestation, during a window of high susceptibility of the developing brain (corresponding to the level of brain development of early premature infant in humans, about 26-30 weeks of gestation). However, some limitations of our model need to be taken into account. For example, there are some obvious differences between human and rat brains (i.e. pre- vs post-natal maturation, gyrencephalic vs non-gyrencephalic architecture, amount of white matter…). It is also important to keep in mind that the inflammatory stimulus used (LPS from E. Coli) is a specific Toll-Like receptor4 agonist and therefore results cannot be generalized to other types of in utero infections that might be encountered.

Since LPS results in a broad inflammatory response, how come the IL-1Ra was so effective in minimizing placental and brain damage?
IL-1beta being the cytokine that was early and predominantly expressed within placenta exposed to LPS-induced gestational inflammation, we hypothesized that the IL-1 family might be at the apex of the inflammatory cascade of induction of other cytokines and subsequently to perinatal brain damage. Support for such a concept in human disease comes from gout in adult, and polyarthritis in children. We hypothesized that the cytokines all act together and that stopping one might disrupt the whole system. The powerful IL-1Ra protection we observed on the placenta strongly suggests that the beneficial effects on the pups were, at least in part, mediated by an indirect effect of IL-1 blockage that maintained placental integrity and its neurotrophic functions.

What if IL-1Ra were given postnatally?
Although the therapeutic potential of IL-1Ra in adult brain inflammatory model is increasingly recognized, there are to our knowledge no studies that addressed this issue in the neonatal period. Depending on the developmental time window when the IL-1Ra is administered, the impact could be beneficial without any deleterious impact on brain maturation. However, IL-1 might have physiological effects at this stage of development (e.g. likely role in myelination), so the effect of the IL-1Ra treatment should be carefully assessed both on tissue and on animal behaviour.

How do these results fit with what else has been published?
Others have published reports indicating a potential role of IL-1 in perinatal infectious/inflammatory and/or hypoxic-ischemic (HI) brain damage:

• Cai’s group showed that intra-cerebral injection of IL-1 induced brain damage (2)
• Gressens group showed that systemic IL-1 injection enhanced excitotoxic brain lesions, and the impact of maternal infection on brain development (3,4)
• Hagberg’s group showed that IL-1Ra protected against post-natal HI (5)
• Our group showed in human brain and in preclinical models, the temporal-spatial association between IL-1 expression  and neonatal brain damage (6).

This is just a short overview of the large amount of work that has been done on the role of IL-1 in perinatal brain damage. Thus, our results are in line with what has been hypothesized previously, and helps establish a causal role of IL-1 in the molecular cascade linking gestational inflammation and brain damage in the offspring. Altogether, these data suggest that post-natal IL-1 blockade might add some benefits to the prenatal blockade, not only in the initial inflammatory insult, but also in continued/sustained/prolonged inflammation.  We are currently testing this hypothesis on our preclinical models.

What is the relevancy of this to humans?
The use of IL-1Ra is less broad spectrum than, for example, glucocorticoids which are known to have some deleterious effects of brain development. Thus, a more specific treatment, aiming at one cytokine might be the key to selectively limit the negative effects of inflammation while keeping the likely role of cytokines during this important period of development. In our work, the fact that we studied the impact of IL-1Ra treatment on several end-points, including placenta integrity, cytokines expression, pups’ survival and brain development (i.e. histology and behavioural outcomes) without any short term deleterious effects is encouraging for potential translation. However, attention should be paid to the potential risk of deleterious effects of cytokine blockers, even before preclinical models are considered.

Encouragingly, there has been a recent single case report of IL-1Ra administration throughout pregnancy (as a treatment for Still disease) without any apparent deleterious impact on the fetus, birth and postnatal development so far (7). IL-1Ra is also used to treat cohorts of adults who have gout, and is also used in newborns and infants with inflammatory diseases (e.g. CAPS syndrome, CINCA/NOMID syndrome, Still disease) and seem to be efficient and well tolerated (8-10).

