Intrapartum Hypoxia-ischemia Research Articles

Risk Factors for Term-Born Spastic Diplegic Cerebral Palsy: A Case-Control Study

BackgroundTo identify if a predetermined set of potential risk factors are associated with spastic diplegic cerebral palsy (SDCP) in term-born children. MethodsThis is a case-control study with cases (n = 134) extracted from the Canadian Cerebral Palsy Registry (CCPR) and controls (n = 1950) from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Our primary variable was the SDCP phenotype in term-born children. Possible risk factors were selected a priori and include extreme maternal age (<19 or >35 years), pregnancy complications, maternal disease, substance use, perinatal infection, mode of delivery, perinatal adversity (i.e., neonatal encephalopathy presumably on the basis of intrapartum hypoxia-ischemia), sex, and birth weight. Multivariable analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). ResultsMultivariable analysis revealed associations between term-born SDCP and pregnancy complications (OR = 4.73; 95% CI = 1.91 to 10.56), maternal disease (OR = 2.52; 95% CI = 1.57 to 3.93), substance use (OR = 3.11; 95% CI = 2.10 to 4.55), perinatal infection (OR = 2.72; 95% CI 1.32 to 5.10), Caesarean section (OR = 2.35; 95% CI = 1.62 to 3.40), and perinatal adversity (OR = 2.91; 95% CI = 1.94 to 4.50). Multiple regression analysis revealed associations between SDCP and pregnancy complications (OR = 3.28; 95% CI 1.20 to 8.15), maternal disease (OR = 2.52; 95% CI 1.50 to 4.12), substance use (OR = 3.59; 95% CI 2.37 to 5.40), perinatal infection (OR = 3.78, 95% CI 1.71 to 7.72), Caesarean section (OR = 2.72; 95% CI 1.82 to 4.03), and perinatal adversity (OR = 4.16; 95% CI 2.67 to 6.70). InterpretationAntenatal (pregnancy complications, maternal disease, substance use) and perinatal (infections, Caesarean section, and perinatal adversity) risk factors are associated with an increased risk of SDCP in term-born children, suggesting variable interactions between risk factors to provide a clinicopathologic framework that is different from SDCP observed in preterm-born children.

Comparing the efficacy in reducing brain injury of different neuroprotective agents following neonatal hypoxia–ischemia in newborn rats: a multi-drug randomized controlled screening trial

Intrapartum hypoxia–ischemia leading to neonatal encephalopathy (NE) results in significant neonatal mortality and morbidity worldwide, with > 85% of cases occurring in low- and middle-income countries (LMIC). Therapeutic hypothermia (HT) is currently the only available safe and effective treatment of HIE in high-income countries (HIC); however, it has shown limited safety or efficacy in LMIC. Therefore, other therapies are urgently required. We aimed to compare the treatment effects of putative neuroprotective drug candidates following neonatal hypoxic-ischemic (HI) brain injury in an established P7 rat Vannucci model. We conducted the first multi-drug randomized controlled preclinical screening trial, investigating 25 potential therapeutic agents using a standardized experimental setting in which P7 rat pups were exposed to unilateral HI brain injury. The brains were analysed for unilateral hemispheric brain area loss after 7 days survival. Twenty animal experiments were performed. Eight of the 25 therapeutic agents significantly reduced brain area loss with the strongest treatment effect for Caffeine, Sonic Hedgehog Agonist (SAG) and Allopurinol, followed by Melatonin, Clemastine, ß-Hydroxybutyrate, Omegaven, and Iodide. The probability of efficacy was superior to that of HT for Caffeine, SAG, Allopurinol, Melatonin, Clemastine, ß-hydroxybutyrate, and Omegaven. We provide the results of the first systematic preclinical screening of potential neuroprotective treatments and present alternative single therapies that may be promising treatment options for HT in LMIC.

Risk Factors for Term-Born Periventricular White Matter Injury in Children With Cerebral Palsy: A Case-Control Study.

