Brain damage in preterm infants: etiological pathways.

Preterm newborns represent a high-risk population for brain damage, primarily affecting the white matter, and for related neurodevelopmental disabilities. Determinants of brain damage have been extensively investigated, but there are still many controversies on how these factors can influence the developing brain and provoke damage. The concept of etiological pathway, instead of a single determinant, appears to better explain pathogenetic mechanisms: the brain damage may represent the final outcome of exposure to several combinations of risk factors in the same pathway or in different pathways and can change according to the gestational age. The aim of this article is to review the current knowledge on the pathogenesis of brain damage in preterm infants, within the frame of two main theoretical models, the ischemic and the inflammatory pathway. The relationship between the two pathways and the contribution of genetic susceptibility to ischemic and/or inflammatory insult, in modulating the extent and severity of brain damage, is also discussed.

Postnatal laboratory timers of antenatal hypoxemic-ischemic brain damage.

OBJECTIVE: Markers were sought to identify the antenatal starting times and rates at which brain damage advanced in children with hypoxemic-ischemic cerebral palsy. STUDY DESIGN: Fetal bradycardia's onset marked the damage's start. Using this baseline, the following were tested as additional timers of the damage's onset: serial blood counts of neonates' normoblasts, platelets, lymphocytes,differences at birth between base excess values in umbilical arterial and venous bloods,brain damage patterns. RESULTS: Each timer had a broad antenatal time frame within which it could identify specific damage starting times. The broad time frames are as follows: Blood lymphocyte counts: 0.45 to 13.8 hours before birth, blood normoblast counts: 0.45 to 55.0 hours before birth, blood platelet counts: 0.5 to >72 hours before birth. Brain damage patterns: 0.4 to >0.7 hour before birth. Hyperventilating and hyperoxygenating neonates greatly accelerated the damage's advance. CONCLUSIONS: Commonly obtained laboratory values and brain images can identify when such brain damage began and the rate at which it advanced.

Contribution of fetal MR imaging in the evaluation of cerebral ischemic lesions.

BACKGROUND AND PURPOSE: Little is known about the different patterns of fetal cerebral ischemic lesions at MR imaging. Our purpose was to evaluate the contribution of MR imaging in the evaluation of such lesions by correlating the results with ultrasonography (US) and neurofetopathologic (NFP) findings. METHODS: We examined 28 fetuses (mean, 28 weeks' gestation) with cerebral ischemic lesions on NFP examination. MR findings were correlated with US and NFP results with regard to the depiction of gyration and parenchymal abnormalities. RESULTS: MR imaging added to US findings in 24 cases by revealing lesions (gyration abnormalities, parenchymal lesions). These results were either overlooked during US (n = 16) or more extensive than expected with US (n = 8). MR findings were always confirmed by NFP. NFP yielded additional findings for 14 lesions that were overlooked during MR imaging (n = 4) or that were more extensive than expected with MR imaging (n = 10). T1-, T2-, and T2*-weighted MR patterns of different lesions (cavitations, gliosis, softening of the white matter, laminar necrosis, calcified leukomalacia, old hemorrhage) were identified. CONCLUSION: MR imaging is a valuable tool in the evaluation of fetal brain ischemia. The results of this study emphasize the role of the different sequences (T1-, T2-, T2*-weighted) required to detect fetal cerebral ischemic lesions. MR imaging is more accurate in the detection of small focal lesions than in the evaluation of diffuse white matter abnormalities.

The effects of low-dose endotoxin on the umbilicoplacental circulation in preterm sheep.

OBJECTIVE: In the present study we examined the effects of low-dose endotoxin (lipopolysaccharides, LPS) on continuously recorded umbilical blood flow. METHODS: Twenty fetal sheep were catheterized at a gestational age of 107 +/- 1 days. A flow probe was placed around either the common umbilical artery or one single umbilical artery. Three days later fetuses received either 100 or 500 nanograms of LPS (n = 14) or 2 mL saline (n = 6) intravenously. Six fetuses died within 12 hours after LPS. Fetal heart rate (FHR), mean arterial pressure (MAP), and umbilical blood flow (Q(umb)) were monitored for 3 days. RESULTS: FHR increased by 25 +/- 4% at 4-5 hours after LPS (P <.01) and was elevated for 15 hours after LPS. MAP increased by 18 +/- 5% 1 hour after LPS (P <.01) and returned to control value 4-5 hours after LPS. Q(umb) began to decrease 1 hour after LPS and was minimal (-30 +/- 7%, P <.001) at 4-5 hours after LPS. Q(umb) slowly returned to the control value at 12 hours after LPS. Placental vascular resistance increased by 73 +/- 37% (P <.01), whereas pH did not appreciably change. CONCLUSION: Intravenous application of endotoxin caused a substantial and long-lasting decrease in umbilical blood flow resulting in fetal hypoxemia without acidemia. These effects may be of significance in the development of fetal brain damage associated with intrauterine infection.

