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ORIGINAL RESEARCH |
From the University of Southern California Keck School of Medicine; and Division of Neonatology, Department of Pediatrics, and Department of Pathology, Women’s and Children’s Hospital, Los Angeles County + University of Southern California Medical Center, Los Angeles, California.
Address reprint requests to: Joan E. Hodgman, MD, Women’s and Children’s Hospital, Division of Neonatology, 1240 North Mission Road, Room L-919, Los Angeles, CA 90033; E-mail: hodgman{at}hsc.usc.edu.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: We conducted a retrospective review from January 1994 through December 1998 for placental histopathology, maternal factors, neonatal intensive care unit course, growth, neurologic/special sense status, and development at 2 years of age corrected for prematurity.
RESULTS: Of the 104 neonates weighing 600 g or less, 24 survived to nursery discharge (23%). Two infants died of chronic lung disease after discharge, and 21 of the remaining 22 infants (95%) returned for follow-up. Placental pathology was available for 21 (95%); acute inflammation was present in 67%, and other abnormalities occurred in 76%. Mean birth weight was 537 (430–600) g, and mean gestational age was 24 (22–27) weeks. At birth, 55% were below the tenth percentile for birth weight. At nursery discharge and 2 years of age, 94% were below the tenth percentile for weight, length, and head circumference. Nineteen of 21 (90%) infants were abnormal on neurodevelopmental follow-up. Major problems were cerebral palsy, blindness, gastrostomies, and ventriculoperitoneal shunts.
CONCLUSION: Abnormal placental histology was present in all but one infant, suggesting fetal injury before birth. Only eight of 20 infants with chorioamnionitis were diagnosed clinically, and all infants had a complicated course. We found a high incidence of intrauterine growth restriction and an almost universal pattern of impaired postnatal growth with extremely poor neurodevelopmental outcome at 2 years of age.
Survival rates have been increasing for extremely low birth weight 1000-g or lower infants during the 1990s.1 This increase has been particularly notable in the smallest and least mature infants of birth weights less than 750 g and gestational ages less than 28 weeks. The important question of intact survival and limit of viability in these infants has not been completely answered. Many of the reports on mortality and long-term morbidity are restricted to infants 500–1500-g birth weight, thus diluting the results for the most vulnerable. Most reports lump the extremely low birth weight infant into 500–1000-g or less than 750-g groups and do not provide results by 100-g birth weight intervals or week to week gestation.2 It is universally agreed that both mortality and long-term morbidity increase with decreasing birth weight and gestational age. Consequently, results reported for infants less than 1000 g or less than 750 g will be too optimistic for the lower limit of the group. Two authors report 60% and 67% long-term handicap for infants of 500-g or lower and 500–599-g birth weight, respectively.3,4 Outcome reported by gestation has varied from 66–72% handicap at 24 weeks or less and 38–53% at 25 weeks.5,6
We could find little information about the role of placental pathology in the long-term outcome of preterm survivors.
In an effort to better describe the perinatal factors in infants born at the threshold of viability, we report the 2-year neurodevelopmental outcome of infants of birth weight 600 g or lower. All but one had histologic examination of the placenta and were discharged from our hospital during 1994–1998.
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MATERIALS AND METHODS |
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We documented the following perinatal information: maternal age; race; gravidity/parity; gestational age; drug, tobacco, and alcohol use; maternal-fetal medical conditions (specifically, preeclampsia, oligohydramnios, placenta previa, clinical diagnosis of chorioamnionitis, birth trauma, vaginal bleeding, and fetal distress); antenatal steroid administration; delivery method; presentation; premature rupture of membranes; and Apgar scores. We used the gestational age based on maternal dates unless that number differed from the gestational age as determined using the Ballard score7 by greater than 2 weeks, in which case the gestational age based on examination was used.
Placental pathology reports were reviewed by a pediatric pathologist (ZP) and assessed for evidence of acute inflammation and other placental abnormalities. The pathologist was unaware of the clinical course or outcome of the infants. Acute inflammation, specifically acute chorioamnionitis and/or funisitis, was diagnosed by the presence of neutrophils. Chronic nonspecific villitis and/or chronic deciduitis was diagnosed by the presence of lymphocytes, histiocytes, and/or plasma cells. Chorioangiosis was defined as ten or more capillaries in ten or more villi in ten or more microscopic fields at x 10 magnification.