The aim of this study was to identify possible risk factors associated with term-born children with cerebral palsy (CP) and periventricular white matter injury (PVWMI) on imaging. This is a case-controlled study restricted to term-born children with CP with the cases extracted from the Canadian Cerebral Palsy Registry and controls from Alberta Pregnancy Outcomes and Nutrition (APrON) study. A diagnosis of PVWMI was performed based on expert categorization of MRI reports. Risk factor variables were selected a priori; these included pregnancy complications, antenatal toxin exposure, perinatal infection, sex, small for gestational age, and perinatal adversity (i.e., neonatal encephalopathy presumably on the basis of intrapartum hypoxia-ischemia). We used multivariable analyses to calculate odds ratios (ORs) and their 95% CIs. A total of 160 cases (7.06% of the registry sample) were compared with 1,950 controls. Of the term-born PVWMI participants, 59.4% were male and 13.5% were born to mothers of extreme maternal age. Multivariable analysis of each risk factor controlled for weight showed PVWMI is associated with pregnancy complications (OR = 3.35; 95% CI = 2.23-4.94), antenatal toxin exposure (OR = 2.45; 95% CI = 1.67-3.55), perinatal infection (OR = 3.61; 95% CI = 1.96-6.29), and perinatal adversity (OR = 2.03; 95% CI = 1.42-2.94). Term-born male participants were not more likely to experience PVWMI compared with female participants (OR = 1.37; 95% CI = 0.98-1.93). Multiple regression analyses suggested independent associations between PVWMI and pregnancy complications (OR = 3.75; 95% CI 2.46-5.62), antenatal toxin exposure (OR = 2.80; 95% CI 1.88-4.12), perinatal infection (OR = 4.62; 95% CI 2.46-8.42), and perinatal adversity (OR = 2.49; 95% CI = 1.71-3.69). Risk factors such as pregnancy complications, antenatal toxin exposure, perinatal infection, and perinatal adversity are associated with PVWMI in term-born children, suggesting perhaps variable interactions between antenatal and perinatal factors to yield this under-recognized CP phenotype.

Intrapartum uterine activity and neonatal outcomes: a systematic review

BackgroundIncreased uterine activity (UA) may not allow adequate recovery time for foetal oxygenation.MethodsThe aim of the study was to determine if increased UA during labour is associated with an increased risk of either short- or long-term neurological injury in term neonates, or with neonatal proxy measures of intrapartum hypoxia-ischemia. MEDLINE, CINAHL, and ClinicalTrials.gov were searched using the following terms: uterine activity, excessive uterine activity, XSUA, uterine hyperstimulation, and tachysystole. Any study that analysed the relationship between UA during term labour and neurological outcomes/selected proxy neurological outcomes was eligible for inclusion. Outcomes from individual studies were reported in tables and presented descriptively with odds ratios (OR) and 95% confidence intervals (CI) for dichotomous outcomes and means with standard deviations for continuous outcomes. Where group numbers were provided, ORs and their CIs were calculated according to Altman.Main resultsTwelve studies met the inclusion criteria. Seven studies featured umbilical artery pH as an individual outcome. Umbilical artery base excess and Apgar scores were both reported as individual outcomes in four studies. No study examined long term neurodevelopmental outcomes and only one study reported on encephalopathy as an outcome. The evidence for a relationship between UA and adverse infant outcomes was inconsistent. The reported estimated effect size varied from non-existent to clinically significant.ConclusionsThere is some evidence that increased UA may be a non-specific predictor of depressed neurological function in the newborn, but it is inconsistent and insufficient to support the conclusion that an association generally exists.

Hematologic Changes in Newborns with Neonatal Encephalopathy

Neonatal encephalopathy is a disorder frequently observed by clinicians caring for sick neonates. One of the causes of this disorder is intrapartum hypoxia-ischemia. Caregivers are frequently called on to determine the etiology of neonatal encephalopathy, manage the disorder, and estimate the timing of any associated brain injury. Components of a complete blood cell count may be useful in assessing infants with neonatal encephalopathy. In this review, we discuss the usefulness of these parameters.