Role of mitochondrial permeability transition in fetal brain damage in rats.

Recirculation after transient in utero ischemia has previously been found to be accompanied by delayed deterioration of cellular bioenergetic state and of mitochondrial function in the fetal rat brain. Our objective was to assess whether the delayed deterioration is a result of the activation of mitochondrial permeability transition which is observed ultrastructurally as mitochondrial swelling. The respiratory activities and ultrastructure of isolated mitochondria and the cellular bioenergetic state in fetal rat brain were examined at the end of 30 minutes of in utero ischemia and after 1, 2, 3 and 4 hours of recirculation. Cyclosporin A, a potent and virtually specific mitochondrial permeability transition blocker, or vehicle was administered 1 hour after recirculation. In the vehicle-treated animals, the transient ischemia was associated with a delayed deterioration of cellular bioenergetic state and mitochondrial activities at 4 hours of recirculation. The number of swollen mitochondria increased markedly after 4 hours of recirculation. The deterioration and the swelling were prevented by cyclosporin A. The present study indicates that cyclosporin A treatment improves recovery of fetal brain energy metabolism and inhibits the mitochondrial swelling after transient in utero ischemia. The results suggest that mitochondria and mitochondrial permeability transition may be involved in the development of ischemic brain damage in the immature rat.

Prenatal contributions to epilepsy: lessons from the bedside.

While epilepsy can present at any age, this condition often occurs because of adverse events early in life. Pathogenetic mechanisms also cause deleterious consequences to the brain during prenatal life. For the epileptologist to fully appreciate developmental epileptogenesis, one must apply an ontogenetic approach (i.e. "nature-nurture-niche") in order to study the epileptic condition from a fetal neurology perspective. Genetic susceptibility can involve pre-fertilization and post-fertilization mechanisms that dictate the timing and form of major malformations associated with specific epileptic syndromes. Maternal, fetal, and placental disease conditions also contribute to either brain malformations or injuries, depending on events during the first or second half of pregnancy. Sequential stages during prenatal brain development, from embryonic through perinatal periods, specify which gray and white matter structures may be adversely altered, with later expression of seizures in the context of motor, cognitive and behavioral deficits. Translational research from bench to bedside should consider the acquired causes of pediatric and adult epilepsies in the context of the patient's genetic environment.

Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep.

Glucocorticoids regulate oligodendrocyte maturation and the myelin biosynthetic pathways. Synthetic glucocorticoids, the corticosteroids have been successfully used in clinical practice as a single course to enhance lung maturation and reduce mortality and morbidity in preterm infants with no long-term neurologic or cognitive side effects. However, a trend has arisen to use repeated courses despite an absence of safety data from clinical trials. We examined the effects of clinically appropriate, maternally administrated, repeated courses of corticosteroids on myelination of the corpus callosum using sheep as a large animal model. The corpus callosum is a major white matter tract that undergoes protracted myelination, underpins higher order cognitive processing and developmental damage to which is associated with, for example, cerebral palsy, mental retardation and attention deficit hyperactivity disorder. Pregnant ewes were given saline or betamethasone (0.5 mg/kg) at 104,111,118 and 124 days gestation, stages equivalent to the third trimester in humans. Lambs were delivered at 145 days (term), perfused and the corpus callosum examined light and electron microscopically. Total axon numbers were unaffected (P>0.05). However, myelination was significantly delayed. Myelinated axons were 5.7% in the experimental group and 9.2% in controls (P<0.05); conversely, unmyelinated axons were 88.3 and 83.7% (P<0.05). Myelinated axon diameter and myelin sheath thickness were also reduced (0.68 vs. 0.94 and 0.11 vs. 0.14 microm, P<0.05). Our data suggest that repeated prenatal corticosteroid administration delays myelination of the corpus callosum and that further safety data are needed to evaluate clinical practice.

Iodine deficiency as a cause of brain damage.