The NICU and clinic records were reviewed for diagnoses of intraventricular hemorrhage and periventricular leukomalacia using serial cranial head ultrasounds and/or magnetic resonance imaging of the head. The presence of seizures, abnormal electroencephalograms, hydrocephalus, need for ventriculoperitoneal shunt, retinopathy of prematurity, medications, congenital malformations, presence of blindness, deafness, or cerebral palsy, as well as complications of respiratory distress syndrome and chronic lung disease were noted. Chronic lung disease was defined as dependency on supplemental oxygen at 36 weeks postconceptual age. Ophthalmologic examinations were done at 4–6 weeks after delivery, and follow-up eye examinations were done weekly or biweekly, as indicated. Infants who met the criteria used in the multicenter trial of cryotherapy for retinopathy of prematurity received peripheral laser photocoagulation.8 Hearing was evaluated by brainstem auditory-evoked potentials at the time of discharge, repeated during clinic visits as necessary and at 8 months corrected age. All other diagnoses and complications in the NICU were noted including gastrointestinal problems requiring surgery or feeding gastrostomies. All hospital admissions after initial discharge were documented.
Growth was assessed at three time points: birth, discharge from the NICU, and at 2 years of age corrected for prematurity. Using the Denver intrauterine growth chart, length, weight, and head circumference were each evaluated. For those neonates born less than 24 weeks’ gestation, the growth chart was extrapolated down to provide a best approximation of expected percentiles. In the clinic, the charts from the National Center for Health Statistics were used.
Neurodevelopmental evaluation was performed using the Bayley Scales of Infant Development9 and a standard neurologic examination. The Bayley Scales were administered by a clinical psychologist unaware of details of the infants’ hospital course. Bayley scores of 100 ± 15 represent the mean ± one standard deviation. A score of less than 70 is two standard deviations below the mean. For the purposes of calculation of mean values, those infants who were deemed untestable were assigned a score of 49. Cerebral palsy was diagnosed clinically based on the neurologic examination. All neurologic examinations were performed serially every 2 months by one of the authors (IP). The patients were assessed for the presence of abnormal muscle tone or movement, persistent primitive reflexes, and delayed motor function. The diagnosis of cerebral palsy was made when functional impairment was present. Patients with severe cerebral palsy required significant physical assistance with activities of daily living, whereas those with moderate cerebral palsy required some assistance, and those with mild cerebral palsy had impaired ambulation and function but were not dependent on assistance. Hemiplegia indicated a unilateral neurologic abnormality, diplegia that the lower extremities were more severely affected than the upper extremities, whereas quadriplegia described infants with impaired function of all four extremities.
No statistical tests of the results were deemed necessary.
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RESULTS |
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Maternal characteristics for the study population are shown in Table 1
. Mean maternal age was 31 years, and 77% of mothers were Hispanic. Antenatal steroids were used in 64% of the mothers. The remaining mothers came in advanced labor or were less than 23 weeks’ gestation. Illicit drug use (18%) was higher than in our general population. Pregnancy-related complications such as preeclampsia (41%), oligohydramnios (36%), and preterm prolonged rupture of membranes (18%) were also very common. Chorioamnionitis was diagnosed clinically in only 36% of the mothers, even though histologic evidence of acute chorioamnionitis was present in 67% of the placentas. In addition to the characteristics listed in Table 1, there was one mother who had eclampsia with hemolysis, elevated liver enzymes, low platelets syndrome, one with alcohol use, one with a traumatic injury, and one with diabetes. Ultrasound was routinely done before delivery to assess size and gestation of the fetus. No anomalies were detected. Two-thirds of the mothers were given magnesium sulfate during labor.
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). Fourteen (67%) had evidence of acute inflammation, nine (43%) of chronic nonspecific villitis, and 16 (76%) showed other abnormalities. Eight had changes consistent with maternal hypertension such as atherosis of maternal vessels, abruptio, infarcts, and sequelae of hypoxia, ie, choriangiosis, increased syncytial knots, and nucleated red blood cells. In all eight of these women, a clinical diagnosis of maternal hypertension was documented. Of the nine mothers with a clinical diagnosis of preeclampsia, eight had evidence of pathologic changes in the placenta. Two patients showed abruptio, and one had decidual hemorrhage with extensive recent parenchymal infarcts. There was one instance of placental accreta, one had a single umbilical artery, and a third was meconium stained, the latter an unusual finding at these early gestations. One placenta was normal but was associated with a uterine myoma. Acute inflammation was more common in the normally grown (ten of 14 versus four of 14), and structural changes were more common in pregnancies with intrauterine growth restriction (seven of 11 versus four of 11).
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. Birth weights ranged from 430 to 600 g, with four neonates weighing less than 500 g. The gestational age ranged from 22 to 26 weeks, with four at 22 weeks, seven at 23 weeks, two at 24 weeks, two at 25 weeks, five at 26 weeks, and one each at 27 and 28 weeks. All infants required intubation and ventilation for extended periods of time and had significant complications in the NICU. Ten infants had evidence of osteopenia, rickets, and/or fractures (45%). All infants received dexamethasone for the prevention/treatment of bronchopulmonary dysplasia. Eight infants were blind (38%), one with cortical blindness, and another five had impaired vision (24%). Sixteen (76%) received peripheral laser photocoagulation for threshold retinopathy of prematurity.