Citations

1. Girard S, Tremblay L, Lepage M, Sébire G. IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation. J Immunol 2010;184:3997-4005.
2. Cai Z, Lin S, Pang, Rhodes PG. Brain injury induced by intracerebral injection of interleukin-1beta and tumor necrosis factor-alpha in the neonatal rat. Pediatr. Res 2004;56:377–384.
3. Plaisant F, Dommergues MA, Spedding M, Cecchelli R, Brillault J, Kato G, Muñoz C, Gressens P. Neuroprotective properties of tianeptine: interactions with cytokines. Neuropharmacology 2003;44:801-9.
4. Rousset CI, Chalon S, Cantagrel S, Bodard S, Andres C, Gressens P, Saliba E. 2006. Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats. Pediatr. Res. 59:428–433.
5. Hagberg H, Gilland E, Bona E, Hanson LA, Hahin-Zoric M, Blennow M, Holst M, McRae A, Söder O. Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats. Pediatr Res 1996;40:603-9.
6. Girard, S., H. Kadhim, A. Larouche, M. Roy, F. Gobeil, and G. Se´bire. Pro-inflammatory disequilibrium of the IL-1 beta/IL-1ra ratio in an experimental model of perinatal brain damages induced by lipopolysaccharide and hypoxiaischemia. Cytokine 2008;43:54–62.
7. Berger CT, Recher M, Steiner U, Hauser TM. A patient’s wish: anakinra in pregnancy. Ann Rheum Dis 2009;68:1794-5.
8. Goldbach-Mansky R. Blocking interleukin-1 in rheumatic diseases. Ann N Y Acad Sci 2009;1182:111-23.
9. Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, Pinto G, Pagnier A, Bodemer C, Bodaghi B, Tardieu M, Prieur AM, Quartier P. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum 2010;62:258-67.
10. Miyamae T, Inaba Y, Nishimura G, Kikuchi M, Kishi T, Hara R, Kaneko U, Shinoki T, Imagawa T, Yokokta S. Effect of anakinra on arthropathy in CINCA/NOMID syndrome. Pediatr Rheumatol Online J 2010;8:9.

Dr John Thorp, an OB-GYN the University of North Carolina (UNC) at Chapel Hill conducted a large clinical trial at 20 different sites to examine the effect of magnesium sulfate on the rate of stillbirth or infant death, and the rate of moderate or severe cerebral palsy at or after the age of 2 years.

They enlisted 2,241 women diagnosed as being at high risk for going into premature labor between weeks 24 and 31 of their term. The women were randomized to receive either an intravenous infusion of magnesium sulfate solution, or a placebo that looked exactly the same. The infusions were started just before delivery was thought to be starting, at a dose rate of 6 grams over 20 to 30 minutes. This was then followed by a maintenance infusion at a dose rate of 2 grams an hour. If delivery did not take place within 12 hours, the infusion was stopped and started again later, when it looked like delivery was about to take place again.

The results showed that:

There was no significant difference in the risk of infant death between the magnesium sulfate and placebo group.

However, moderate or severe cerebral palsy occurred about half as often in the magnesium sulfate group (1.9 per cent) than in the placebo group (3.5 per cent).

This is an extremely important finding. This may well change the way obstetrical medicine is practiced, and MUCH MORE RESEARCH IS NECESSARY to determine HOW and WHY magnesium sulfate appears to be neuroprotective, if it may be useful in different doses, at different times during pregnancy and delivery and even in the growing infant and child.

UCP Research and Educational Foundation is very proud that the seminal work for this discovery was supported by our Foundation 13 years ago during the brilliant leadership of Dr. Murray Goldstein Medical Director, Jack Hausman Chairman of the Board and Leonard Goldenson, Vice-Chairman of the Board.  High quality research supported today will pay off in our lifetime!!

Neuroprotection, once just used to characterize compounds that prevent cell death, now encompasses organizational, therapeutic and environment-modifying interventions that promote normal development and prevent disability in children at risk for developmental disorders. At risk children include those of low socioeconomic status, prematurity and/or low birth weight. Early stimulation programs are considered to be an environment-modifying type of neuroprotective interventions.

The ability of the brain to reorganize neural pathways based on new experiences is known as plasticity. Special education therapy programs activate the plasticity of the developing brain. Studies of animal models have established that plasticity allows for reorganization of cortical maps after early brain injury. Cortical plasticity has been described for the auditory, tactile, olfactory and motor systems. Whether and to what extent plasticity can compensate for failure of cognitive functions to develop within the first years of life has been of considerable interest.

Because of the increasing awareness among pediatricians for the role of the environment in mental and cognitive development, early stimulation programs were developed that targeted preservation of the mother-infant relationship and enhanced bonding, provided stress reduction in the hospital, and improved relative lack of stimulation to which preterm infants in neonatal units were exposed.

The infant health and development program (IHDP) was designed for the post-hospital period for premature, low birth weight babies. The program includes home visits by professionals, attendance at a development center between the ages of 1 and 3 years and monthly meetings with the parents. When children from the conventional care program, were compared to the IHDP children, the intervention group showed a significant difference in IQ scores (10 points higher) at 24 and 36 months than the control group even though there was no difference at 12 months.

