Survival and outcome
Extreme prematurity
Advances in antenatal and perinatal medicine and enhanced neonatal interventions for management of nutrition and respiratory function have resulted in improved survival of very preterm infants in the past 20 years, including infants at the limits of viability (22 to 25 weeks).
Survival rates in the early 2000s were approximately 85% for very low birthweight (VLBW, ≤1500 g) and 70% for ELBW infants. A 2012 NICHD study of infants 404 to 1000 g between 22 and 27-6/7 weeks’ gestation born in 2002-2008 reported a death rate of 61% for infants of 22 to 24 weeks compared to 19% for infants 25 to 27 weeks’ gestation.
The rate of combined death or neurodevelopmental impairment or death was 77% for infants 22 to 24 weeks and 38% for infants 25 to 27 weeks.
Center variation
Wide center variations in obstetrical and neonatal interventions among infants at 22 to 24 weeks’ gestation are reported.
Wide center variation in management is a factor that contributes to survival and outcome.
In a 2012 report of infants 22 to 27 weeks’ gestation, center rates of use of antenatal corticosteroids ranged from 28% to 100%, cesarean section ranged from 13% to 65%, and resuscitation from 30% to 100%. Centers with higher rates of antenatal corticosteroid use had the lower rates of death and neonatal morbidities.
Table 50-1 shows recent reports of survival of infants 22 to 25 weeks’ gestation from the United States and abroad. Survival at 22 weeks remains less than 10% except for a single report from Japan. Most recent studies report at least 40% survival by 24 weeks.
Survival and outcome
Improvements in survival have not always been accompanied by proportional reductions in the incidence of adverse neurologic, developmental, and behavioral outcomes.
Survival of infants 22 to 25 weeks’ gestation
| Region | Years | 22 weeks | 23 weeks | 24 weeks | 25 weeks |
|---|---|---|---|---|---|
United States NRN | 1998-2003 | 5% | 26% | 56% | 75% |
United States NRN | 2004-2005 | 2% | 22.5% | 53.5% | NA |
| Sweden | 2004-2007 | 10% | 53% | 67% | 81% |
| Japan | 2005 | 34% | 54% | 77% | 85% |
| United Kingdom | 1994-2005 2000-2005 | 0% 0% | 19% 18% | 24% 41% | 52% 63% |
| United Kingdom | 2006 | 2% | 19% | 40% | 66% |
According to corrected age in preterm infants and actual age in high-risk term infants.
Motor development assessment
Motor assessments for the very high-risk infants (ELBW, HIE, CDH, etc) should be considered at 1 month postdischarge, and 4 and 9 months.
After 9 months, motor evaluations should be done in conjunction with evaluation of other developmental domains (cognitive, language, behavior).
Complete neurodevelopmental testing
Recommended intervals for neurodevelopmental assessment include
12 months
18 to 24 months
3 to 4 years
6 years
8 years
Assessing development in infants
The primary focus of most published reports of neurodevelopmental outcome in infancy is the incidence of moderate to severe disability, often defined as mental retardation, cerebral palsy, blindness, and/or hearing impairment. This has been the outcome of interest due to the severity of the impact of severe and combined morbidities on the infant and on the family.
In the NICHD Neonatal Research Network, neurodevelopmental impairment (NDI) is defined as the presence of any of the following: moderate to severe cerebral palsy, cognitive or motor scores more than 2 standard deviations below the mean on standardized testing, bilateral hearing impairment requiring amplification, or bilateral blindness.
Developmental/cognitive outcomes
The most common impairment seen in preterm infants at 18 and 30 months is early developmental/cognitive impairment, defined as scores that are more than 2 standard deviations below the mean on standardized cognitive testing.
Early developmental/cognitive function of preterm children has traditionally been assessed using the Bayley Scales of Infant Development.
Although used for many years, a limitation of the Bayley Scales of Infant Development, Second Edition (Bayley II) is the test produces only two developmental scores, the Mental Developmental Index (MDI), a composite of cognitive, receptive language, and expressive language tasks, and the Psychomotor Developmental Index (PDI), a composite of fine and gross motor skills.
The more recently published Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), contains three individual developmental scores: a cognitive composite score (Cog), a language composite score (with receptive and expressive subscores), and a motor composite score (with gross and fine motor subscores), in addition to social-emotional and adaptive behavior domains.
However, it has been identified in several reports that the mean Bayley III cognitive scores are higher (by 11 points) than mean Bayley II cognitive scores. It is not yet entirely clear if the Bayley II underestimates scores or if the Bayley III overestimates scores. Caution is, therefore, advised in comparing studies using the different Bayley tests.