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Neurodevelopmental outcome was poor (Table 4). Bayley score results were available for 20 of the 22 infants at 2 years of age corrected for prematurity. Fifteen (75%) tested below a score of 50 in both mental developmental index and psychomotor developmental index and were categorized as untestable because of the severity of their developmental delay. Diagnosis of cerebral palsy was prevalent. No infant had normal muscle tone. Five (24%) had a diagnosis of suspect neurologic changes, and 16 (76%) had clinical diagnoses of cerebral palsy. Of these, three were mild, five were moderate, and eight were severe. Three infants were diagnosed as having hemiplegia, eight as diplegia, and five as quadriplegia.
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Growth patterns for these infants were significantly impaired. Although approximately 55% were below the tenth percentile for length, weight, and head circumference at birth, 94% of these infants were below the tenth percentile by nursery discharge and at 1 and 2 years of age corrected for prematurity.
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DISCUSSION |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Evidence of acute placental infection was particularly common. Importantly, one half of the inflammation was subclinical and was diagnosed only with placental pathologic examination. Chorioamnionitis has been proposed as a cause of spontaneous premature delivery.14 Placental abnormalities have also been correlated with increased risk for neonatal central nervous system injury. Chorioamnionitis appears to make the very preterm infant particularly vulnerable to central nervous system damage. Alexander et al15 demonstrated a correlation between chorioamnionitis and increased risk for sepsis, respiratory distress syndrome, periventricular leucomalacia, intraventricular hemorrhage, and seizures. O’Shea et al16 reported an association between spastic diplegia and chorioamnionitis in a study of 80 low birth weight infants (500–1500 g) with cerebral palsy at 1 year of age. Our results are consistent with this association.
Current research has sought to determine the specific mechanism of injury to the fetal central nervous system caused by placental inflammation. Elevated levels of proinflammatory cytokines such as interleukin-6, interleukin-1ß, and tumor necrosis factor-
were found in the amniotic fluid from pregnancies with newborns who subsequently had periventricular white matter lesions.17 Such inflammatory cytokines may be acting to increase permeability of the immature blood brain barrier and may have a direct cytotoxic effect on oligodendrocytes.18 These investigators concluded that interleukin-6 and interleukin-1ß levels in the amniotic fluid could identify infants at risk for development of white matter lesions. Jones et al19 from our institution showed that premature infants produce elevated levels of proinflammatory cytokines, but have decreased levels of interleukin-10 and other anti-inflammatory cytokines. Thus, these infants are unable to temper the proinflammatory response secondary to chorioamnionitis.
Additionally, neurologic injury may be caused by fetal placental vascular lesions. Redline et al20 found an increased risk of neurologic impairment in newborns whose mothers had chorioamnionitis and whose placentas had nonocclusive thrombi of the chorionic plate. Furthermore, there has been recent evidence that fetal and neonatal neurologic damage and cerebral palsy may be related to maternal thrombophilia and the resultant placental thrombosis, possibly even involving the fetal cerebral vessels.21
The prevalence of pathologic findings is of particular significance when one considers that only eight of these mothers had clinical findings of chorioamnionitis. This raises the question of how best to identify and treat such women before the delivery becomes unavoidable. Future efforts to improve the quality of life in these tiny preterm infants need to focus on fetal well-being before delivery, as well as aggressive postnatal interventions.
The infants followed in this study showed consistently poor growth patterns throughout the period of evaluation. Similarly, we noted a high incidence of bone disease in our cohort. These findings suggest that we are failing to properly support these neonates after they come into our care in the NICU and after they go home. The most recently reported study from the National Institute of Child Health and Human Development Neonatal Research Network reports 100% of surviving extremely low birth weigth infants below the tenth percentile for weight at 36 weeks ( Lemos JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January, 1995 through December 1996 [electronic abstract]. Pediatrics 2001;107:164). Inadequate nutritional support both during fetal life and after birth may play an important role in the pathogenesis of the neurodevelopmental retardation. Small head circumference has been shown to correlate with poor neurologic function.22 That 94% of our infants showed head circumferences less than the tenth percentile at 2 years of age corrected for prematurity suggests that there was a common pattern of impaired neural growth correlating with almost universally poor neurodevelopmental outcome.
Our findings must be considered in light of the NICU medical trends that guided care during the period under evaluation. Postnatal steroid use has been correlated with poor outcome in neonates.12 All of the infants in our study received dexamethasone during their stay in the NICU.