Non-epileptic phenomena in hypoxic-ischemic encephalopathy

Hypoxic-ischemic encephalopathy (HIE) is a clinical syndrome typically described in newborns after a period of intrapartum or perinatal hypoxia-ischemia (HI) [1]. The acute neurological manifestations of HIE have been well described [1,2] and are characterized by clinical evidence of diffuse cerebral dysfunction; impaired brainstem function, autonomic dysregulation, various abnormalities in mental state, epileptic seizures, and, in addition to tone and other motor abnormalities, non-epileptic movements i.e. myoclonus and tremors. The severity of the phenotype is dependent on the degree of cerebral insult, extent of subsequent injury incurred; with some correlation with outcome [1–4]. Because of the wide variety and often changing signs and symptoms post HI, coupled with the numerous co-morbid metabolic and systemic problems and the frequent occurrence of seizures which can be very difficult to differentiate clinically, this article will concentrate solely on describing the hyperkinetic non-epileptic movement disorder observed following transient HI in the term newborn.

Repérage de l’asphyxie au cours du travail

Intrapartum asphyxia is defined as metabolic acidemia measured at birth with pH < 7.00 and base deficit ≥ 12 mmol/L. It is today established that the proportion of cerebral palsy associated with intrapartum hypoxia-ischemia is about 14.5%. Intrapartum asphyxia is screened in France by the continuous fetal heart rate (FHR) monitoring which presents a good sensitivity for its detection. His low specificity justifies the use of second line methods to reduce the increase of cesarean deliveries associated with the use of continuous FHR monitoring. Fetal scalp pH and lactate measurements are still the reference method. The conclusions of the last meta-analysis on the RCTs of the use of the fetal electrocardiogram (STAN®) appear to be disappointing, because no differences were found in the rates of metabolic acidosis and the rates of cesarean deliveries. Intrapartum asphyxia’s diagnostic can be made by analysis of the acidbase status on the cord arterial blood. Therefore, it should be systematically performed after every births.

Therapeutic Hypothermia Following Intrapartum Hypoxia Ischemia. An Advisory Statement from the Neonatal Task Force of the International Liaison Committee on Resuscitation

2010 ILCOR RecommendationOn the basis of the published data to date the Neonatal Task Force of the International Liaison Committee on Resuscitation (ILCOR) made the following recommendation on February 2010 with regard to therapeutic hypothermia: Newly born infants born at term or near-term with evolving moderate to severe hypoxic-ischemic encephalopathy should be offered therapeutic hypothermia. whole-body cooling and selective head cooling are both appropriate strategies. Cooling should be initiated and conducted in neonatal intensive care facilities using protocols consistent with those used in the randomized clinical trials i.e. commence within 6 h, continue for 72 h and rewarm over at least 4 h. Carefully monitor for known adverse effects of cooling – thrombocytopenia and hypotension. All treated infants should be followed longitudinally.

Phosphorus magnetic resonance spectroscopy 2 h after perinatal cerebral hypoxia‐ischemia prognosticates outcome in the newborn piglet

Phosphorus magnetic resonance spectroscopy ((31)P MRS) often reveals apparently normal brain metabolism in the first hours after intrapartum hypoxia-ischemia (HI) at a time when conventional clinical assessment of injury severity is problematic. We aimed to elucidate very-early, injury-severity biomarkers. Twenty-seven newborn piglets underwent cerebral HI: (31)P-MRS measures approximately 2 h after HI were compared between injury groups defined by secondary-energy-failure severity as quantified by the minimum nucleotide triphosphate (NTP) observed after 6 h. For severe and moderate injury versus baseline, [Pi]/[total exchangeable high-energy phosphate pool (EPP)] was increased (p < 0.001 and < 0.02, respectively), and [NTP]/[EPP] decreased (p < 0.03 and < 0.006, respectively): severe-injury [Pi]/[EPP] was also increased versus mild injury (p < 0.04). Mild-injury [phosphocreatine]/[EPP] was increased (p < 0.004). Severe-injury intracellular pH was alkaline versus baseline (p < 0.002). For severe and moderate injury [total Mg]/[ATP] (p < 0.0002 and < 0.02, respectively) and [free Mg] (p < 0.0001 and < 0.02, respectively) were increased versus baseline. [Pi]/[EPP], [phosphocreatine]/[Pi] and [NTP]/[EPP] correlated linearly with injury severity (p < 0.005, < 0.005 and < 0.02, respectively). Increased [Pi]/[EPP], intracellular pH and intracellular Mg approximately 2 h after intrapartum HI may prognosticate severe injury, whereas increased [phosphocreatine]/[EPP] may suggest mild damage. In vivo(31)P MRS may have potential to provide very-early prognosis in neonatal encephalopathy.

