Prenatal tobacco smoke exposure and neurological impairment at 10 years of age among children born extremely preterm: a prospective cohort.

OBJECTIVE: To determine the association between prenatal tobacco smoke exposure and neurological impairment at 10 years of age among children born extremely preterm (<28 weeks of gestation). DESIGN: The Extremely Low Gestational Age Newborn (ELGAN) Study, a prospective cohort. SETTING: Ten-year follow-up of extremely preterm infants born at 14 US hospitals between 2002 and 2004. METHODS: Prenatal tobacco smoke exposure was defined as a mother's report at enrolment of active (i.e. maternal) and passive smoking during pregnancy. Poisson regression with generalized estimating equations was used. Models adjusted for mother's age, race/ethnicity, education, insurance, pre-pregnancy body mass index, US region, multiple gestation and infant's sex; and in sensitivity analysis, gestational age at delivery and clinical subtype of preterm birth, given their classification as intermediate and non-confounding variables. MAIN OUTCOMES: Neurological impairment at 10 years, epilepsy, cerebral palsy and cognitive impairment. RESULTS: Of 1200 ELGAN study survivors, 856 were assessed at 10 years of age with neurological outcomes, of whom 14% (118/856) had active tobacco exposure during pregnancy and 24% (207/852) had passive tobacco exposure. Compared with children who were not exposed prenatally to tobacco, children exposed to active tobacco use during pregnancy had a higher risk of epilepsy (14% versus 5%; adjusted relative risk: 1.68, 95% CI 1.45-1.92). This risk remained after adjustment for gestational age at delivery and clinical subtype of preterm birth. Prenatal tobacco smoke exposure was not associated with other assessed neurological outcomes, including cerebral palsy and multiple measures of cognitive impairment. CONCLUSIONS: Among children born extremely preterm, prenatal active tobacco smoke exposure was associated with an increased risk of epilepsy at 10 years of life. TWEETABLE ABSTRACT: Among infants born before 28 weeks of gestation, prenatal active tobacco smoke exposure was associated with an increased risk of epilepsy at 10 years of life.

Neonatal white matter damage and the fetal inflammatory response.

In 1962 a long-recognized pathologic abnormality in neonatal brains characterized by multiple telencephalic focal white matter necroses was renamed periventricular leukomalacia (PVL) and the authors inappropriately asserted that their entity was caused by anoxia. They also failed to include three other white matter histologic abnormalities. In this essay, we identify the breadth of white matter pathology, especially in very preterm newborns, and show that none of the four histologic expressions of white matter damage, including focal necrosis, are associated with hypoxemia or correlates as hypotension, but are instead associated with markers of fetal or perinatal inflammation, particularly in preterm babies. We begin with the background needed to evaluate the evidence.

Early postnatal illness severity scores predict neurodevelopmental impairments at 10 years of age in children born extremely preterm.

OBJECTIVE: A neonatal illness severity score, The Score for Neonatal Acute Physiology-II (SNAP-II), predicts neurodevelopmental impairments at two years of age among children born extremely preterm. We sought to evaluate to what extent SNAP-II is predictive of cognitive and other neurodevelopmental impairments at 10 years of age. STUDY DESIGN: In a cohort of 874 children born before 28 weeks of gestation, we prospectively collected clinical, physiologic and laboratory data to calculate SNAP-II for each infant. When the children were 10 years old, examiners who were unaware of the child's medical history assessed neurodevelopmental outcomes, including neurocognitive, gross motor, social and communication functions, diagnosis and treatment of seizures or attention deficit hyperactivity disorder (ADHD), academic achievement, and quality of life. We used logistic regression to adjust for potential confounders. RESULTS: An undesirably high SNAP-II (⩾30), present in 23% of participants, was associated with an increased risk of cognitive impairment (IQ, executive function, language ability), adverse neurological outcomes (epilepsy, impaired gross motor function), behavioral abnormalities (attention deficit disorder and hyperactivity), social dysfunction (autistic spectrum disorder) and education-related adversities (school achievement and need for educational supports. In analyses that adjusted for potential confounders, Z-scores ⩽-1 on 11 of 18 cognitive outcomes were associated with SNAP-II in the highest category, and 6 of 18 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals ranged from 1.4 (1.01, 2.1) to 2.1 (1.4, 3.1). Similarly, 2 of the 8 social dysfunctions were associated with SNAP-II in the highest category, and 3 of 8 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals were slightly higher for these assessments, ranging from 1.6 (1.1, 2.4) to 2.3 (1.2, 4.6). CONCLUSION: Among very preterm newborns, physiologic derangements present in the first 12 postnatal hours are associated with dysfunctions in several neurodevelopmental domains at 10 years of age. We are unable to make inferences about causality.