This editorial reviews the impact of iodine deficiency (1) on thyroid function in pregnant women and neonates and (2) on the neurointellectual development of infants and children. All degrees of iodine deficiency (mild: iodine intake of 50-99 microg/day, moderate: 20-49 microg/day, and severe: <20 microg/day) affect thyroid function of the mother and the neonate as well as the mental development of the child. The damage increases with the degree of the deficiency, with overt endemic cretinism as the severest consequence. Maternal hypothyroxinaemia during early pregnancy is a key factor in the development of the neurological damage in the cretin. Selenium deficiency combined with iodine deficiency partly prevents the neurological damage but precipitates severe hypothyroidism in cretins. Iodine deficiency results in a global loss of 10-15 IQ points at a population level and constitutes the world's greatest single cause of preventable brain damage and mental retardation.

Pathophysiology of perinatal brain damage.

Perinatal brain damage in the mature fetus is usually brought about by severe intrauterine asphyxia following an acute reduction of the uterine or umbilical circulation. The areas most heavily affected are the parasagittal region of the cerebral cortex and the basal ganglia. The fetus reacts to a severe lack of oxygen with activation of the sympathetic-adrenergic nervous system and a redistribution of cardiac output in favour of the central organs (brain, heart and adrenals). If the asphyxic insult persists, the fetus is unable to maintain circulatory centralisation, and the cardiac output and extent of cerebral perfusion fall. Owing to the acute reduction in oxygen supply, oxidative phosphorylation in the brain comes to a standstill. The Na(+)/K(+) pump at the cell membrane has no more energy to maintain the ionic gradients. In the absence of a membrane potential, large amounts of calcium ions flow through the voltage-dependent ion channel, down an extreme extra-/intracellular concentration gradient, into the cell. Current research suggests that the excessive increase in levels of intracellular calcium, so-called calcium overload, leads to cell damage through the activation of proteases, lipases and endonucleases. During ischemia, besides the influx of calcium ions into the cells via voltage-dependent calcium channels, more calcium enters the cells through glutamate-regulated ion channels. Glutamate, an excitatory neurotransmitter, is released from presynaptic vesicles during ischemia following anoxic cell depolarisation. The acute lack of cellular energy arising during ischemia induces almost complete inhibition of cerebral protein biosynthesis. Once the ischemic period is over, protein biosynthesis returns to pre-ischemic levels in non-vulnerable regions of the brain, while in more vulnerable areas it remains inhibited. The inhibition of protein synthesis, therefore, appears to be an early indicator of subsequent neuronal cell death. A second wave of neuronal cell damage occurs during the reperfusion phase. This cell damage is thought to be caused by the post-ischemic release of oxygen radicals, synthesis of nitric oxide (NO), inflammatory reactions and an imbalance between the excitatory and inhibitory neurotransmitter systems. Part of the secondary neuronal cell damage may be caused by induction of a kind of cellular suicide programme known as apoptosis. Knowledge of these pathophysiological mechanisms has enabled scientists to develop new therapeutic strategies with successful results in animal experiments. The potential of such therapies is discussed here, particularly the promising effects of i.v. administration of magnesium or post-ischemic induction of cerebral hypothermia.

Diffuse brain damage caused by acute twin-twin transfusion during late pregnancy.

BACKGROUND: Monoamniotic twinning is a relatively rare event with increased antenatal and perinatal mortality. We describe a brain damage detected in a surviving monoamniotic twin after intrauterine death of the co-twin at 37 weeks of gestation. RESULTS: Severe entanglement and knotting of the umbilical cords was apparent at the time of delivery and a portion of the cord to the dead twin was narrowed significantly. It was suggested that transfer of blood occurred across placental anastomoses from the survivor to the dead fetus, resulting in transient but severe hypovolemia in the survivor. It is difficult to prevent this type of brain damage because the course of acute twin-twin transfusion is very rapid and the damage has already occurred by the time the death of the twin is diagnosed. CONCLUSIONS: We suggest that elective delivery should be considered in cases of monoamniotic twin pregnancies with additional risk factors.

Maturational change in the cortical response to hypoperfusion injury in the fetal sheep.