Average MDI score at 18 to 22 months’ corrected age for ELBW infants in the NICHD NRN is 76 but varies from center to center with a range of 70 to 83. Others report average MDIs of 84 to 86 in ELBW infants at 20 month follow-up.
Like rates of NDI, rates of cognitive impairment vary worldwide, and are inversely proportional to gestational age and birthweight.
Worldwide rates of cognitive impairment throughout childhood range from 14% to 39% at 24 weeks, 10% to 30% at 25 weeks, 4% to 24% at <26 weeks, and 11% to 18% at <29 weeks.
In the NICHD, rates of cognitive impairment are reported at 37% to 47% in 22- to 26-week infants, 23% to 30% in 27- to 32-week infants, and 34% to 37% in all infants <1000 g.
While developmental functioning can be measured in infancy, it is not predictive of cognitive functioning later in life.
The assessment of an infant’s cognitive function is highly dependent on age and on their motor, language, social-emotional development, and the environment to which they are exposed, and services they receive.
Learning and academic disabilities/challenges are detected in 50% to 70% of children born VLBW at school age.
These include relative impairments of executive functioning, visual-motor skills, and memory, especially verbal memory.
In addition former VLBW and ELBW infants score lower on tests of academic achievement, have poor perceptual-organizational skills, difficulty with visual processing tasks, and delays in adaptive functioning compared to their normal birthweight peers.
Rates of learning disabilities are high, especially in math, ranging from 25% to 40%.
It is important to recognize that high-risk infants in good environments (higher parental education and two-parent family) have the potential for recovery of academic performance with increasing age.
Speech/language outcomes
Speech and language may also develop atypically during early childhood in previously ELBW infants, with delays in the acquisition of expressive language, receptive language, and articulation.
Language delay may be associated with additional neurosensory morbidities or be observed independently.
There is limited information about the effects of the language environment in the NICU on language outcomes.
It has been reported that preterm infants begin to make vocalizations at least 8 weeks before their projected due date and significantly increase their number of vocalizations between 32 and 36 weeks.
Although infant exposure to language increased over time, adult language accounted for only a small percentage of the sounds to which an infant is exposed in the NICU.
Exposure to parental talk was a significantly stronger predictor of infant vocalizations at 32 weeks and conversational turns at 32 and 36 weeks than language from other adults. These findings highlight the powerful impact that parent talk has on the appearance and increment of vocalizations in preterm infants in the NICU, and suggests that efforts at language intervention should begin in the NICU.
An NICHD Neonatal Research Network study reported Bayley III scores of ELBW infants with mean language composite score at 18 to 22 months’ corrected age was 83 ± 18 and 20% had a language composite score <70.
Significant effects of race and ethnicity are seen on Bayley III language scores. In adjusted analyses for medical confounders, children who were black and Hispanic had similar cognitive scores but lower language scores than white children. The authors note that the Bayley III has no standardized Spanish version and, therefore, may provide a bias for non-English speaking children. They do acknowledge that minority status suggests vulnerability for language delay and recommend monitoring and early intervention for these children.
Speech therapy services
33.7% of preterm infants at 18 to 22 months’ corrected age were receiving speech therapy and 55.7% were receiving early intervention.
Rate of receiving speech therapy services increased from 25.6% for infants born at 27 weeks’ gestation to 41.2% for infants born ≤24 weeks. In addition, 24% of parents reported that their child was not receiving services but needed speech/language services.
These data point out the increased need for early speech language intervention services for preterm infants.
A meta-analysis of language studies of preterm children ages 3 to 12 years identified that preterm children scored significantly lower compared with term-born children on both simple and complex language function tests, even in the absence of major disabilities and independent of social economic status. They also found that preterm children had increasing difficulty with complex language function, but not for simple language function, with increasing age.
Specific language deficits in preterm children that may persist at school age include phonological short-term memory and prosodic processing.
At 12 years of age, children who were born at <1250 g and participated in the Indomethacin Prevention Trial had less pronounced differences on tests of lower level language skills (phonological processing, phonemic decoding, and sight word reading) compared to term controls, but exhibited significantly more difficulty with higher level skills (syntax, semantics, verbal language memory, and reading comprehension).
At age 12, they continued to have significantly lower scores (92 vs 105) on the PPVT and higher rates of vocabulary impairment (13% vs 4%), as well as lower expressive, receptive, and total scores on the CELF (85 to 87 vs 100 to 103) and higher rates of impairment (22% to 24% vs 3% to 4%).
