Karin B. Nelson

Placental infarction identified by macroscopic examination and risk of cerebral palsy in infants at 35 weeks of gestational age and over

OBJECTIVEnWe sought to investigate whether placental infarction determined by macroscopic examination was associated with risk of cerebral palsy (CP).nnnSTUDY DESIGNnThis was a population-based study of macroscopic placental infarcts in singletons>35 weeks gestational age, in 158 perinatal deaths, 445 infants with CP, and 491 controls matched with CP cases for gestational age.nnnRESULTSnPlacental infarcts were recorded in 2.0% of controls, 4.4% of deaths (relative risk [RR], 2.2; 95% confidence interval [CI], 0.8-5.6]), 5.2% of infants with CP (P<.05, RR, 2.5; 95% CI, 1.2-5.3), and 8.4% with spastic quadriplegic CP (P=.0026; RR, 4.4; 95% CI, 1.8-10.6). In children with CP, unlike controls, placental infarction was associated with reduced fetal growth, older maternal age, more prior miscarriages, and poor neonatal condition, but not with maternal preeclampsia.nnnCONCLUSIONnPlacental infarction identified by macroscopic examination was associated with increased risk of CP and the CP subtype, spastic quadriplegic CP. Antecedents of placental infarction differed in children with CP compared with control children.

The association of cerebral palsy with birth asphyxia: a definitional quagmire.

Aimu2002 The aim of this study was to investigate whether current literature provides a useful body of evidence reflecting the proportion of cerebral palsy (CP) that is attributable to birth asphyxia.

Fetal growth restriction and risk of cerebral palsy in singletons born after at least 35 weeks' gestation

OBJECTIVEnThe objective of the study was to improve the understanding of etiological paths to cerebral palsy (CP) that include fetal growth restriction by examining factors associated with growth restriction that modify CP risk.nnnSTUDY DESIGNnIn a total population of singletons born at or after 35 weeks, there were 493 children with CP and 508 matched controls for whom appropriateness of fetal growth could be estimated. Fetal growth was considered markedly restricted if birthweight was more than 2 SD below optimal for gender, gestation, maternal height, and parity. We examined maternal blood pressure in pregnancy, smoking, birth asphyxia, and major birth defects recognized by age 6 years as potential modifiers of CP risk in growth-restricted births.nnnRESULTSnMore than 80% of term and late preterm markedly growth-restricted singletons were born following a normotensive pregnancy and were at statistically significantly increased risk of CP (odds ratio, 4.81; 95% confidence interval, 2.7-8.5), whereas growth-restricted births following a hypertensive pregnancy were not. Neither a clinical diagnosis of birth asphyxia nor potentially asphyxiating birth events occurred more frequently among growth-restricted than among appropriately grown infants with CP. Major birth defects, particularly cerebral defects, occurred in an increasing proportion of CP with increasing growth deficit. The factor most predictive of CP in growth-restricted singletons was a major birth defect, present in 53% of markedly growth-restricted neonates with later CP. Defects observed in CP were similar whether growth restricted or not, except for an excess of isolated congenital microcephaly in those born growth restricted. The highest observed CP risk was in infants with both growth restriction and a major birth defect (8.9% of total CP in this gestational age group, 0.4% of controls: odds ratio, 30.9; 95% confidence interval, 7.0-136).nnnCONCLUSIONnThe risk of CP was increased in antenatally growth-restricted singletons born at or near term to normotensive mothers. In growth-restricted singletons, a major birth defect was the dominant predictor, associated with a 30-fold increase in odds of CP. Identification of birth defects in the growth-restricted fetus or neonate may provide significant prognostic information.

Seizures in acute childhood stroke.

OBJECTIVESnTo describe the risk of seizures in children with acute stroke and identify factors predicting their later risk of epilepsy.nnnSTUDY DESIGNnData for patients >3.5 years of age at a tertiary care childrens hospital with acute stroke were collected and reviewed.nnnRESULTSnSeventy-seven patients were identified (mean age, 8.4 years); 21% had clinical seizures. An additional 10% of patients had a clinical seizure during the acute hospitalization. Status epilepticus was common in infants and patients with cortical strokes. Non-convulsive status epilepticus was captured only in patients with prolonged electroencephalograms and always within 24 hours of monitoring. Six months after their stroke, 24% of our patients had epilepsy, all of whom experienced seizures at initial presentation with stroke.nnnCONCLUSIONnIn our series of pediatric patients with stroke, most of the clinical seizures occurred within the first 24 hours of presentation and did not vary in stroke subtype. Status epilepticus was common, especially in infants. Epilepsy had a high likelihood of developing in the next 6 months in children with seizures in the first 24 hours of stroke onset. Prolonged electroencephalogram monitoring was useful in detecting non-convulsive status epilepticus, but not in predicting the risk of epilepsy at 6 months.