The antecedents and correlates of necrotizing enterocolitis and spontaneous intestinal perforation among infants born before the 28th week of gestation.

OBJECTIVE: To identify antecedents of "medical" necrotizing enterocolitis (mNEC), "surgical" NEC (sNEC), and spontaneous intestinal perforation (SIP) in newborns delivered before 28 weeks gestation. STUDY DESIGN: Prospective multicenter cohort study. During study period, 2002- 2004, women delivering before 28 weeks gestation at one of 14 participating institutions were enrolled. Well defined antenatal and postnatal variables were collected. Bivariate analyses were performed to identify candidates for developing multinomial multivariable time-oriented logistic regression models. RESULTS: Of the 1320 infants, 5% had mNEC, 6% had sNEC, and 4% had SIP. Antecedents of mNEC included mother's identification as Black, consumption of aspirin during the pregnancy, and vaginal bleeding after the 12th week of gestation. For sNEC the antecedents were maternal self- support, obesity and anemia during the pregnancy, birth before the 24th week, birth weight ≤750gm, and receipt of fresh frozen plasma (FFP) during the first postnatal week. An infant was at increased risk of SIP if the placenta had increased syncytial knots, birth occurred before the 24th week, and received FFP during the first week. CONCLUSIONS: Maternal and neonatal characteristics might help identify at-risk ELGANs for NEC and SIP, who then may potentially benefit from targeted preventive strategies.

Systems Epidemiology: What's in a Name?

Systems biology is an interdisciplinary effort to integrate molecular, cellular, tissue, organ, and organism levels of function into computational models that facilitate the identification of general principles. Systems medicine adds a disease focus. Systems epidemiology adds yet another level consisting of antecedents that might contribute to the disease process in populations. In etiologic and prevention research, systems-type thinking about multiple levels of causation will allow epidemiologists to identify contributors to disease at multiple levels as well as their interactions. In public health, systems epidemiology will contribute to the improvement of syndromic surveillance methods. We encourage the creation of computational simulation models that integrate information about disease etiology, pathogenetic data, and the expertise of investigators from different disciplines.

Perinatal systemic inflammatory responses of growth-restricted preterm newborns.

AIM: To compare the early post-natal pattern of systemic inflammation in growth-restricted infants born before the 28th week of gestation to that of appropriately grown peers. METHODS: We measured the concentrations of 25 inflammation-related proteins in blood spots collected from 939 newborns during the first 2 post-natal weeks. We calculated the odds ratios (99% confidence intervals) that concentrations would be in the highest quartile. RESULTS: Severely growth-restricted infants (birth weight Z-score <-2) were not at increased risk of systemic inflammation shortly after birth. On post-natal day 14, however, they were significantly more likely than their peers to have a CRP, IL-1ß, IL-6, TNF-α, IL-8, MCP-4, ICAM-1, ICAM-3, E-SEL, MMP-9, VEGF-R2 and/or IGFBP-1 concentration in the highest quartile. These increased risks could not be attributed to delivery indication, bacteremia or duration of ventilation. CONCLUSION: Growth-restricted preterm newborns appear to be at increased risk of elevated concentrations of inflammation-associated proteins by post-natal day 14.

Early postnatal hypotension is not associated with indicators of white matter damage or cerebral palsy in extremely low gestational age newborns.

OBJECTIVE: To evaluate, in extremely low gestational age newborns (ELGANs), relationships between indicators of early postnatal hypotension and cranial ultrasound indicators of cerebral white matter damage imaged in the nursery and cerebral palsy diagnoses at 24 months follow-up. STUDY DESIGN: The 1041 infants in this prospective study were born at <28 weeks gestation, were assessed for three indicators of hypotension in the first 24 postnatal hours, had at least one set of protocol cranial ultrasound scans and were evaluated with a structured neurological exam at 24 months corrected age. Indicators of hypotension included: (1) lowest mean arterial pressure (MAP) in the lowest quartile for gestational age; (2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile of the difference between each infant's lowest and highest MAP. Outcomes included indicators of cerebral white matter damage, that is, moderate/severe ventriculomegaly or an echolucent lesion on cranial ultrasound and cerebral palsy diagnoses at 24 months gestation. Logistic regression was used to evaluate relationships among hypotension indicators and outcomes, adjusting for potential confounders. RESULT: Twenty-one percent of surviving infants had a lowest blood pressure in the lowest quartile for gestational age, 24% were treated with vasopressors and 24% had labile blood pressure. Among infants with these hypotension indicators, 10% percent developed ventriculomegaly and 7% developed an echolucent lesion. At 24 months follow-up, 6% had developed quadriparesis, 4% diparesis and 2% hemiparesis. After adjusting for confounders, we found no association between indicators of hypotension, and indicators of cerebral white matter damage or a cerebral palsy diagnosis. CONCLUSION: The absence of an association between indicators of hypotension and cerebral white matter damage and or cerebral palsy suggests that early hypotension may not be important in the pathogenesis of brain injury in ELGANs.

