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ARTICLE |
a Pediatrix Medical Group of Dallas, Richardson, Texas
b Statistics and Epidemiology Division, RTI International, Research Triangle Park, North Carolina
c Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
d Department of Pediatrics, Genetics Counseling Center, Rhode Island Hospital and Hasbro Children's Hospital/Warren Alpert School of Medicine of Brown University, Providence, Rhode Island
e Department of Pediatrics, Women and Infants Hospital/Warren Alpert School of Medicine of Brown University, Providence, Rhode Island
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. The purpose of this work was to compare growth and neurodevelopmental outcomes of extremely low birth weight infants with major anomalies to extremely low birth weight infants without these findings. It was hypothesized that infants with severe anomalies would have worse growth, neurodevelopmental, and survival outcomes.
METHODS. A retrospective cohort analysis was performed on 5920 extremely low birth weight infants surviving beyond 12 hours of life at 19 neonatal network centers between 1998 and 2001. Infants with significant anomalies were more likely to die before 18 to 22 months' corrected age. A total of 3705 children underwent neurodevelopmental and anthropometric evaluation at 18 to 22 months' corrected age. Statistical significance for unadjusted comparisons was determined by Wilcoxon tests for continuous variables and 
2 or Fisher's exact tests for categorical variables. Regression models were used to compare the outcomes after adjusting for potential confounders.
RESULTS. Children with major congenital anomalies were more likely to have Bayley Mental Development Index scores of 
70, Psychomotor Development Index scores of 70, neurodevelopmental impairment, moderate-to-severe cerebral palsy, length in the 10th percentile, head circumference in the 10th percentile, more rehospitalizations, and higher rates of early intervention use at 18 to 22 months' corrected age.
CONCLUSIONS. At 18 to 22 months' corrected age, extremely low birth weight infants born with major anomalies have nearly twice the risk for neurodevelopmental impairment, increased risk of poor growth, and >3 times greater risk of rehospitalization when compared with extremely low birth weight infants without major anomalies. This information may be valuable for counseling parents regarding the outcomes of these infants and for the facilitation of appropriate support and intervention services.
Key Words: congenital anomalies • extremely low birth weight • outcomes
Abbreviations: ELBW—extremely low birth weight • BW—birth weight • CA—corrected age • NRN—Neonatal Research Network • GA—gestational age • SGA—small for gestational age • RDS—respiratory distress syndrome • PDA—patent ductus arteriosus • IVH—intraventricular hemorrhage • PVL—periventricular leukomalacia • CLD—chronic lung disease • CNS—central nervous system • PDI—Psychomotor Development Index • MDI—Mental Development Index • NDI—neurodevelopmental impairment • HC—head circumference • RR—relative risk
It is well known that most congenital syndromes are associated with significant neurodevelopmental delays.1 Trisomy 21 carries a 100% risk of mental retardation, although the severity is variable. Trisomies 13 and 18 are largely lethal during the first year of life, and the few survivors universally have profound mental retardation. Many other congenital syndromes are also known to carry risks of neurodevelopmental impairment.1,2
Not all serious congenital anomalies are associated with syndromes; in fact, many, such as congenital heart disease, may be isolated. In the case of a child with congenital cardiac disease, the possibility of chronically low oxygen saturations may place the child at risk for brain hypoxemia. In addition, some of these patients may experience decreased mobility and lack of normal infant socialization and stimulation because of chronic or repeat hospitalizations. There is evidence that some major congenital anomalies may be associated with neurodevelopmental delays, even without evidence of structural brain abnormalities.3–5 Therefore, the finding of a major congenital anomaly should raise the concern for possible neurodevelopmental impairment in the future, with contributions from both underlying medical and psychosocial factors.
Congenital anomalies and syndromes are associated with premature labor. In fact, many of these fetuses are spontaneously aborted very early in pregnancy.6,7 Of those who are carried beyond the first half of pregnancy, more than half are delivered preterm,8,9 and they may have restricted intrauterine growth.10 Some anomalies and syndromes are associated with both preterm delivery and intrauterine growth restriction.