These two programs targeted different populations, but demonstrated similar effects in that efficacy was greatest when both parent and child were involved, long term stimulation improved cognitive outcomes; cognition showed greater improvements than motor skills and larger benefits were obtained in families that had several risk factors including low education attainment by the mothers. Two hypotheses may explain findings: 1) early stimulation may compensate for loss of exposure to stimulation from the family, 2) and/or it may prevent the relative cognitive decline seen in controls. The optimal duration and timing of early stimulation programs remains to be determined.

*Bonnier, C. ‘Evaluation of early stimulation programs for enhancing brain development’ Acta Paediatrica 2008 97, pp 853-858

                                    Karin B. Nelson and Taeun Chang
                        Current Opinion in Neurology 2008, 21:129-135

Introduction: The causes of cerebral palsy, and thus approaches to prevention, differ by gestational age group and by clinical subtype. In premature infants, the most common CP subtype is spastic diplegia (hypertonia and spasticity of the legs, hips and pelvis) with the underlying pathology being white matter damage associated with either a hypoxic-ischemic event, inflammatory conditions and exposure to cytokines, or a combination of both. In term infants, quadriplegic CP (spasticity in all four limbs) with dyskinesia, is most often associated with acute asphyxia during the process of birth. Other potential causes of dyskinetic CP include hyperbilirubinemia.

Etiological Factors and their Preventability
1. Birth Asphyxia
Electric Fetal Monitoring – Controlled studies in defined populations over two decades confirm that severe birth asphyxia is not a common cause of CP. However, in the past, many thought it to be the primary cause of CP, and electric fetal monitoring was introduced in the 1970’s in the belief and that it could alert caregivers of impending asphyxia and thus prevent neurologic injury. Subsequent randomized clinical trials showed that use of the EFM did not result in a decline in the occurrence of CP.
Therapeutic Hypothermia – A recent meta-analysis of 8 randomized controlled clinical trials have demonstrated a significant reduction in infant mortality and major neurodevelopmental disability after administration of therapeutic hypothermia to term infants with moderate encephalopathy as a result of birth asphyxia. It appears that therapeutic hypothermia can be neuroprotective if administered early enough after injury and maintained long enough with a gradual rewarming.

2. Prematurity
Prematurity is a major risk factor for CP. The rate of preterm birth in the US is now 12.7% and rising. Causes of preterm birth include infection, congenital maldevelopment and genetic factors. Strategies to prevent premature birth have not been consistently successful in decreasing the frequency of preterm birth.
Nitric Oxide – A systematic review of 11 randomized trials of nitric oxide administration to premature infants concluded that inhaled nitric oxide may decrease serious brain injury in mildly, but not in severely ill preterm infants. In term infants, nitric oxide was not associated with less disability later on.
Magnesium Sulfate – Animal data and an observational clinical study suggested that administration of magnesium sulfate to women in preterm labor may provide neuroprotection for the infant and a lower rate of motor handicap. However, in a review of four additional clinical trials, a diagnosis of CP was only marginally significantly reduced.

3. Intrauterine exposure to infection/inflammation
To date there is no-evidence based approach to prevention of CP or other adverse long-term neurological outcomes due to infection/inflammation of the placenta other than that related to meningitis or encephalitis.

4. Perinatal Stroke
Perinatal ischemic stroke has in recent years been recognized to be a common cause of CP, especially in term infants. About half of infants with stroke have thrombophilias. However, perinatal stroke rarely repeats in siblings thus indicating that environmental factors are important. It is likely that it is a combination of thrombophillic risk factors and environmental factors that determines whether a perinatal stroke will occur. Identification of factors leading to thrombosis in fetal or neonatal stroke is still a work in progress. No study has yet tried to establish selective criteria for women to receive anti-coagulation therapy in pregnancy for women to purpose of avoiding stroke in the infant and none has examined whether stroke is more or less frequent in infants following anti-coagulation of the mother for maternal or pregnancy complications.

5. Multiple Gestation
Twins and higher order multiple births have a higher rate of CP, accounted for in part by the commonly associated prematurity, but also by death of a co-twin. Advanced maternal age and assistive reproductive technologies are associated with a higher rate of multiple births and prematurity which may account for much or all of the increased risk of CP in babies born of assistive reproductive techniques.