Post-resuscitation strategies to avoid ongoing injury following intrapartum hypoxia–ischemia

The interruption of placental blood flow during labor with redistribution of cardiac output resulting in increased flow to brain, heart, and adrenal glands at the expense of flow to kidney, gut, and skin can result in systemic organ as well as cerebral injury. Thus, post-resuscitation strategies should focus on both the management of potential systemic organ dysfunction and on methods of preventing ongoing brain injury in high-risk infants. General management strategies should include ventilator management to maintain pCO(2) values in the normal range, close attention to blood pressure to avoid hypotension, striving to avoid hypoglycemia, and control of seizures. Modest hypothermia administered within the first 6 hours has been shown to reduce neurodevelopmental deficits and death in those infants at highest-risk infants for developing hypoxic-ischemic brain injury.

Strategies for the management of neonatal hypoxic–ischemic brain injury

Accumulating evidence points to an evolving process of brain injury after intrapartum hypoxia–ischemia that initiates in utero and extends into a recovery period. The processes leading to cell death include necrosis or apoptosis, and result from the combined effects of cellular energy failure, acidosis, glutamate release, intracellular Ca2+ accumulation and generation of free radicals that serve to disrupt essential components of the cell. Secondary cerebral energy failure occurs from 6 to 48 h after the primary event and involves mitochondrial dysfunction secondary to extended reactions from primary insults. Treatment strategies to prevent or ameliorate ongoing brain injury include early identification of high-risk infants, supportive therapy and neuroprotection. Currently, hypothermia offers the greatest promise as a neuroprotective strategy and has shown benefit particularly in a subset of infants who present with moderate encephalopathy and without seizures. Future directions will probably include hyp...

Pathogenesis of hypoxic-ischemic brain injury

Accumulating evidence points to an evolving process of brain injury after intrapartum hypoxia-ischemia that initiates in utero and extends into a recovery period. The processes leading to cell death include necrosis or apoptosis, and result from the combined effects of cellular energy failure, acidosis, glutamate release, intracellular Ca2+ accumulation, generation of free radicals that serve to disrupt essential components of the cell. Many factors including the duration or severity of the insult influence the progression of cellular injury after hypoxia-ischemia. A secondary cerebral energy failure occurs from 6 to 48 h after the primary event and involves mitochondrial dysfunction secondary to extended reactions from primary insults (e.g., calcium influx, excitatory neurotoxicity and oxygen free radicals) as well as the release of circulatory and endogenous inflammatory cells/mediators that also contribute to ongoing brain injury. Strategies aimed at neuroprotection need to be comprehensive targeting the pathways leading to eventual mitochondrial injury.