The ELGAN study of the brain and related disorders in extremely low gestational age newborns.

BACKGROUND: Extremely low gestational age newborns (ELGANs) are at increased risk for structural and functional brain abnormalities. AIM: To identify factors that contribute to brain damage in ELGANs. STUDY DESIGN: Multi-center cohort study. SUBJECTS: We enrolled 1506 ELGANs born before 28 weeks gestation at 14 sites; 1201 (80%) survived to 2 years corrected age. Information about exposures and characteristics was collected by maternal interview, from chart review, microbiologic and histological examination of placentas, and measurement of proteins in umbilical cord and early postnatal blood spots. OUTCOME MEASURES: Indicators of white matter damage, i.e. ventriculomegaly and echolucent lesions, on protocol cranial ultrasound scans; head circumference and developmental outcomes at 24 months adjusted age, i.e., cerebral palsy, mental and motor scales of the Bayley Scales of Infant Development, and a screen for autism spectrum disorders. RESULTS: ELGAN Study publications thus far provide evidence that the following are associated with ultrasongraphically detected white matter damage, cerebral palsy, or both: preterm delivery attributed to preterm labor, prelabor premature rupture of membranes, or cervical insufficiency; recovery of microorganisms in the placenta parenchyma, including species categorized as human skin microflora; histological evidence of placental inflammation; lower gestational age at delivery; greater neonatal illness severity; severe chronic lung disease; neonatal bacteremia; and necrotizing enterocolitis. CONCLUSIONS: In addition to supporting a potential role for many previously identified antecedents of brain damage in ELGANs, our study is the first to provide strong evidence that brain damage in extremely preterm infants is associated with microorganisms in placenta parenchyma.

Pregnancy disorders that lead to delivery before the 28th week of gestation: an epidemiologic approach to classification.

Epidemiologists have grouped the multiple disorders that lead to preterm delivery before the 28th week of gestation in a variety of ways. The authors sought to identify characteristics that would help guide how to classify disorders that lead to such preterm delivery. They enrolled 1,006 women who delivered a liveborn singleton infant of less than 28 weeks' gestation at 14 centers in the United States between 2002 and 2004. Each delivery was classified by presentation: preterm labor (40%), prelabor premature rupture of membranes (23%), preeclampsia (18%), placental abruption (11%), cervical incompetence (5%), and fetal indication/intrauterine growth restriction (3%). Using factor analysis (eigenvalue = 1.73) to compare characteristics identified by standardized interview, chart review, placental histology, and placental microbiology among the presentation groups, the authors found 2 broad patterns. One pattern, characterized by histologic chorioamnionitis and placental microbe recovery, was associated with preterm labor, prelabor premature rupture of membranes, placental abruption, and cervical insufficiency. The other, characterized by a paucity of organisms and inflammation but the presence of histologic features of dysfunctional placentation, was associated with preeclampsia and fetal indication/intrauterine growth restriction. Disorders leading to preterm delivery may be separated into two groups: those associated with intrauterine inflammation and those associated with aberrations of placentation.

Reference weights for placentas delivered before the 28th week of gestation.

CONTEXT: Very few studies have measured the weight of large numbers of placentas delivered before the 28th post-menstrual week. METHODS: We measured the weight of 930 singleton placentas delivered before the 28th post-menstrual week, and examined the distributions of weights in selected groups (week of gestation, reason for preterm birth, birth weight Z-score categories, placenta histology). We excluded 90 singleton placentas based on growth restriction as indicated by birth weight Z-score, resulting in a normative sample of 840 placentas. Weights for unfused twin placentas are also presented. RESULTS: Standard weights derived from our data set differ from those previously published, partly due to a larger sample size. Placenta weight varied with birth weight. Placentas from pregnancies ending due to preeclampsia, fetal indications or those showing evidence of poor perfusion on histology were among the smallest and their weights correlated with the smallest birth weights for gestational age. CONCLUSIONS: Placenta weights appear to be influenced by multiple maternal and fetal processes. We present a standard weight table for singleton placentas among live infants born between 23 and 27 completed weeks.

Fetal vasculitis in preterm newborns: interrelationships, modifiers, and antecedents.