6. Genes
The occurrence of CP has been observed to run in families with high consanguinity and a Swedish national database indicates familial risk for CP. Inherited thrombophilias occur in greater numbers of children with perinatal stroke than in the general population, very preterm infants with CP, and in CP overall. A genetic variant of an imflammatory cytokine is associated with CP risk as is an apoliprotein E genotype.
There are genetic components of a number of risk factors for CP, including preterm birth, abruption of placenta, chorioamnionitis and preeclampsia. Research into the interaction of genetic susceptibilities with environmental factors has only recently started and may provide a fruitful avenue for prevention.

The Future of Research into CP Prevention

Advancements in information technology, such as electronic medical records, will help to create large and representative databases of newborns of all gestational ages that will allow for studies of uncommon maternal and pregnancy conditions resulting in a diagnosis of CP to further elucidate risk factors. Also improvements in and greater access to neuroimaging technology for infants and children along with improvements in remote digital technology will enable multicenter trials of treatment and preventive measures. Development of consensus on methodology and interpretation of placental pathology, and incorporation of placental investigation into studies in obstetrics and neonatology are likely to add important information.

Researchers from McGill University in Canada, Children’s Hospital in Boston, Harvard Medical School and Brigham and Women’s Hospital* published an article in Pediatrics this month that reports, for the first time, a high prevalence of positive initial screening for autism spectrum behaviors in survivors of extreme prematurity. They found that several factors are associated with a positive screening, including lower birth weight and gestational age, male gender, prenatal infection, more severe illness at birth and abnormal MRI scans.

Major advances in neonatal intensive care have decreased the mortality of preterm infants, but have not led to a comparable decrease in long-term neurodevelopmental conditions such as cerebral palsy. This trend underlies the ever increasing population of very low birth weight (VLBW) children with significant and costly developmental disabilities. In addition, it has been reported that there is a high prevalence of atypical psychosocial development in VLBW children with symptoms such as difficulty with social integration, excessive shyness, attentional difficulties and hyperactivity. These symptoms are similar to those typically seen in children with autism spectrum disorder; however, the prevalence of autism spectrum disorder has never been explored in the VLBW population. These researchers sought to use validated screening tools for detection of early autistic features in a cohort of children with a history of VLBW as well as to identify clinical predictors of positive autism screening results.

Using the Modified Checklist for Autism in Toddlers (M-CHAT), the researchers screened 91 infants with a history of VLBW, aged 18 to 24 months. In addition, they used the Child Behavior Checklist (CBCL) questionnaire for caregivers that assess the frequency of behavioral and emotional problems in young children as well as the Vineland Adaptive Behavior Scale (VABS) that measures functional status in communication, daily living, socialization and motor skills in children 0 to 18 years of age. Finally, demographic, maternal, prenatal, delivery, post-delivery and short-term outcome data was collected on all of the infants in the study. This included such clinical data as gestational age, weight, maternal age, prenatal infection, fetal heart rate, Apgar scores, placental pathology reports, postnatal blood gases and MRI results.

Results indicated a population of infants with a gestational age of 23 to 30 weeks and a birth weight of 460 to 1490 grams. Sixty-five percent were delivered by cesarean section, 88% required ventilatory resuscitation at birth and there was evidence of intrauterine infection in 31% of these infants. Screening of these infants with the M-CHAT indicated that 25% had positive results for early signs of autism. Twenty-nine percent of the infants had functional delays in motor abilities, 23% had communication deficits and 29% experienced socialization difficulties as assessed by the VABS. Behavioral outcomes as assessed by the CBCL indicated that 29% experienced internalizing behavior problems and 13% experienced external behavioral problems such as attention problems and aggression. Those who screened positive for early signs of autism also showed internalizing behavior problems such as being withdrawn and emotionally reactive as indicated by the CBCL. These children also showed difficulties in socialization and communication skills but did not show delays in functional mobility as assessed by the VABS. The MRI studies indicated that 67% had normal results and 33% had abnormal results such as diffuse periventricular leukomalacia (PVL), periventricular hemorrhagic infarction (PVHI), cerebellar hemorrhagic injury and ventriculomegaly.

Statistical analyses of the clinical data found that lower birth weight and gestational age, male gender, more severe illness at birth, intrauterine infection and acute intrapartum hemorrhage were associated with a positive screen for autism. In addition, long term complications and abnormal MRI were also associated with a positive screen. More specifically, the preterm infants with cerebellar hemorrhagic injury and combined supratentorial and infratentorial parenchymal lesions were more likely to have a positive screen for early autistic features than those with PVL or PVHI.