Intervention strategies for neonatal hypoxic-ischemic cerebral injury

Background: Accumulating evidence points to an evolving process of brain injury after intrapartum hypoxia-ischemia that initiates in utero and extends into a recovery period. It is during this recovery period that the potential for neuroprotection exists. Objective: This discussion briefly reviews the cellular characteristics of hypoxic-ischemic cerebral injury and the current and future therapeutic strategies aimed at ameliorating ongoing brain injury after intrapartum hypoxia-ischemia. Methods: As part of the Newborn Drug Development Initiative, the National Institute of Child Health and Human Development and the US Food and Drug Administration cosponsored a workshop held March 29 and 30, 2004, in Baltimore, Maryland. Information for this article was gathered during that workshop. Literature searches of MEDLINE (Ovid) and EMBASE (1996–2005) were also conducted; search terms included newborn, infant, hypoxia-ischemia, hypoxic-ischemic encepbalopatby, asphyxia, pathogenesis, treatment, reperfusion injury, and mechanisms, as well as numerous interventions (ie, therapeutic bypotbermia, magnesium, and barbiturates). Results: The acute brain injury results from the combined effects of cellular energy failure, acidosis, glutamate release, intracellular calcium accumulation, lipid peroxidation, and nitric oxide neurotoxicity that serve to disrupt essential components of the cell, resulting in death. Many factors, including the duration or severity of the insult, influence the progression of cellular injury after hypoxia-ischemia. A secondary cerebral energy failure occurs from 6 to 48 hours after the primary event and may involve mitochondrial dysfunction secondary to extended reactions from primary insults (eg, calcium influx, excitatory neurotoxicity, oxygen free radicals, or nitric oxide formation). Some evidence suggests that circulatory and endogenous inflammatory cells/mediators also contribute to ongoing brain injury. The goals of management of a newborn infant who has sustained a hypoxic-ischemic insult and is at risk for injury should include early identification of the infant at highest risk for evolving injury, supportive care to facilitate adequate perfusion and nutrients to the brain, attempts to maintain glucose homeostasis, and consideration of interventions to ameliorate the processes of ongoing brain injury. Recent evidence suggests a potential role for modest hypothermia (ie, a reduction in core body temperature to −34°C) administered to high-risk term infants within 6 hours of birth. Either selective (head) or systemic (body) cooling reduces the incidence of death and/or moderate to severe disability at 18-month follow-up. Additional strategies—including the use of oxygen free radical inhibitors and scavengers, excitatory amino acid antagonists, and growth factors; prevention of nitric oxide formation; and blockage of apoptotic pathways—have been evaluated experimentally but have not been replicated in a systematic manner in the human neonate. Other avenues of potential neuroprotection that have been studied in immature animals include platelet-activating factor antagonists, adenosinergic agents, monosialoganglioside GM1, insulin-like growth factor-1, and erythropoietin. Conclusions: Much progress has been made toward understanding the mechanisms contributing to ongoing brain injury after intrapartum hypoxiaischemia. This should facilitate more specific pharmacologic intervention strategies that might provide neuroprotection during the reperfusion phase of injury.

Induced hypothermia: A novel neuroprotective treatment of neonatal encephalopathy after intrapartum hypoxia-ischemia

The current treatment approach to an infant at risk for progression to neonatal encephalopathy after intrapartum hypoxia-ischemia is threefold: 1) early identification of the infant at highest risk for evolving brain injury based on the criteria of a sentinel event during labor, prolonged depression at birth with the need for resuscitation, and evidence of severe fetal acidemia based on a cord umbilical arterial pH less than 7 and/or a base deficit more than -16 meq per L, with early clinical and/or electroencephalogram assessment of moderate to severe encephalopathy; 2) supportive therapy instituted to maintain adequate ventilation and in particular pCO2 levels in a normal range, mean arterial blood pressure within a normal range so as to avoid perturbations in cerebral perfusion, glucose in a normal range to avoid hypoglycemia, and the judicious treatment of seizures; and 3) neuroprotection--induced hypothermia is currently the only strategy that has been rigorously evaluated in two large, multicenter randomized studies. The first study used selective cooling with a cool cap to a rectal temperature at 34.5 degrees C, and the second study used total body cooling to an esophageal temperature of 33.5 degrees C, with the temperature in both studies maintained for 72 hours. No significant side effects were noted with this degree of cooling. The combined data indicate that hypothermia is associated with a reduction in the incidence of death and/or severe disability at 18 months follow-up, with the most significant effect observed in infants who at the initiation of therapy present with modest encephalopathy and/or do not exhibit electrographic seizures.

Perinatal depression at 34 weeks is not commonly associated with intrapartum metabolic acidosis