A characteristic of perinatal encephalopathies are the distinct patterns of neuronal and glial cell loss. Cerebral hypoperfusion is thought to be a major cause of these lesions. Gestational age is likely to influence outcome. This study compares the cortical electrophysiologic and histopathologic responses to hypoperfusion injury between preterm and near term fetuses. Chronically instrumented 0.65 (93-99-d, n = 9) and 0.9 (119-133-d, n = 6) gestation fetal sheep underwent 30 min of cerebral hypoperfusion injury. The parasagittal cortical EEG and impedance (measure of cytotoxic edema) responses plus histologic outcome (3 d) were compared. The acute rise in impedance was similar in amplitude, but the onset was delayed (5.0 +/- 0.7 versus 9.1 +/- 1.1 min, p < 0.05) in the preterm fetuses relative to those near term. In contrast the extent of the secondary rise was reduced (p < 0.01) and peaked earlier in the preterm fetuses (19.8 +/- 1.0 versus 40.5 +/- 3.5 h, p < 0.01). Both groups had a similar fall in EEG spectral edge frequency. The preterm fetuses had a milder loss of EEG intensity at 72 h (-7.7 +/- 1.5 versus -12.8 +/- 0.9 dB, p < 0.05). At both ages there was a predominantly parasagittal cortical distribution of damage with a similar pattern of neuronal loss in the thalamus and striatum. There was extensive selective neuronal loss within the upper layers of the cortex in those near term. In contrast the preterm fetuses developed subcortical infarcts (p < 0.05). The cortical response to injury altered during the last trimester. The results suggest the severity of the delayed phase of cortical neuronal injury and selective neuronal loss increased near term. In contrast, the preterm fetuses had a more rapidly evolving injury leading to necrosis of the subcortical white matter.

Behavioral consequences of abnormal cortical development: insights into developmental disabilities.

Cerebral cortical development occurs in precisely-timed stages that can be divided into neurogenesis, neuronal migration and neuronal differentiation. These events occur during discrete time windows that span the late prenatal and early postnatal periods in both rodents and primates, including humans. Insults at particular developmental stages can lead to distinctive cortical abnormalities including cortical hypoplasia (reduced cell number), cortical ectopias (abnormalities in migration) and cortical dysplasias (abnormalities in the shapes or numbers of dendrites). In this review, we examine some of the most extensively-studied animal models of disrupted stages of cortical development and we compare long-term anatomical, neurochemical, and behavior abnormalities in these models. The behavioral abnormalities in these models range from alterations in simple motor behaviors to food hoarding and maternal behaviors as well as cognitive behaviors. Although we examine concisely animal models of cortical hypoplasia and cortical ectopias, we focus here on developmental manipulations that affect cortical differentiation, particularly, those that interrupt the normal ontogeny of the neurotransmitter-defined cortical afferent systems: norepinephrine, serotonin, dopamine and acetylcholine. All of these afferents presumably play a critical role in the maturation of their cortical targets; the timing of the afferents' entry into the cortex and their effects on their cortical targets, however, are different. We, therefore, compare the specific anatomical, neurochemical and behavioral effects of manipulations of the different cortical afferents. Because of the considerable evidence that cortical development proceeds differently in the two sexes, when data are available, we address whether perinatal insults differentially affect the sexes. Finally, we discuss how these developmental studies provide insights into cellular and neurochemical correlates of behavioral functional abnormalities and the relevance of these data to understanding developmental disabilities in humans.

[Maternal environment and developmental brain damages].

To estimate and to prevent the developmental brain damage caused by maternal environmental agents, the results were compared between epidemiological and experimental studies. I. Ethanol. The features of CNS involvement in human FAS (fetal alcohol syndrome) and FAE (fetal alcohol effects) were developmental delay and intellectual impairment. In rat FAS or FAE, a beneficial effect of supplementary zinc on the fetal cerebrum was observed, but was limited. The consistent dysformation of synapses during early brain development may be associated with the functional impairment of CNS in FAS and FAE II. Caffeine. A reduction in the fetal cerebral weight was observed with caffeine ingestion during pregnancy at levels of 1.5-3.0 micrograms caffeine/ml or g wet wt. in dams and fetuses. Maternal caffeine disturbs the neonatal cerebrum and produces behavioral abnormalities in developing rats. III. X-irradiation. Our study provides evidence of the protection by vitamin E of neuronal development in X-irradiated rat fetuses, through its antioxidant properties, against attacks by free radicals and/or lipid peroxide. IV. Low copper level in brain. A teratogenic effect of triethylene tetramine dihydrochloride, a chelating drug for copper, on the mouse brain was noted, both grossly and microscopically, with a dose of higher than 6,000 micrograms/l, which is twenty times as high as the clinical treatment dose. V. Tobacco. Thirty-three percent of human FTS (fetal tobacco syndrome) cases had CNS involvement, which was characterized by developmental delay. Fifty percent or more of FTS children of women who smoked more than 20 cigarettes per day had CNS involvement. In conclusion, the concomitant effects of maternal environmental agents on human brain development should be studied.