Discussion

This study suggests that there is a high prevalence of early autistic behaviors in very low birth weight infants, a previously unrecognized feature of this population. Larger studies with longer follow-up are needed to corroborate these findings. The clinical and testing data presented here seem to suggest, however, that although the risk factors for autism and other neurodevelopmental conditions such as epilepsy and cerebral palsy may have commonality, the etiologic pathways are different. Nonetheless, these conditions can co-occur in children as it has been reported that 1 in 9 children with cerebral palsy have features of autism and 1 in 4 children with cerebral palsy also have epilepsy. Furthermore, many of the common risk factors for autism and cerebral palsy (50% of children with cerebral palsy are born prematurely) are ones that can be addressed through research to prevent prematurity and improve maternal health.

Positive Screening for Autism in Ex-preterm Infants: Prevalence and Risk Factors
Catherine Limperopoulus, Haim Bassan, Nancy R. Sullivan, Janet S. Soul, Richard L. Robertson, Jr, Marianne Moore, Steven A. Ringer, Joseph J. Volpe, and Andre J. du Plessis. Pediatrics 2008;121;758-765

Internationally, researchers are engaged in developing noninvasive methods for identifying infants who are likely to later show developmental delays, impairments and disabilities. Most neuroscientists and clinicians agree that the human brain possesses great potential for plasticity and that experience can modify development.

Furthermore, pharmacologic and cellular interventions to improve the nervous system damage present in cerebral palsy and other conditions that lead to abnormalities in brain development are on the horizon. Early detection will some day allow early intervention. For these reasons, and to prepare families and caregivers, early prediction of later impairment is critically important.

A cautionary note, however, is necessary. Early abnormalities in diagnostic tests can prove to be “false positives”. In other words, such abnormal findings on tests could end up giving children labels that later prove inaccurate. So, although in theory, early diagnoses would allow for early intervention when the brain is most plastic, these findings are not yet ready for incorporating into pediatric practice.

Some children with substantial abnormalities present on brain imaging will ultimately grow into healthy adults and some with completely normal looking magnetic resonance imaging will have substantial impairment from cerebral palsy.

Nonetheless, accurate early detection will eventually be available and will no doubt be very helpful for diagnosis, prognosis and to guide earliest intervention. It is an area of science that begs further investigation.

Literature: Imaging Technologies

Pediatricians and neurologists in Boston are using magnetic resonance imaging to study the brains of neonates ¹. At this stage, they have been able to show that it is possible, using volumetric diffusion tensor magnetic resonance imaging and adapting algorithms currently used for adult studies, to accurately visualize 3-dimensional structures of cerebral white matter fiber tracts in preterm infants and full term infants (as young as 28 weeks postconceptional age). White matter fiber bundles from the genu and the splenium of corpus callosum, the corticospinal tracts, the inferior fronto-occipital fasciculi, and optic radiations were visualized.

Comment:

What does this mean? What is remarkable about this work is that such detail is now visible, despite the very small amount tissue present in these infants. Magnetic resonance imaging is steadily improving, allowing clinicians to look inside the body with extraordinary clarity and accuracy. Technical advancements in the equipment and in the computer programs that analyze the images, it is possible to look into the tiny brain of the premature infant and see not only gross abnormalities (such as enlarged ventricles or evidence for bleeding) but detailed neuroanatomy. It is possible to see specific bundles of nerves (axons) which transmit information about movement, sensation, vision, hearing and other critical functions. Very soon it may be possible to identify abnormally developing pathways. Long term follow-up studies will be necessary to determine the clinical importance of the white matter changes imaged in this manner.

¹ Yoo SS, Park HJ, Soul JS, Mamata H, Park H, Westin CF, Bassan H, Du Plessis AJ, Robertson RL Jr, Maier SE, Ringer SA, Volpe JJ, Zientara GP. In vivo visualization of white matter fiber tracts of preterm- and term-infant brains with diffusion tensor magnetic resonance imaging. Invest Radiol 2005;40:110-5.

Two recent studies present evidence suggesting that inflammation of the placenta alone is insufficient to produce cerebral palsy in the premature infant. Neither addresses potential effects of inflammation elsewhere in the mother nor in the postpartum infant. Kaukola and her colleagues observed that the combination of inflammation and placental defects were predictive of cerebral palsy.

In December 2004 the Research Fact Sheet reported on a very large study performed by the National Institute of Child Health and Human Development implicating either maternal or fetal infection as a major element in the cause of Cerebral Palsy. Among other findings, that Fact Sheet1 reported that For cerebral palsy alone, 16% of children who acquired any kind of infection in the post natal period developed cerebral palsy while only 8% of those without infection developed cerebral palsy.