INTRAPARTUM METABOLIC ACIDOSIS ANADIR SILVA (F), ALICE COOTAUCO, ABIMBOLA AINA-MUMUNEY, PAMELA DONOHUE, ERNEST GRAHAM, Johns Hopkins University, Obstetrics and Gynecology, Baltimore, Maryland, Johns Hopkins University, Pediatrics, Baltimore, Maryland OBJECTIVE: Signs of perinatal depression (PD) at or near term are commonly ascribed to intrapartum hypoxia-ischemia without objective evidence. Our objective was to use cord gas data to determine the presence of severe metabolic acidosis (pH! 7.0 or BE! 12 mmol/L) in depressed infants born at R34 weeks. STUDY DESIGN: We identified 111 infants born at R34 weeks at a single hospital between 7/91 to 10/04 depressed enough at birth to require resuscitation and NICU admission. Neonates with major congenital and chromosomal abnormalities were excluded. Each case was matched by gestational age (GA) within 7 days to the subsequent delivery without PD admitted to the regular nursery. Umbilical arterial gas data was available for 87 cases and 65 controls. Continuous data were compared by independent sample t-test, and categorical data by chi square of Fisher’s exact with p ! 0.05 considered significant. RESULTS: Cases and controls were matched by GA and had similar birth weights. The cases had longer length of stay, 1 min Apgar ! 7 and 5 min Apgar ! 7.

Severe fetal acidemia and subsequent neonatal encephalopathy in the larger premature infant

The contribution of intrapartum hypoxia-ischemia to neonatal encephalopathy in the larger preterm infant remains poorly defined. Such infants could become potential candidates for neuroprotective strategies. The objective of this study was to determine in preterm infants of gestation 31 to 36 weeks, with severe fetal acidemia (i.e., cord arterial pH < 7.00) the incidence of moderate to severe neonatal encephalopathy as well as the perinatal characteristics that may facilitate early identification. The data of 61 preterm infants of mean birth weight 1998 gm and mean gestation of 33.6 weeks were retrieved. Short-term abnormal neurologic outcome measures included evidence of encephalopathy with or without seizures or neuroimaging abnormalities. Eight (13%) of 61 infants developed an abnormal neonatal neurologic outcome. More infants with abnormal vs normal outcome had 1-minute Apgar of 0, i.e., 4/8 vs 3/53, 5-minute Apgar score </=5 (7/8 vs 17/53), required chest compressions (5/8 vs 6/53), cord pH (6.75 vs 6.90), and base deficit 20 vs 18 (P < 0.05). By multivariate analysis, only gestation was associated with abnormal outcome (P = 0.0003). We conclude that the larger depressed preterm infant is at increased risk for moderate to severe encephalopathy. Such infants could also be considered potential candidates for neuroprotective strategies.

Hypoxic–ischemic brain injury in the term infant-current concepts

An enhanced understanding of the cellular characteristics contributing to ongoing brain injury following intrapartum hypoxia-ischemia has resulted in the implementation of targeted neuroprotective strategies in the newborn period. This review briefly covers the pathogenesis of hypoxic-ischemic injury with an emphasis on reperfusion injury; the role of magnetic resonance imaging in the detection of such injury, and focuses on potential strategies both supportive and neuroprotective to prevent ongoing injury with a specific emphasis on modest hypothermia.

Neonatal cerebral white matter injury in preterm infants is associated with culture positive infections and only rarely with metabolic acidosis

Neonatal cerebral white matter injury represents a major precursor for neurological impairment and cerebral palsy. Our objective was to identify risk factors associated with its development. This retrospective case-control study of all births between 23 and 34 weeks gestation at a single university hospital between May 1994 and September 2001 identified 150 cases with white matter injury characterized by periventricular leukomalacia or ventricular dilatation from white matter atrophy that were chromosomally normal and did not have other congenital anomalies. Cases were matched to controls without brain injury by the next delivery within 7 days of their gestational age. There were small differences between controls and cases in gestational age (27.5 +/- 2.7, 27.4 +/- 2.6 weeks, P = .01) and birth weight (1053 +/- 402, 966 +/- 285 g, P = .002) that were statistically but not clinically significant. There was no difference in the percentage of controls and cases delivered by cesarean (45%, 49%, P = .64). There were no differences between controls and cases in umbilical arterial pH (7.27 +/- 0.11, 7.25 +/- 0.15, P = .19), base excess (-2.1 +/- 2.7, -3.0 +/- 4.1 mmol/L, P = .28), pH less than 7.0 (2/122 [2%], 3/107 [3%], P = 1.0), or base excess less than -12 mmol/L (4/121 [3%], 6/106 [6%], P = .75). The cases had a significant increase in positive blood (19%, 29%, P = .036), cerebrospinal fluid (6%, 17%, P = .002), and tracheal (9%, 22%, P = .003) cultures during the neonatal period. Conditional logistic regression showed a significant association among multiple gestations ( P = .02), intraventricular hemorrhage ( P < .001), and positive tracheal cultures ( P = .02) with cerebral white matter injury. Culture-positive infection was associated with an increased risk of cerebral white matter injury in preterm neonates. Intrapartum hypoxia-ischemia as manifested by metabolic acidosis was rarely associated with white matter injury and was not different from the incidence in premature neonates without injury.