Physical comorbidity of migraine and other headaches in US adolescents.

OBJECTIVEnTo examine the pattern and extent to which other physical conditions are comorbid with migraine and other headaches in youth in a representative sample of the US population.nnnSTUDY DESIGNnThe National Comorbidity Survey-Adolescent Supplement is a face-to-face survey of adolescents aged 13-18 years in the continental US. Sufficient information to assess the International Headache Societys criteria for migraine with and without aura over the past 12 months was available in the diagnostic module. A caretaker/parental self-administered report was used to assess a broad range of other physical conditions. The sample for these analyses was 6843 adolescents with systematic caretaker/parent reports.nnnRESULTSnAdolescents with any headaches reported higher rates of other neurologic conditions, including epilepsy (OR, 2.02; 95% CI, 1.04-3.94), persistent nightmares (OR, 2.28; 95% CI, 1.34-3.87), and motion sickness (OR, 1.6; 95% CI, 1.07-2.4), as well as abdominal complaints (OR, 2.36; 95% CI, 1.59-3.51). Asthma (OR, 2.22; 95% CI, 1.26-3.92) and seasonal allergies (OR, 1.66; 95% CI, 1.12-2.48) were more common in adolescents with migraines than in adolescents with nonspecific headaches.nnnCONCLUSIONnAdolescent migraine is associated with inflammatory conditions such as asthma and seasonal allergies, as well as with epilepsy, persistent nightmares, and motion sickness. Our findings suggest that comorbid medical conditions should be evaluated comprehensively in determining treatment options in youth with headache. Such comorbidity also could be an important source of the clinical and etiologic heterogeneity in migraine.

The placenta and neurologic and psychiatric outcomes in the child: Study design matters

Much information exists about functions of the human placenta and about potential mechanisms by which the placenta may influence human health or disease, including developmental disorders of brain. Recent studies indicate a high frequency of placental pathology in infants with developmental brain disorders, or with risk factors for such disorders. However, most clinical studies of the association of placental features with adverse neurologic or psychiatric outcome have substantial methodologic limitations. We discuss issues of study design as they relate to studies of the placenta and human brain disorders. In addition to the need for further consensus on procedures and terminology for placental evaluation, there are a number of special features that make clinical studies of the association of placental features with neurologic and psychiatric disorders especially difficult: most such disorders are not diagnosed until months or years after the majority of placentas have been discarded; these disorders are individually uncommon, so that prospective studies - needed to provide denominator data to enable estimation of risks - will require very large sample sizes; the administrative structures required to relate features of the placenta with clinical outcome will be complicated and costly. We offer some suggestions concerning study design in the face of these practical difficulties. Systematic and methodologically rigorous exploration of the role of the placenta in human developmental brain disorders has scarcely begun. A new generation of studies, difficult but potentially enormously rewarding, will be needed for clinical investigations of the placenta and fetal brain development.

Is it HIE? And why that matters

In the presence of a major placental abruption or rupture of the uterus, the infant may be born acidotic and neurologically depressed, with hypotonia, delay in initiating respiration and other characteristics that are summarized in low Apgar scores. Neonatal seizures may occur. When this sequence of clinical events is observed in a term or late preterm infant, a diagnosis of hypoxic-ischemic encephalopathy (HIE) is made. The risk of death or adverse long-term neurologic outcome, especially cerebral palsy, is increased in these infants. What about neonates who display similar characteristics, but in whose birth history there is no clear evidence of abruption or other antepartum or intrapartum events likely to compromise oxygen supply to the foetus? Is it a good idea to accept the label ‘HIE’ for these? In four population-based studies of term infants, most of those with encephalopathy in the newborn period had not experienced obvious causes of asphyxia during or soon before birth (1–3). Furthermore, a large majority of term-born children with spastic cerebral palsy had not had either asphyxial antecedents (4,5) or HIE as neonates (6,7). It appears, then, that encephalopathy in the term and late preterm infant (and later cerebral palsy) often occurs without obvious asphyxial antecedents. When an asphyxial aetiology is not apparent in the encephalopathic infant, a diagnosis of HIE is not justified and the more general term, neonatal encephalopathy (NE), is appropriate (8). What evidence-based knowledge do we have about nonasphyxial causes of encephalopathy in the term and nearterm neonate? Case reports make it clear that a variety of infectious and metabolic problems, perinatal ischemic stroke and thrombotic placental vasculopathy can underlie NE. We have only a few controlled population-based studies that examine whether non-asphyxial risk factors contribute

Neonatal encephalopathy or hypoxic–ischemic encephalopathy?

golf course exposure. Four others had occupational exposures to various chemicals: 3 to solvents and 1, a synthetic chemist, to organophosphate pesticides. A fifth patient was a chemist, but his exposure is unknown. Twenty-six cases can only raise a question, but given the potential health risk should there be an association between living within close proximity to a golf course and parkinsonism, we hope that someone with a large enough patient base will adequately address this question.