Two recent papers recently published have addressed the specific question as to whether infection of the placenta (chorioamnionitis) may be a causal factor in the development of cerebral palsy in the premature infant. Our readers are reminded that the placenta is actually part of the child and not of the mother.

Polam and his associates2 at the University of New Jersey studied the outcome of surviving infants born after 22-29 weeks of gestation whose placentas had been examined pathologically for evidence of inflammation. Evidence of inflammation was found in 186 placentas (including 37 placentas from infants who died) while 251 placentas had no evidence of inflammation. Children were physically examined at several ages with an average follow up of 19 months corrected age. Some children were lost to follow up. Children whose placentas were inflamed (102) were compared with a selected control group of children (75) whose placentas were not. Those with inflammation had higher rates of bleeding into their cerebral ventricles and a higher incidence of visual impairment but the rates of cerebral palsy were approximately the same (8.6% vs. 8%).

Kaukola and her associates3 at the University of Oulu in Finland performed a similar study. They followed 61 extremely low birth weight infants not only examining the placenta for evidence of inflammation but also collecting placental blood for evidence of inflammation. Both were predictors of premature birth and bleeding into the cerebral ventricles. Although neither placental inflammation nor evidence of inflammation in the cord blood predicted the development of cerebral palsy, the combination did.

Comment:

There is a great deal of interest in the relative contributions of inflammation and hypoxia/ischemia as causative agents producing cerebral palsy in the premature infant. In parallel with these investigations, other research is targeting the resulting biochemical reactions in order to develop interventions that may reduce the incidence of cerebral diplegia. Although inflammation placenta alone may not be enough to produce cerebral palsy, these studies do not address the possible effect of inflammation elsewhere in the mother or the infant, especially in the infant in the immediate neonatal period. The second study presents some intriguing data to support the idea that inflammation and hypoxia/ischemia work together as causes of cerebral diplegia.

1United Cerebral Palsy Research and Educational Foundation. Research Fact Sheet December 2004.

2Polam MD, Koons A, Anwar M, Shen-Schwartz S, Hegyi T. Effect of chorioamnionitis on neurodevelopmental outcome in preterm infants.Archives of Pediatrics & Adolescent Medicine 2005; 159 (Nov) : 1032-1035.

3Kaukola T, Herva R, Perhomaa M, et al. Chorioamnionitis and cord serum proinflammatory cytokines: Lack of association with brain damage and neurological outcome in very premature preterm infants. Pediatric Research 2005. 58 (Sep): 1-6.

Summary:

Three articles are reviewed that lend support to the usefulness of one or more techniques of hypothermia in the prevention of death and cerebral palsy among term babies born with evidence of hypoxic-ischemic encephalopathy. The study conducted under the auspices of the National Institute of Child Health and Human Development contains the most significant data.

Previous Research Fact Sheets (April 1998 and February 2003) have commented on the potential role of hypothermia in preventing cerebral palsy and have reported on encouraging animal research models. Cooling inhibits a number of potentially damaging chemical reactions in the hypoxic brain and is ready for human trials. Two approaches are under evaluation: whole body cooling and selective cooling of the head using a device called the Cool-Cap®.

Seetha Shrankaran and her many colleagues report on a multicenter study on whole body infant cooling financed by the National Institute of Child Health and Human Development¹. They studied newborn infants with evidence of hypoxic-ischemic brain injury randomized within 6 hours of birth to either traditional care plus whole body hypothermia for 72 hours (hypothermia group) or traditional care without hypothermia (control group). 102 infants were assigned to the hypothermia group and 106 to the control group. The authors followed the surviving babies in both groups out to 18-22 months of age. Follow-up was available on all the babies treated with hypothermia and all but 5 of the babies in the control group.

Their statistics clearly showed that fewer babies in the hypothermia group died or survived with severe disabilities. The difference was statistically significant, although individual outcome measures showed only trends. However, the trends within the study were very encouraging. 76% of the hypothermic treated babies survived compared to 63% of the controls. Concerns that the increased survival rate might translate into increased numbers of severely handicapped children, proved to be unfounded. In the control group, 30% of surviving children in the control group had disabling cerebral palsy compared to only 19% of the hypothermic babies. Only 55% of the control babies had IQ’s of 85 or better compared to 62% of the hypothermic babies. Similar reductions were seen in severe vision and hearing impairment.

Some months earlier, Gluckman and his associates² reported a similar study cooling only the heads of the babies using the Cool-Cap®. They applied EEG criteria to divide infants into those with moderate and those with severe brain injury. 66% of babies in the control group died or had severe disabilities compared to 55% in the hypothermic group. Among the survivors, 31% of controls have severe neurosensory deficits compared to 19% of the babies treated with head cooling. Although these numbers did not reach statistical significance, their findings reinforce those of the whole body cooling study. The trend is encouraging.