Histologic expressions of the fetal inflammatory response predict preterm delivery and neonatal disorders. We examined 1146 placentas in the Developmental Epidemiology Network data set for histologic evidence of membrane inflammation (subchorionitis, chorionitis, and chorioamnionitis) and fetal vasculitis (acute umbilical vasculitis or chorionic vasculitis). Our main findings are that (1) in the presence of membrane inflammation, fetal vasculitis is common, (2) duration of membrane rupture and gestational age appear to modify the risk of fetal vasculitis, (3) this risk modification differs for the different components of fetal vasculitis, i.e. umbilical and chorionic vasculitis, and (4) antecedents can be identified that appear to increase or decrease the risk of fetal vasculitis among births with membrane inflammation. We conclude that fetal vasculitis, the morphologic component of the fetal inflammatory response, might not be a homogeneous entity and deserves further study.

A review of the literature relating caffeine consumption by women to their risk of reproductive hazards.

From this detailed review of the literature, several conclusions can be drawn: (a) An association between caffeine consumption and a reproductive hazard is more likely to be seen in lower-quality studies than in studies that come closer to approximating the ideal. This is especially evident for "lower" birthweight and congenital anomalies. (b) The association between caffeine consumption and spontaneous abortion may well reflect the Stein-Susser epiphenomenon (women with prominent nausea tend to reduce caffeine consumption and nausea appears to be a marker of good implantation, perhaps reflecting a favorable balance of hormones produced by a healthy placenta). (c) The claim that caffeine consumption by women delays conception has not been followed by convincing support. (d) Reproductive hazards associated with cigarette smoking tend to be associated with caffeine/coffee consumption. Sometimes this appears to be a consequence of residual confounding associated with inadequate adjustment for cigarette smoking, which is over-represented among those who drink the most coffee/caffeine. Sometimes this reflects the tendency of women to underreport socially undesirable behaviors (e.g. smoking) while accurately reporting socially neutral behaviors (e.g. coffee and caffeine consumption). Thus, it seems reasonable to conclude that no convincing evidence has been presented to show that caffeine consumption increases the risk of any reproductive adversity.

Brain damage markers in children. Neurobiological and clinical aspects.

UNLABELLED: The presence in blood of proteins normally confined to the cytoplasm of brain cells is considered peripheral evidence of brain damage. Only recently have these proteins been measured in the blood of children at risk of brain damage. To show the value and limitations of measuring these proteins, we review their biology and the adult literature that has correlated the blood concentrations of these proteins with lesion size and dysfunction. CONCLUSION: We conclude that brain damage markers will increasingly be measured in the blood of newborns and other children at risk of brain damage.

Adult stroke and perinatal brain damage: like grandparent, like grandchild?

Biomarkers of inflammation are found in the circulation of adults who have had a stroke. Although these biomarkers may, in part, be indicators of damage, some appear to contribute to damage. Similar biomarkers are found in newborns with cerebral white matter damage or at risk of cerebral palsy. Can we learn about the pathogenesis of neonatal white matter damage from what has been learned about the inflammatory correlates of adult stroke? We discuss relevant findings about systemic inflammatory markers in adult stroke and relate this information to our current understanding of cerebral white matter damage in newborns, especially those born at an extremely low gestational age. We also describe desirable characteristics of future studies of perinatal brain damage that involve measurements of systemic biomarkers.

Congenital microcephaly: phenotypic features in a consecutive sample of newborn infants.

OBJECTIVE: We compared the prevalence of major and minor anomalies in a consecutive sample of newborn infants with congenital microcephaly with that among normocephalic infants. STUDY DESIGN: Head measurements from >19,000 liveborn infants at 1 hospital during the years 1991 and 1992 were reviewed. Infants whose head circumference was in the lowest quartile (n = 850) were remeasured by research assistants to identify all whose head circumference was 2 SD below the mean for gestational age; 106 infants with congenital microcephaly were identified. Infants with microcephaly (n = 65) and 294 infants in a control group were examined systematically for major malformations and minor physical features. RESULTS: Four (6.2%) of the 65 infants examined either had a major malformation or were considered dysmorphic. One of the 4 had a specific multiple malformation syndrome, and 1 dysmorphic infant had a rare metabolic defect. Overall, the infants with microcephaly did not have a higher frequency of minor anomalies. However, there was a higher frequency of frontal bossing, small chin, and short nose with anteverted nares, which was associated with small body size rather than microcephaly. CONCLUSIONS: Congenital microcephaly is infrequently accompanied by major malformations and occurs rarely as part of a recognizable syndrome.

Growth-restricted premature infants are at increased risk for low thyroxine.