Preventing cerebral palsy: paths not (yet) taken

The causes of cerebral palsy (CP) remain only partially understood. Asphyxial birth events are over-represented among infants who develop CP, but such events alone account for only a minority, perhaps a small minority, of CP cases. Interventions designed to prevent oxygen deprivation of the fetus have not, to date, been successful in producing a net decrease in CP, either in term infants or in total births. So where can we look for progress? Clinical research has yielded some clues, but none of these has been followed through to a real understanding of a causal pathway. Therefore, whether these clues are indicators of ways forward to more effective strategies for intervention, or dead ends, remains unknown. Several studies have related disorders of thyroid function in mother or infant to motor disability or CP in the child, and to cognitive limitation or deafness. Three other studies found a link between disordered thyroid function and that important precursor of CP in term infants, neonatal encephalopathy. In developed countries, the most common cause of thyroid disorder in women of reproductive age is autoimmune thyroid disease. Ten to 20 per cent of pregnant women have anti-thyroid antibodies as do 1 ⁄ 10 of newborn infants. Whether it is abnormal levels of the hormone or the presence of anti-thyroid antibodies that matter most to outcome in the infant brain is not known. Much of CP and of other developmental disability awaits explanation; does thyroid disease, a common and potentially treatable group of disorders, contribute to these disabilities? Three controlled studies in representative populations have observed that prolonged or irregular maternal menstrual cycles are risk factors for CP. The most common cause of prolonged or irregular menstrual cycles is polycystic ovary syndrome (PCOS), a disorder with pro-inflammatory and pro-coagulant features. As PCOS is both common and treatable, a link with CP might warrant investigation. But if it isn’t PCOS, then what is it that explains the association of maternal menstrual cycle variants with infant CP? The many unresolved questions about the association of intrauterine exposure to inflammation or maternal fever in labor, with CP in the infant, were recently discussed in this journal. Randomized trials indicate that mild therapeutic hypothermia reduces the risk of CP in term infants. Magnesium sulfate administered to women about to give birth very preterm, or administered soon after birth to term infants with serious neonatal neurological depression, have improved neurological outcomes. The former of these studies observed a lower frequency of CP in infants exposed to magnesium. Might magnesium infusion during delivery on evidence of fetal distress be helpful? In adult stroke, and in animal models, combining hypothermia with magnesium administration may be further neuroprotective; might hypothermia plus magnesium be worth considering in the perinatal period? Research on the etiology of perinatal stroke, an important cause of CP, has focused on genetics, with little attention given so far as to the specific environmental factors to which patients of a particular genotype are vulnerable. Perinatal stroke seldom repeats within a sibship, suggesting that environmental factors in pregnancy and birth may be important, and may warrant much more research than they have received to date. A quarter of CP in term infants arises in survivors of neonatal encephalopathy. Only a minority of infants with encephalopathy as neonates had asphyxial births; what accounts for the remainder? Only one clinical study examined a range of antecedents and identified the following as suspects: maternal fever in labor, thyroid disorder, family history of neurological disorder or seizures, low socioeconomic status, and placental abnormalities. The association of some of these factors with CP risk has been confirmed in subsequent studies, but there has been no further research towards increasing our understanding or identifying potentially preventive interventions. Albert Einstein defined madness as doing the same thing over and over again, and expecting different results. Our preoccupation with asphyxia as a cause of CP may have diverted us from finding other, perhaps more readily remediable, causes of CP. We need a new generation of clinical research to pursue the existing clues, and to generate new hypotheses. Registries and searchable linkable databases will help in undertaking sufficiently large studies in representative populations, enabling better understanding, development of more relevant animal models, and – hopefully – new strategies for prevention.

Innervation of the placenta and uterus: competition between cytotrophoblasts and nerves?

In normal pregnancy, invasion of the uterus by trophoblasts is followed by dramatic elimination of the rich uterine innervation present in the non-pregnant state, and by remodeling of maternal spiral arteries. In general, the healthy survival of vascular smooth muscle requires innervation, but whether denervation plays a role in stripping of vascular smooth muscle from spiral arteries in normal pregnancy has not been explored. We propose that the temporal and spatial association of trophoblast invasion with denervation in pregnancy may involve competitive interaction between the invading trophoblast and persisting neurons. We suggest feasible experiments to explore the possible effects of such trophoblast-nerve competition on spiral artery remodeling.