In a smaller study, Inder and her group³ demonstrated that among 26 infants randomized to control and hypothermic treatment, the hypothermic babies had much less abnormality in the cortical grey mater than did the controls.

Comment:

Term babies with hypoxic-ischemic encephalopathy are at risk for spastic hemiplegic cerebral palsy as well as other forms. Although statistically significant results are most convincing, the trends reported in these three studies are certainly encouraging. Historically, one would hope we would soon see additional studies showing improved outcomes after technical fine tuning. It is just possible that we are on our way to a management strategy capable of preventing cerebral palsy in a significant number of children.

¹ Whole body hypothermia for neonates with hypoxic-ischemic encephalopathy. New England Journal of Medicine 2005; Vol 353: Pg. 1574-84.
² Gluckman PD et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter, randomized trial. The Lancet 2005; Vol 365: Pg. 632-634.
³ Inder, TE et al. Randomized trial of systemic hypothermia selectively protects the cortex on MRI in term hypoxic-ischemic encephalopathy. J. Pediatrics 2004; Vol 145:Pg 835-7.

© UCP Research & Educational Foundation, November 2005

Inhalation of nitric oxide is a newly introduced intervention in infants with low birth weights who experience respiratory distress despite standard treatment. The first of two studies reports it does little to improve survival or to prevent lung abnormalities. The second had previously reported some improvement in survival and now reports the follow-up of survivors. Those who received nitric oxide had fewer neurodevelopmental defects, mostly in the intellectual realm. The incidence of cerebral palsy was essentially the same in the two groups, but the types were different.

Neonatologists (Pediatricians specializing in the care of newborn children) are constantly striving to improve the survival and quality of life of prematurely born children. This month we will review two articles published in the July 7, 2005 New England Journal of Medicine. Although the results are not very encouraging, they do show some benefit. It is also useful to note that those responsible for the well being of premature children keep working to improve outcomes.

Van Meurs and her associates¹ did a multi-center controlled study of the benefits of adding small amounts of nitric oxide to the gasses breathed by infants between 401 and 1500 grams (about 1-3 pounds) who were suffering respiratory distress that had not been relieved by standard means. They found across the range of premature infants that nitric oxide did not improve the rate of survival nor did it prevent the development of pulmonary dysfunction. However, it did improve oxygenation of the infants’ blood. They did note that in a subset of infants weighing more than 1000 grams (about 2 pounds) there was a small improvement in both survival and prevention of later pulmonary complications.

In another study, Mesten² and her colleagues reported the neurodevelopmental outcome of children enrolled in a single center, randomized, placebo controlled trial where about half of the infants were given nitric oxide and half had not (the “placebo arm”). This study³ of 207 infants was previously published and described the results of treatment on the survival and pulmonary complications of children receiving nitric oxide. In that report, they noted that 24% of the children in the placebo arm, but only 9% in the nitric oxide group, developed white mater disease or bleeding surrounding the cerebral ventricles (periventricular leucomalacia or PVL).

In the present study, they compared 70 children in the treated group with 69 children in the placebo group at 2 years of age. There were many dropouts in the study but most could be accounted for. Overall in the nitric oxide group, 24% were found to have neurodevelopmental disorders while in the control group 46% were found to have neurodevelopmental disorders. There was little difference in the incidence of cerebral palsy between the two groups, but a considerable difference in the number of children who had Mental Development Index Scores better than 70 and in developmental delay without disability.

Among the children who developed cerebral palsy, there were differences in the types of disability between the two groups. In the nitric oxide group, all six children with CP were diplegic. Among the eight in the control group, four were hemiparetic (one sided spasticity), one quariparetic (4 limb spasticity), and two diplegic (both lower limb spasticity). The type of cerebral palsy in one child was unstated.

Comment:

Very often medical progress proceeds by small steps rather than by giant bounds. Mental retardation commonly accompanies cerebral palsy. Although nitric oxide did not produce a decrease in the overall incidence of cerebral palsy, who could deny that improvement in their intellectual domain would not be a benefit for those children? This issue was not specifically addressed in the article due to the small numbers of children with cerebral palsy. It is also interesting that the types of cerebral palsy were different. There is no evident explanation for this difference.