Although the immature brain at the time of birth may be an important contributor to language delays and capabilities, some preterm infants clearly improve their language skills with increasing age.
Some very preterm children demonstrated catch-up gains in receptive vocabulary between 8 and 16 years of age.
In addition, subgroups of very preterm children (65%) displayed developmental trajectories of vocabulary similar to term controls.
Higher level of maternal education has been associated with catch-up for preterm children, suggesting that a more optimal learning environment with fewer barriers to resources is beneficial.
Motor/cerebral palsy outcomes (see also Chapter 24)
Cerebral palsy
Typically defined as a disorder of movement and posture that involves abnormalities in tone, reflexes, coordination and movement, delay in motor milestone achievement, and aberration in primitive reflexes.
It is a disorder that is permanent, but not unchanging and is due to a nonprogressive interference, lesion, or abnormality of the developing immature brain.
It can be further categorized by type (spastic, dyskinetic, or dystonic), topography (number of limbs involved), and descriptors including monoplegia, diplegia, hemiplegia, and quadriplegia.
The most common form of cerebral palsy (CP) in former preterm infants is spastic diplegia, accounting for 40% to 50% of all cases, followed by spastic quadriplegia and hemiplegia.
In the United Kingdom CP database for children at least 2 years of age, the CP rate for children with a birthweight <1000 g was 41 per 1000, and for infants 1000 to 1499 g the rate was 57 per 1000 compared to a rate of 1.2 per 1000 for all live births. Sick term infants were more likely to have the most severe forms of CP compared to infants <1000 g (23% vs 15%; p <0.001).
In the United States, CP outcomes for preterm infants have been reported at corrected ages of 18, 24, and 30 months. At 18 months’ CA the rate of CP was 15% in an NRN cohort of ELBW infants with 27% in the category of moderate to severe. The stability of a diagnosis of CP between 18 and 30 months’ CA was 91%. Of the infants seen both times 9% switched category over the study period suggesting the diagnosis of CP may be delayed in some infants. At 30 months 13% had mild CP, 4% moderate CP, and 2% severe CP.
Overall rates of CP and moderate to severe disability are inversely related to gestational age. Table 50-2 shows CP and motor outcome data reported by gestational age group for the most vulnerable infants of 22 to 25 weeks’ gestation. Outcome data for infants born at 22 weeks remain limited because of low survival and, therefore, numbers are frequently bundled with 23-week data. These data clearly depict the increased vulnerability for CP and disability at 22 and 23 weeks’ gestation.
Recent outcome data in the United States and abroad suggest the incidence of CP may be decreasing among very preterm infants.
Motor functioning
Functional assessment evaluates a child’s ability to perform the tasks of daily living and to fulfill the social roles expected of a physically and emotionally healthy person of the same age and culture.
For children, the tasks include feeding, dressing, bathing, maintaining continence, mobility, communication, play, and social interaction.
Functional delays are observed in VLBW infants with and without severe impairments such as CP.
Among a cohort of ELBW infants CA 93% of infants achieved sitting balance, 83% walked, and 86% fed themselves independently by 18 to 22 months’ corrected age, more subtle functional deficits become apparent later in life.
Transient dystonia
While CP is potentially the most disabling motor abnormality associated with prematurity, it remains a relatively low incidence morbidity compared to the relatively high incidence of fine and gross motor coordination deficits identified in former preterm infants.
During the first year of life transient dystonia (increased extensor tone and atypical movements) is a common deviation in the motor development of VLBW infants.
Transient dystonia occurs in 21% to 36% of preterm infants with a peak incidence at 7 months’ corrected age.
It involves increased extensor tone of the trunk and lower extremities and increased adductor tone in the lower extremities, leading to shoulder retraction and hip rotation, persistent primitive reflexes, head lag on pull to sit, and delayed supportive responses.
The presence of these findings increases the risk of later cognitive and motor problems including CP. Twenty percent of infants with transient dystonia go on to be diagnosed with CP.
But the specificity of these findings is low, as they are truly transient in 80% of the infants in which they occur, disappearing gradually between 8 and 12 months of age.
Developmental coordination disorder
Overall, however, children born preterm are more likely to have difficulty with motor coordination than term children.
In the past, these children were often labeled as “clumsy” but in recent years the diagnosis of developmental coordination disorder (DCD) has been used.
DCD is defined as impairment in motor performance sufficient to produce functional impairment that cannot be otherwise explained by the child’s age, cognitive ability, or neurologic or psychiatric diagnosis.