Association of Prematurity and Neonatal Infection With Neurologic Morbidity in Very Low Birth Weight Infants

In Brief OBJECTIVE To identify risk factors predictive of neurologic morbidity in very low birth weight (VLBW) infants. METHODS This is a case–control study of all infants weighing 1500 g or less admitted to a single tertiary neonatal intensive care unit between April 1999 and December 2001. The case group were those neonates with neurologic morbidity including intraventricular hemorrhage, seizures, hydrocephalus, and periventricular leukomalacia. The control group were those without neurologic morbidity. Wilcoxon rank-sum, Fisher exact test, χ2, and univariate and stepwise multiple logistic regression were performed, with P < 0.05 considered significant. RESULTS Of 213 VLBW infants, 77 had neurologic morbidity: 61 had intraventricular hemorrhage, eight had seizures, 13 had hydrocephalus, and nine had periventricular leukomalacia. Several infants had more than one morbidity. Gestational age (odds ratio [OR] 0.95; 95% confidence interval [CI] 0.94, 0.96; P < .005), birth weight (OR 0.62; 95% CI 0.49, 0.79; P < .005), and neonatal infection (OR 1.36; 95% CI 1.17, 1.58; P < .005) were highly associated with neurologic morbidity. There was no difference in mean umbilical arterial cord pH (7.25 ± 0.15, 7.28 ± 0.09, P = .45) or base excess (−3.8 ± 4.8 mEq/L, −2.3 ± 3.0, P = .10). Only three of 52 infants (5.8%) in the case group had an umbilical arterial pH of less than 7. CONCLUSION Prematurity and neonatal infection were the dominant factors associated with neurologic morbidity in VLBW infants. Intrapartum acidosis occurred in less than 6% of those with neurologic morbidity. Prematurity and neonatal infection but not intrapartum hypoxia–ischemia are associated with neonatal neurologic morbidity in very low birth weight infants.

Evidence of Intrapartum Hypoxia-Ischemia Is Not Present in the Majority of Cases of Neonatal Seizures

Although external fetal monitoring reportedly has had the effect of reducing neonatal seizures, the incidence of cerebral palsy has changed little over the past four decades. Seizures are the commonest indication of neurologic disorder in the first month of life. This case-control study was an attempt to quantify the association between neonatal seizures and intrapartum hypoxia-ischemia as manifested by metabolic acidosis. Newborn infants seen at a single center with seizures were matched in a 2:1 ratio with control infants of similar gestational age who had no seizures. Over the 11 years of the study, 1988 to 1999, 13 neonates had seizures; 1 of these neonates was excluded because of a chromosomal abnormality. The 12 case infants had a mean gestational age of 35 weeks at the time of delivery. Four deliveries were preterm, as were 8 of 24 deliveries of control infants. The two groups did not differ significantly in maternal age, parity, or race. Seizures significantly extended the hospital stay. A 5-minute Apgar score less than 7 was twice as frequent in case infants (33% vs. 17%), but the difference was not statistically significant. The mean base excess in arterial cord blood was -7.6 mEq/liter in case infants and -2.8 mEq/liter in control infants. The mean umbilical arterial pH was 7.17 for case infants and 7.28 for control infants. Only 3 of 10 the case infants evaluated (and none of the control infants) had a pH less than 7.00. One of these 3 infants was a preterm birth. These findings do not support the supposition that most newborn infants with seizures also have intrapartum hypoxia-ischemia. More than two thirds of the present neonates with seizures lacked evidence of metabolic acidosis at the time they were born.