OBJECTIVE: To evaluate, in extremely premature infants, the relationship between growth restriction and early total thyroxine levels, and to determine how maternal, prenatal, perinatal and neonatal variables influence the relationship. STUDY DESIGN: 719 infants born at four medical centers in Massachusetts, New York and New Jersey between 1991 and 1993 were studied. Entry criteria included: gestational age 23--30 weeks, birth weight 500--1500 g, and a serum thyroxine level obtained in the first week of life. Infants born to mothers with a history of thyroid disease were excluded. Birth weight and total thyroxine level are expressed as z-scores (standard deviation units) to adjust for their relationship to gestational age. RESULTS: In linear regression analysis, there was a 0.18 decrease in the total thyroxine z-score for each 1.0 (1 standard deviation unit) decrease in birth weight z-score (p=0.0001). Adjustment for multiple potential maternal, prenatal, perinatal and neonatal confounders failed to identify a factor or factors that could account for the observed association. CONCLUSIONS: The early total thyroxine level in extremely preterm infants was significantly associated with birth weight z-score. This relationship persisted even after adjustment for maternal, prenatal, perinatal and neonatal confounders suggesting antenatal influences. Of clinical importance, growth-restricted infants are at increased risk for early hypothyroxinemia and, possibly, to its related morbidities.

Topography of cerebral white-matter disease of prematurity studied prospectively in 1607 very-low-birthweight infants.

The objective of this study was to evaluate to what extent (1) the characteristics of localization, distribution, and size of echodense and echolucent abnormalities enable individuals to be designated as having either periventricular hemorrhagic infarction or periventricular leukomalacia and (2) the characteristics of periventricular hemorrhagic infarction and periventricular leukomalacia are independent occurrences. The population for this study consisted of 1607 infants with birthweights of 500 to 1500 g, born between January 1991 and December 1993, who had at least one cranial ultrasound scan read independently by at least two ultrasonographers. The ultrasound data collection form diagrammed six standard coronal views. The cerebrum was divided into 17 zones in each hemisphere. All abnormalities were described as being echodense or echolucent and were classified on the basis of their size, laterality, location, and evolution. Eight percent (134/1607) of infants had at least one white-matter abnormality. The prevalence of white-matter disease decreased with increasing gestational age. Most abnormalities were small or medium sized and unilateral; only large echodensities tended to be bilateral and asymmetric. Large abnormalities, whether echodense or echolucent, were more likely than smaller abnormalities to be widespread, and the extent of cerebral involvement was independent of whether abnormalities were unilateral or bilateral. Large abnormalities were relatively more likely than small abnormalities to involve anterior planes. Small abnormalities, whether echodense or echolucent, or whether unilateral or bilateral, preferentially occurred near the trigone. Using the characteristics of location, size, and laterality/symmetry, we were able to allocate only 53% of infants with white-matter abnormalities to periventricular hemorrhagic infarction or periventricular leukomalacia. Assuming that periventricular leukomalacia and periventricular hemorrhagic infarction are independent and do not share risk factors, and that each occurs in approximately 5% of infants, we would have expected 0.25%, or about 4 individuals, to have abnormalities with characteristics of both periventricular leukomalacia and periventricular hemorrhagic infarction, whereas we found 63 such infants. Most infants with white-matter disease could not be clearly designated as having periventricular hemorrhagic infarction or periventricular leukomalacia only. Periventricular hemorrhagic infarction contributes to the risk of periventricular leukomalacia occurrence, or the two sorts of abnormalities share common risk antecedent factors. The descriptive term echodense or echolucent and the generic term white-matter disease of prematurity should be used instead of periventricular leukomalacia or periventricular hemorrhagic infarction when referring to sonographically defined white-matter abnormalities.

Do white cells matter in white matter damage?

Support is provided for the hypothesis that activated leukocytes, especially monocytes/macrophages, contribute to cerebral white matter damage in extremely low gestational age newborns. Much of the evidence is indirect and comes from analogies to brain diseases in adults, and from models of brain damage in adult and newborn animals. If the recruitment of circulating cells to the brain contributes to white matter damage in extremely low gestational age newborns, then minimizing the transendothelial migration of circulating cells by pharmacological manipulation might prevent or reduce the occurrence of neonatal white matter damage and the disabilities that follow.

Possible strategies to protect the preterm brain against the fetal inflammatory response.

The accruing evidence that a fetal inflammatory response is the link between antenatal infection and white matter damage in the preterm newborn infant offers room for speculation how this harmful sequence could be interrupted. Enhancement of endogenous protection, response modification, and damage limitation downstream could be helpful strategies for intervention design. Appropriate observational and experimental studies are needed before clinical interventions can be initiated.