¹ Van Muers, KP et al. Inhaled nitric oxide for premature infants with severe respiratory failure. New England Journal of Medicine. 2005 (July 7); 353:13-22.
² Mesten, KL et al. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. New England Journal of Medicine. 2005 (July 7); 353:23-32.
³ Schreiber, MD et al. Inhaled nitric oxide in infants with respiratory distress syndrome. New England Journal of Medicine. 2003; 349:2099-2107.

© UCP Research & Educational Foundation, September 2005

This observational study reported that mothers who completed a series of steroid injections within 48 hours of premature delivery were less likely to have a child who later developed cerebral palsy. However, the number of mothers involved was small and the overall benefit was difficult to evaluate. This is a promising approach, but clearly one requiring additional evaluation.

It is well established that white matter changes (changes to the covering of nerve cell fibers) surrounding the cerebral ventricles in premature infants (called periventricular leucomalacia or PVL) are associated with the later development of cerebral palsy. This is especially true if bleeding has occurred into the area of PVL. Opinions differ as to the relative roles of maternal inflammation and of decreased oxygen (hypoxia) in producing this condition subsequent cerebral palsy. Some argue that both must be present for the development of cerebral palsy.

Several exciting approaches to preventing cerebral palsy based on either the inflammatory or the hypoxic theories are in trials of one sort or another. A study from Australia attempted to measure the benefit of administering adrenal steroids to mothers threatening to deliver their babies prematurely. These agents are now commonly used to suppress inflammation in a number of disorders including multiple sclerosis and optic neuritis (inflammation of the optic nerve) which are also disorders of white matter in the brain. The specific medication used is dexamethazone, a long acting steroid commonly used to treat brain inflammation.

Kent, et al¹ reviewed the outcome of 220 children born before 30 weeks of gestation (40 weeks is normal). The membranes covering the fetus and the umbilical cords of these children had been carefully examined and any steroid treatment prior to birth had been noted. These children were divided into 3 groups on the basis of the degree and location of inflammation:

      1. Those with no apparent inflammation.
      2. Those with inflammation of the fetal membranes only.
      3. Those with inflammation of the infants umbilical cord (considered to be the most severe exposure).

PVL was evaluated with cerebral ultrasound, and children were examined for cerebral palsy at one and three years of age. Unfortunately, many children were not available for follow-up. Most of the mothers had at least some steroid treatment before the child’s birth, but only 72% received the full treatment. Twelve infants died. There was no relationship between steroid use and survival.

Two thirds of the children had no evidence of inflammation. Thirty one infants in this group had been given no steroids or incomplete steroid coverage and were available for follow-up. Only one developed cerebral palsy (3%). Among the 77 with complete steroid coverage, 5 developed cerebral palsy (7%). Due to the small size of the groups, this difference did not reach statistical significance, meaning that it could have occurred by chance.

One third of the infants had evidence of inflammation either in the membranes or the umbilical cord. Lower gestational age was associated with evidence of inflammation. Nine children in this group whose mothers did not have the complete steroid treatment were available for follow-up study. Three had cerebral palsy (33%). Among the 49 who received the full steroid treatment, only 5 developed cerebral palsy (10%). This was statistically significant despite the small numbers.

Comment:

The authors refer to previous observations that the use of steroids in mothers delivering prematurely may decrease the risk of cerebral palsy. They concede that other studies have suggested that dexamethazone is not the best choice of steroid for this purpose. Their study is purely observational (see Research Fact Sheet- Terms Used in Research, May 2005) but it was carefully done and adds some weight to the argument in favor of steroid use.

It should be noted that infants with no pathological evidence of infection developed cerebral palsy. This suggests that either cerebral palsy can occur in the absence of infection or that the methods they used were insufficient. Many would argue that evidence of inflammation in the mother’s blood would have been a better marker of infection than examination of the fetal membranes and umbilical cord. However, inflammation can be caused by factors other than infection and suggests that these may be common.

If only the infants available for follow-up are considered, 4 developed cerebral palsy among the 40 who had either no steroids or an incomplete course (10%). Among the 126 who had the full course, 10 developed cerebral palsy (8%). This is a rather small difference and similar to reported incidence rates (see Research Fact Sheet- Ultrasound and the Prediction of Cerebral Palsy (CP), October 2004 and, Research Fact Sheet- Infection in the Newborn as a Cause of Cerebral Palsy, December 2004).Thus, the findings suggest that steroid treatment of mothers of premature infants may be helpful for preventing cerebral palsy; but the study results are clearly suggestive rather than conclusive.

¹Kent A, Lomas F, Hurrion E, Dahlstrom JE. Journal of Pediatrics and Child Health. 2005 Apr; 41(4)186-90.

© UCP Research & Educational Foundation, June 2005