Many of these infants who deliver prematurely not only have visible structural defects but are identified as having abnormalities on chromosomal analysis, and many have multiple anomalies rather than solely localized anomalies. It is estimated that approximately half of all fetuses spontaneously aborted by 20 weeks' gestation have a chromosomal abnormality.11 The most common chromosomal abnormality in spontaneously aborted fetuses is 45X, followed by triploidy. The trisomies as a group account for >50% of chromosomally abnormal pregnancy losses,12 and it is well documented that infants with chromosomal abnormalities often deliver prematurely.13
Extremely low birth weight (ELBW) infants without anomalies are at significantly increased risk for neonatal morbidities, such as bronchopulmonary dysplasia and necrotizing enterocolitis, that compromise the premature infant's ability to achieve adequate nutrition for growth.14 The incidence of these neonatal morbidities in ELBW infants with severe, life-threatening congenital anomalies is unknown. Premature ELBW infants without major anomalies are also known to be at increased risk for postdischarge growth impairment and developmental delay.15–18 There are few studies, however, that comment on the combined effects of ELBW and major congenital anomalies on neurodevelopmental outcome. Some outcome studies do not specifically identify these patients in their study populations,15 whereas others outright exclude patients with major congenital anomalies.14,16
The purpose of this study was to compare the neonatal morbidities, growth, and neurodevelopmental outcomes in ELBW premature infants with 
1 major anomaly with a comparison group of ELBW infants. The second objective was to identify the effects of major anomalies on outcomes after adjusting for known confounders. The hypothesis was that ELBW premature infants born with major congenital anomalies would have an increased risk of death, poor growth, and adverse neurodevelopmental outcomes at 18 to 22 months' corrected age (CA) compared with the ELBW comparison group.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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1000 g at birth are invited to return for a comprehensive assessment at 18 to 22 months' CA. The registry study was approved by the institutional review board at each study center, and either verbal or written consent was obtained for participation in follow-up.
Infants who died before 12 hours of life or who had missing anomaly information were excluded from this study. Maternal and neonatal data examined included infant's BW, gestational age (GA), gender, race, small-for-GA (SGA) status, receipt of 1 dose of surfactant, antenatal steroids, or postnatal steroids, existence of respiratory distress syndrome (RDS), patent ductus arteriosus (PDA), intraventricular hemorrhage grade (IVH) III or IV, periventricular leukomalacia (PVL), chronic lung disease (CLD; defined as the need for supplemental oxygen at 36 weeks), necrotizing enterocolitis (stage 2 or greater according to Bell's classification system19), seizures, sepsis (early or late onset; positive culture), meningitis, or major congenital anomaly (if present), and length of hospital stay and the mother's age, marital status, and education.
Infants were included in the major congenital anomaly group if they had 1 or more structural defects present at birth that required significant surgical and/or medical intervention without which survival would not be possible. The comparison group was composed of all of the infants without major anomalies (minor or no anomalies). Diagnostic information recorded in the medical chart was used to classify infants into the following categories of major congenital anomalies: central nervous system (CNS), cardiovascular, gastrointestinal, genitourinary, chromosomal, and nonspecific. Infants with >1 anomaly were classified into multiple categories, and infants with chromosomal abnormalities were placed into the chromosomal abnormality group only because of the inability to distinguish specific organ system involvement in each patient. For example, simple documentation of trisomy 21 did not make it clear whether the infant had cardiovascular anomalies.
The 18- to 22-month CA assessment, which has been described previously,15 consisted of a medical and social history, growth parameters, a developmental evaluation, and a neurologic examination based on the Amiel-Tison20 neurologic assessment. The neurologic assessment was performed by a certified examiner and included an evaluation of tone, strength, reflexes, angles, and posture with infants scored as normal if no abnormalities were seen. Cerebral palsy was defined as a nonprogressive CNS disorder characterized by abnormal muscle tone in 1 extremity and abnormal control of movement and posture.21
The Bayley Scales of Infant Development II22 was administered by certified examiners, and scores were reported for the Psychomotor Development Index (PDI) and Mental Development Index (MDI). The adult caretaker who brought the child to the clinic for the visit stayed with the child throughout the Bayley examination. Scores of 100 ± 15 represent the mean ± 1 SD with a score <70 (2 SDs below the mean) indicating significant delay. Children who could not be assessed because of severe developmental delay were assigned MDI and PDI scores of 49.
Hearing status was obtained by parental history or follow-up audiologic tests results (when available). Hearing impairment was defined as the need for amplification. A history of eye examinations and procedures since the initial discharge was obtained, and a standard eye examination was completed to evaluate tracking, esotropia, nystagmus, or roving eye movements. Visual impairment was defined as a lack of normal vision, including the use of corrective lenses, blind with some functional vision, or no useful vision. Blind was defined as corrected vision of <20/200. Neurodevelopmental impairment (NDI) was defined as the presence of 1 of the following: MDI or PDI scores of 70, moderate-to-severe cerebral palsy, bilateral blindness, or bilateral hearing aids.
The use of early intervention services and rehospitalizations in the first year of life was recorded. Weight, length, and head circumference (HC) were obtained at the follow-up visit using standard network procedures,15 and 2000 Centers for Disease Control and Prevention growth curves23 were used to determine whether these measures were at <10th percentile for gender and CA.