The spinal cord lesion in human fetuses with myelomeningocele: implications for fetal surgery.

Recently produced experimental evidence suggests that secondary traumatic injury and degenerative changes, acquired in utero, to the openly exposed neural tissue may be primarily responsible for the massive neurological deficit associated with myelomeningocele (MMC). The goal of this study was to examine the morphology of human fetuses with MMC to determine if acquired trauma to the spinal cord could be identified. The MMC lesions with surrounding tissues from 10 human fetuses ranging in gestational age between 19 and 23 weeks were prepared with serial histological sections. The MMC lesions were characterized by an open vertebral arch, an open dura mater fused laterally to the dermis, and an open pia mater fused laterally to the epidermis. The spinal cord was exposed, without any meningeal, bony, or cutaneous covering, and was resting on the dorsal aspect of the abnormal arachnoid sac created by the fusion of the meninges to the cutaneous tissues. The exposed neural tissue had undergone varying degrees of recent traumatic injury as a result of its exposed position, ranging from nearly complete preservation of neural elements in four cases to nearly complete loss in two cases. The neural tissue remaining in the MMC with partial loss contained hemorrhages and abrasions from recent injury, suggesting that injury occurred during passage through the birth canal. The presence of dorsal and ventral parts of the cord with nerve roots and ganglia demonstrated that these structures had formed during development and that the loss of tissue by injury was a secondary change. The results support the concept that performing in utero surgery could protect the exposed but initially well-developed and uninjured cord, prevent secondary neural injury, and preserve neural function in the human fetus with myelomeningocele.

Paroxysmal kinesigenic choreoathetosis associated with prenatal brain damage.

We describe a 15 year old patient with paroxysmal kinesigenic choreoathetosis. Neurological examinations revealed a paresis of the right arm and hand that was similar to ulnar nerve palsy, a right homonymous hemianopsia and an ocular movement disturbance of smooth pursuit to left. Attacks of dystonic spasms began abruptly, usually following running, and lasted less than 5 min. Magnetic resonance imaging displayed a linear area of increased signal in the T2-weighted images along the lateral margin to the left putamen, atrophies of the frontal and temporal opercula and a large porencephalic cyst in the left parieto-temporo-occipital region. A cerebral blood flow study with single photon emission computed tomography showed hypoperfusion of the lenticular nucleus and the regions corresponding to the atrophies and the porencephalic cyst. Electroencephalograms during the attacks could not demonstrate epileptic abnormality. Only the neuronal plasticity of an immature brain could explain the discrepancy between the observed huge lesions of the brain and the minor neurological symptoms present. Attacks of paroxysmal kinesigenic choreoathetosis might occur when the basal ganglia maturate to some extent, even if the lesions in the brain were caused before birth.

[Cerebral Doppler ultrasound in fetal hydrocephalus]. / Zerebrale Dopplersonographie beim fetalen Hydrocephalus.

Within a six-year period (1988-1993), we diagnosed and treated 143 cases of fetal hydrocephalus. We investigated the relationship between the degree of dilatation of the cerebral ventricles, the thickness of the pallium, and blood flow velocities in cerebral arteries. The assumption that progressive dilatation of the fetal ventricles leads to increasing resistance of the cerebral blood flow and disrupted cerebral perfusion was confirmed. Applying the postnatal pediatric principle of indication for shunt implantation based on Doppler sonographic diagnosis, delivery was instituted immediately in cases with pathologically increased pulsatility indices (PI). In all cases, this indication and the need for immediate shunt implantation were confirmed by postnatal pediatric ultrasonography. Cerebral Doppler velocimetry enables timely identification of fetuses at risk for pressure- or ischemia-induced cerebral tissue damage. The timing of delivery and subsequent neurosurgical therapy can thus be optimized.

Prenatal diagnosis of central nervous system abnormalities.