Based on our findings, we have revised our institutional resuscitation guidelines and now routinely resuscitate infants 500 g or over or 24 weeks or more. We are not alone in using our own institutional data as a guide in developing protocols for resuscitation. Walther et al at the University Medical Center in Leiden have also changed their criteria for routine resuscitation based on a review of the outcome of infants born there.23 Although regionally based studies are helpful in elucidating the broader trends in neonatal survival and outcome, they should not be used exclusively to counsel families. Those results do not reflect the specific experience at each institution, which can be highly variable. Until we can better support these extremely tiny preterm infants, we need to be realistic about their chances for a normal outcome.
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Footnotes |
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Received February 22, 2002. Received in revised form May 16, 2002. Accepted June 12, 2002.
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REFERENCES |
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2. Escobar GJ, Littenberg B, Petitti DB. Outcome among surviving very low birthweight infants: A meta-analysis. Arch Dis Child 1991;66:204–11.[Abstract]
3. Suave RS, Robertson C, Etches P, Byrne PJ, Dayer-Zamora V. Before viability: A geographically based outcome study of infants weighing 500 grams or less at birth. Pediatrics 1998;101:438–45.
4. Hack M, Wilson-Costello D, Friedman H, Taylor GH, Schluchter M, Fanaroff AA. Neurodevelopment and predictors of outcomes of <1000 gram birth weight children born 1992–1995. Arch Pediatr Adolesc Med 2000;154: 725–31.
5. Morrison JJ, Rennie JM. Clinical, scientific and ethical aspects of fetal and neonatal care at extremely preterm periods of gestation. Br J Obstet Gynaecol 1997;104: 1341–50.[Medline]
6. Piecuch RE, Leonard CH, Cooper BA, Kilpatrick SJ, Schlueter MA, Sola A. Outcome of infants born at 24–26 weeks gestation: II. Neurodevelopmental outcome. Obstet Gynecol 1997;90:809–14.[Abstract]
7. Ballard JL, Novak KK, Driver M. A Simplified score for assessment of fetal maturation of newly born infants. J Pediatr 1979;95:769–74.[Medline]
8. Schaffer DB. Update on retinopathy of prematurity: The examination guidelines. Semin Opthalmol 1990;5:100–5.
9. Bayley N. Bayley scales of infant development. 2nd ed. San Antonio, Texas: The Psychological Corporation, Harcourt Brace and Company, 1993.
10. Wood NS, Marlow N, Costeloe K, Gibson AT, Wilkinson AR. Neurologic and developmental disability after extremely preterm birth. N Engl J Med 2000;343:378–84.
11. Evans DJ, Levene MI. Evidence of selection bias in preterm survival studies: A systematic review. Arch Dis Child Fetal Neonatal Ed 2001;84:F79–F84.
12. Shinwell ES, Karplus M, Reich D, Weintraub Z, Blazer S, Bader D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed 2000;83:F177–81.
13. Escalona SK. Babies at double hazard: Early development of infants at biologic and social risk. Pediatrics 1982;70: 670–6.
14. Lu GC, Goldenberg RL. Current concepts on the pathogenesis and markers of preterm births. Clin Perinatol 2000;27:263–83.[Medline]
15. Alexander JM, Gilstrap LC, Cox SM, McIntire DM, Leveno KJ. Clinical chorioamnionitis and the prognosis for very low birth weight infants. Obstet Gynecol 1998;91: 725–9.[Abstract]
16. O’Shea TM, Klinepeter KL, Dillard RG. Prenatal events and the risk of cerebral palsy in very low birth weight infants. Am J Epidemiol 1998;147:362–9.
17. Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi JH, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997;177:19–26.[Medline]
18. Yoon BH, Romero R, Kim CJ, Koo JN, Choe G, Syn HC, et al. High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 1997;177:406–11.[Medline]
19. Jones CA, Cayabyab RG, Kwong KY, Stotts C, Wong B, Hamdan H, et al. Undetectable interleukin (IL)-10 and persistent IL-8 expression early in hyaline membrane disease: A possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns. Pediatrics 1996;39:966–75.
20. Redline RW, Wilson-Costello D, Borawski D, Fanaroff AA, Hack M. Placental lesions associated with neurologic impairment and cerebral palsy in very low-birth-weight infants. Arch Pathol Lab Med 1998;122:1091–8.[Medline]
21. Nelson KB, Dambrosia JM, Grether JK, Phillips TM. Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 1998;44:665–75.[Medline]
22. Sommerfelt K, Markestad T, Ellertsen B. Neuropsychological performance in low birth weight preschoolers: A population-based, controlled study. Eur J Pediatr 1998; 157:53–8.[Medline]
23. Sheldon T. Dutch doctors change policy on treating preterm babies. Br Med J 2001;322:1383.
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