Eleven binary outcomes based on the follow-up evaluation were defined: MDI score (70 vs >70), PDI score (70 vs >70), cerebral palsy (yes or no), vision impairment (yes or no), hearing impairment (yes or no), NDI (yes or no), weight at <10th percentile (yes or no), length at <10th percentile (yes or no), HC at <10th percentile (yes or no), 4 rehospitalizations in the first year of life (yes or no), and early intervention services (yes or no).
Children in the 2 study groups were compared with respect to each of the neurodevelopmental and growth outcomes. Statistical significance for unadjusted comparisons was determined by Wilcoxon tests for continuous variables and 2 or Fisher's exact tests for categorical variables. Poisson regression models with robust variance estimators24 were used to compare the anomaly and control groups with respect to each outcome after adjusting for maternal and neonatal variables. All of the models included study group, study site, GA, SGA status, gender, race, antenatal steroid use, postnatal steroid use, surfactant use, RDS, CLD, PDA, severe IVH (grade III or IV), PVL, mother's age, caretaker's education (high school graduate or not), and the presence of sepsis or meningitis. All of the variables were entered as categorical variables. Adjusted relative risks (RRs) and 95% confidence intervals from these models are reported, with statistical significance determined by z tests.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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50% to 60% for those with gastrointestinal, genitourinary, and CNS anomalies and 30% to 39% for those with chromosomal, cardiovascular, and other abnormalities. Follow-up rates ranged from a low of 56% for surviving infants with chromosomal abnormalities to a high of 93% for infants with other anomalies.
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70 (57% vs 31%) and PDI scores of 70 (48% vs 20%), moderate-to-severe cerebral palsy (18% vs 6%), and NDI (65% vs 37%). Among infants with cardiovascular anomalies, the largest subgroup (50%) had MDI scores of <70, 35% had PDI scores of <70, and 61% had NDI. No significant differences were found between the groups in the percentage with visual impairment or hearing impairment.
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4 times in the first year of life compared with 7% of the control group (P < .001), and early intervention services at 18 to 22 months were used by more infants in the study group (78% vs 56%; P < .001).
After adjusting for study center and maternal and neonatal characteristics, children in the major anomaly group were >3 times as likely as those in the control group to have had 4 hospitalizations in the first year of life and were at greater risk for an MDI score of <70 (adjusted RR: 1.84), PDI score of <70 (adjusted RR: 1.76), moderate-to-severe cerebral palsy (adjusted RR: 2.31), and NDI (adjusted RR: 1.61) at 18 to 22 months' CA (Table 4). A statistically significant difference was no longer seen between the groups on weight at follow-up. However, children in the study group were at greater risk for being in the <10th percentile on length (adjusted RR: 1.52) and HC (adjusted RR: 1.39).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This is one of the largest studies to evaluate neonatal and postdischarge outcomes of ELBW infants with severe anomalies who survived beyond 12 hours of life. Although 76% of the infants surviving beyond 12 hours of life in the comparison group were alive at 18 to 22 months' CA, only 50% of the infants in the anomaly group were alive at 18 to 22 months' CA. Thus, the survival rate of ELBW infants in this study was severely reduced when complicated by 1 major congenital anomaly. Because infants who died in the first 12 hours after birth were excluded from the study, these death rates are likely to be underestimates for all of the ELBW live births. The literature supports this increased risk of morbidity and mortality in ELBW infants with birth defects: in a population-based, case-control study, Bacek et al27 reviewed Missouri birth and death certificates for an 8-year period and found that early GA neonates with severe congenital anomalies were at the highest risk for death in the first 28 days of life.
The highest rate of survival in our cohort of children who lived beyond the first 12 hours of life was seen in the group with genitourinary anomalies, with 62% of these infants surviving at 18 to 22 months' CA. Hook13 estimated that the association between chromosomal aberrations and infant and early childhood death was 5% to 7%. Our study identified even higher mortality associated with abnormal karyotypes in ELBW infants, with 70% of the infants with chromosomal abnormalities dying before 18 to 22 months. Tanner et al28 evaluated the influence of prematurity and congenital heart disease on outcomes: the odds ratio for the presence of a cardiovascular malformation in prematurity versus term infants was 2.4, and, not surprisingly, there was an increased risk of first-year mortality among infants born preterm with a cardiovascular malformation when compared with those without cardiovascular malformations (odds ratio: 1.8 at <28 weeks' gestation; odds ratio: 3.7 at 28–31 weeks). Our study confirmed that ELBW infants with cardiovascular anomalies have poor survival, with only 38% still alive at 18 to 22 months' CA.