DCD is found in 31% to 34% of VLBW and 50% of ELBW infants, making it a significantly more common motor outcome than CP.
Table 50-3 lists criteria for increasing level of severity of DCD.
Vision and hearing
While much less common than motor or cognitive disabilities, rates of neurosensory disabilities including vision and hearing impairment are higher in ELBW infants than the general population and have long-term effects.
Most studies report rates of bilateral moderate to severe hearing loss requiring hearing aids or cochlear implant and bilateral legal blindness. Both moderate to severe vision and hearing impairment are more common among infants with co-occurring characteristics including male gender or multiple birth, and morbidities including CP, hydrocephalus, and seizures.
Vision
Unilateral or bilateral blindness may occur in up to 10% of ELBW infants.
Threshold ROP has been shown to be associated with long-term adverse effects on developmental, educational, functional, and social skills at school age.
Milder visual impairments also occur.
Rates of myopia in very preterm infants followed to age 5 ranged from 21.2% at 1 year to 15.7% at 4.5 years.
Total prevalence of strabismus in the first year of life was 14.7%.
Rates of nystagmus have been reported up to 4.6%.
Rates of corrective lenses for both eyes were up to 4.5%.
Hearing
Bilateral hearing impairment requiring amplification is reported in 1% to 9% of ELBW infants.
Rates may be impacted by the age of assessment since these infants are at increased risk of late onset hearing loss and/or progressive hearing loss.
Both the rate of severe hearing impairment and the severity of hearing impairments in this population have increased over time. Some of these changes may be increased ascertainment as a result of universal screening and ongoing surveillance.
Milder hearing impairments have been reported in up to an additional 28% of children.
Behavioral outcomes
Very low birthweight has been associated with a wide variety of behavioral and psychological diagnoses and disabilities.
Increased rates of internalizing behavior and dysregulation have been reported in very preterm children as early as 2 years.
At kindergarten age, compared to term controls, ELBW and extremely preterm children have higher rates of disorders of attention, self-regulation, and socialization.
ELBW children whose behavior was evaluated at 8 years of age by the Child Symptom Inventory had significantly higher mean Symptom Severity Scores for inattention, hyperactivity, combined attention-deficit hyperactivity disorder, generalized anxiety, autism and Asperger syndrome compared to term controls.
Parents and teachers of VLBW/ELBW infants report higher rates of inattention and hyperactivity at school age (8 to 12 years old), with rates of 23% to 27% in VLBW and 33% to 37% in ELBW infants. One-quarter to one-half of children born VLBW/ELBW have symptoms of anxiety and/or social withdrawal, 8% to 14% meet criteria for generalized anxiety disorder (compared to 1% to 4% of peers), and 25% to 28% meet criteria for a psychiatric disorder (compared to 7% to 10% of peers).
Autism spectrum disorder (ASD, see also Chapter 25)
Though low birthweight (<2500 g) may result in a two- to threefold increase in the risk of ASD, true risk of ASD in very preterm infants is unknown.
Two studies reported that 21% to 25% of VLBW infants screen positive on the M-CHAT at 18 months. However, VLBW infants with other severe impairments often have a false-positive screen. The rate of positive screens in those without severe impairment was 10%.
Resource needs
Early intervention services
Interventions to support development should begin in the NICU.
Due to high rates of cognitive, motor, language, functional, and behavioral impairments, ELBW infants require multiple postdischarge multidisciplinary interventions, therapeutic and educational services.
In an NRN report of infants <28 weeks’ gestation at 18 to 22 months’ corrected age, 37% of infants were receiving special outpatient services including social work, visiting nurse, medical specialty, early intervention, speech and language services, occupational therapy and physical therapy, and neurodevelopmental and behavioral services. In addition, within the cohort 55% used more than three services.
A Cochrane review of effects of developmental intervention programs posthospital discharge for preterm infants <37 weeks reported beneficial cognitive and motor effects in infancy with cognitive effects evident at preschool age. Sustained effects to school age, however, were not identified.
Special education services
ELBW and VLBW survivors have increased rates of academic underachievement and need for special education services.
Teachers of VLBW infants report rates of below-average school performance in all academic areas, ranging from 24% to 41%.
Approximately 25% of VLBW infants and up to 62% of ELBW infants receive special education services.
Between 15% and 34% required grade repetition.
Only 56% to 74% of preterm children, significantly fewer than normal birthweight teens, graduate from high school. Significant gender differences exist in graduation rates: 66% of VLBW males compared to 75% for term males and 81% for VLBW females compared to 90% for term females.
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