Fetal anomalies have been the subject of innumerable publications both in the prenatal and neonatal literature. This has significantly increased in the last 10 years, mainly because of the advent of high-resolution ultrasound equipment and improvement of scanning techniques. In addition, guidelines issued by professional organizations involved in prenatal diagnosis have encouraged a more universal approach to the imaging and documentation of prenatal findings. The fetal central nervous system is the most frequently investigated organ system, mainly because of its easy accessibility and prominence even in the early stages of embryologic development. The biparietal diameter was the first fetal measurement to be widely used in determining gestational age. As investigators gained more experience, the appearance of ultrasound images achieved the resolution that allows direct comparisons with gross specimens and more recent sophisticated techniques of computed tomography and magnetic resonance imaging. Now endovaginal ultrasound can document early first trimester development and compare it to known embryologic landmarks. Interest in demonstrating the ultrasound counterpart of central nervous system structures in the early stages of development has resulted in a plethora of articles proving the unique ability of ultrasound in imaging the developing fetus. In view of all these developments, the beginning ultrasound specialist is faced with the challenge and responsibility not only of being familiar with the literature but also of the mastery of scanning techniques that allow accurate prenatal diagnosis. It is therefore helpful to review key developmental milestones in embryologic life and correlate them with the corresponding prenatal ultrasound appearance. In addition, the changing appearance of the developing fetus has created a need for a systematic approach in the evaluation of structures so routine protocols can be established. This has been the subject of other publications that allow the novice to draw from the cumulative experience of different centers around the world. It is important to pay attention to the specifics described in the literature when duplicating results in one's laboratory. The frustration of not being able to reproduce results is common, especially when technical limitations prevent imaging under ideal conditions. This is especially true in patients who are first seen in the later third trimester with no prior prenatal care.(ABSTRACT TRUNCATED AT 400 WORDS)

Normal and abnormal patterns of myelin development of the fetal and infantile human brain using magnetic resonance imaging.

Magnetic resonance imaging allows a noninvasive assessment of myelination during normal brain maturation as well as the detection of genetically determined and acquired diseases that affect the synthesis and maintenance of myelin. If this high sensitivity of magnetic resonance imaging for white matter changes is completed by adequate clinical and biochemical information, a unique diagnostic tool is available to gain new insights in the formation of myelin and pathogenesis of myelin disorders.

[Predictive factors of infantile cerebral lesions during pregnancy and labor]. / Fattori predittivi delle lesioni cerebrali infantili in gravidanza ed in travaglio di parto.

The risks connected with children's cerebral lesions are examined by means of two different surveys related to a retrospective study over a period of about 10 years. One of these surveys is clinical and is based in the obstetric case history of children carrying psychomotor handicaps. The other survey is instrumental and concerns 100 cases of pathologic cardiotocography during labour associated with fetal suffering. The results of border surveys are discusses. For the assessment of the obstetric risk the sum of the pathologic conditions that emerged during pregnancy and delivery have to be taken into consideration. Cardiotocography is still a fundamental diagnostic examination to recognise the suffering fetus and the data collected real a close association between cardiotocography diagnosis and the conditions of the baby at the birth.

Intrauterine death in multiple gestation.

Intrauterine death of one fetus in a multiple gestation is associated with significant morbidity and mortality in the surviving infant. This study is a retrospective review of 38 twin and 3 triplet gestations involving the intrauterine death of at least one fetus. The obstetrical history, placental pathology, autopsy findings, and neonatal history of the surviving infant are reviewed. Three cases involved the recent stillbirth of both twins, the remaining cases involved a surviving infant. In one case, neonatal death of a surviving twin occurred on day 19. In two sets of triplets, two stillbirths occurred, in the third case two infants were liveborn. The incidence of preterm delivery was 34%, which decreased to 18% if fetal cotwin death had occurred before 20 weeks gestation. Cesarean section was the method of delivery in 16 cases. There was an excess of velamentous cord insertions, which was most pronounced in the stillborn twin. Monochorionic placentation was found in 72%, also an excess. Neurological damage was known to have occurred in 19 of the 39 surviving infants. Fifteen of these 19 (79%) were associated with monochorionic placentation. The neurologically damaged twin infants, when compared to the normal infants, had the cotwin die later in gestation (31 vs 16.5 weeks), had a shorter duration between the death of the cotwin and delivery (2.5 vs 21 weeks), and delivered earlier in gestation (36.5 vs 39.5 weeks). The probable cause of neurological damage, in our opinion, was either exsanguination into the dead twin fetus, or disseminated intravascular coagulation which occurred in at least 13 cases. The incidence of antepartum death in a multiple gestation, and the potential for neurological damage is probably higher than previously thought. A review of the literature is presented and the clinical implications of this phenomenon are discussed.