Although infants in the major anomaly group had a 1-week higher mean GA, most of the population characteristics were similar between the 2 groups. Consistent with a published reference source,1 infants with major congenital anomalies or syndromes were more likely to be SGA. In addition, they had an increased rate of CLD and prolonged hospitalization, suggesting greater severity of illness in the study group.
A number of studies have reported the long-term outcomes of cohorts of infants with specific syndromes or congenital anomalies.3,29,30 Dittrich et al3 evaluated neurodevelopmental outcomes at 1 year of life in 90 infants >32 weeks' gestation who were born with congenital heart disease requiring surgical intervention. When compared with a control group of 20 infants with minor or no congenital heart disease, the study group had a much higher rate of neurologic abnormalities: 32% of the infants with surgical cardiac conditions were neurodevelopmentally impaired at 1 year of life compared with only 5% of control infants with minor or no cardiac anomalies. In our study, 11 (61%) of 18 infants with cardiovascular anomalies were classified as neurodevelopmentally impaired, suggesting that ELBW infants with congenital cardiac anomalies have poorer outcomes than term infants with similar birth defects.
Congenital anomalies are frequently associated and chromosomal abnormalities are almost always associated with growth failure.1 For example, disorder-specific growth charts have been developed for children with Down syndrome.31 After adjusting for confounders known to be associated with growth impairment, children in the anomaly group were at greater risk for short stature and smaller HC than those in the comparison group. Growth failure was also associated with chronic illness as reflected by the high rehospitalization rate in the major anomaly group.
Our data provide evidence that infants who are born with the double jeopardy of ELBW and the presence of 1 severe congenital anomaly are more likely to have poor growth and neurodevelopmental outcomes when compared with ELBW infants without these anomalies. Infants with major anomalies had significantly lower Bayley MDI and PDI scores than those in the comparison group. Regression models adjusting for cofounders indicated that infants with severe anomalies had nearly twice the risk of having MDI or PDI scores of <70. NDI was seen in 65% of children in the study group compared with 37% in the control group. These data suggest that if an ELBW infant with a severe anomaly survives to 18 to 22 months' corrected age, he or she is very likely to have significant impairments in both mental and motor development.
Furthermore, 18% of the infants with major anomalies were diagnosed with moderate-to-severe cerebral palsy, whereas only 6% of those in the comparison group met the criteria for this diagnosis. Croen et al32 investigated the association between cerebral palsy and congenital anomalies among children with very low, low, and normal BWs. Congenital anomalies were present in 19% of the children with CP and in only 4% of those without CP. In addition, for each BW group, the percentage of children with birth defects among children with CP was greater than that of the control children.
This study demonstrates that surviving ELBW infants with severe congenital anomalies face challenges greater than those of ELBW infants without anomalies. It was not surprising that resource use was also shown to be much higher in the group with anomalies: 78% of the infants with anomalies were receiving early intervention services at 18 to 22 months' corrected age compared with only 56% of the infants without anomalies. The findings suggest that all ELBW infants with major anomalies would benefit from early intervention services; thus, emphasis must be placed on assuring aggressive support services for these infants after discharge from the NICU.
There was also evidence that these infants remain medically fragile after discharge from the NICU: 30% of the infants with major anomalies were rehospitalized 4 times in the first year of life. This information can be used in providing anticipatory guidance to parents of ELBW infants with major congenital anomalies.
The study was limited by 2 design issues. First, the small sample size of 73 ELBW infant survivors in the severe anomaly group with follow-up data did not permit subgroup analysis of outcomes. Second, the control group included infants with minor anomalies, because the National Institute of Child Health and Human Development NRN protocol includes data collection of only major, and not minor, anomalies. Because minor congenital malformations may be associated with neurodevelopmental and/or growth impairment, it is possible that, by placing these undocumented infants in the comparison group, the results could have been biased toward a null finding. Despite this limitation, significant group differences were identified for all of the study outcomes, with significant relative risks of adverse outcomes for infants with major malformations after adjusting for cofounders. We were, however, unable to evaluate the effects of a minor malformation.
A major strength of this study is that it includes the analysis of both neonatal and 18- to 22-month outcomes of a population of ELBW infants with major congenital anomalies excluded previously from most follow-up studies and a large comparison group. Low-incidence neonatal outcomes, such as major congenital anomalies, are difficult to evaluate outside of a multicenter network. This study provides evidence that ELBW infants with major congenital anomalies have poorer survival, neurodevelopmental, and growth outcomes and greater needs for resource use.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address correspondence to Betty R. Vohr, MD, Women and Infants Hospital, 101 Dudley St, Providence, RI 02905. E-mail: betty_vohr{at}brown.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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