Significant association between circumvallate placenta, placental abruption and acute chorioamnionitis in preterm birth: A 23-year retrospective cohort study.

AIM: circumvallate placenta, placental abruption and acute chorioamnionitis separately are associated with unfavourable clinical outcomes. We aimed to determine the prevalence and define whether an association exists between the three abnormalities. METHODS: 16,042 placenta pathology reports between 1997 and 2020 from a tertiary care centre in the Netherlands were retrospectively analysed. For the statistical analysis, the chi-square test and bootstrapping were used to evaluate an association. RESULTS: In our cohort the prevalence of circumvallate placenta is 2.2 %, placental abruption cases 4.0 % and acute chorioamnionitis 20.6 %. We observed a statistically significant association between all three placental abnormalities: circumvallate placenta, placental abruption and acute chorioamnionitis. In addition, there was also an association between circumvallate placenta and acute chorioamnionitis. CONCLUSION: Our results show that combined presence of circumvallate placenta, placental abruption and acute chorioamnionitis are associated in preterm birth (p = 0.001). A remarkable finding is that the combination of all three abnormalities (circumvallate placenta, placental abruption and acute chorioamnionitis) was not observed in term pregnancies >37 weeks.

The severity of chronic histiocytic intervillositis is associated with gestational age and fetal weight.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta that is associated with poor reproductive outcomes. The intervillous infiltrate consists mostly of maternal mononuclear cells and fibrin depositions, which are both indicators for the severity of the intervillous infiltrate. The severity of the intervillous infiltrate as well as the clinical outcomes of pregnancy differ between cases. Our objective is to determine the relation between the severity of the intervillous infiltrate and the clinical outcomes of CHI. METHODS: Cases of CHI were semi-quantitatively graded based on histopathological severity scores. Hereto, CD68 positive mononuclear cells were quantified, fibrin depositions visualized by both a PTAH stain and an immuohistochemical staining, and placental dysfunction was assessed via thrombomodulin staining. RESULTS: This study included 36 women with CHI. A higher CD68 score was significantly associated with a lower birthweight. Loss of placental thrombomodulin was associated with lower gestational age, lower birthweight, and a lower placenta weight. The combined severity score based on CD68 and PTAH was significantly associated with fetal growth restriction, and the joint score of CD68 and fibrin was associated with birthweight and placental weight. DISCUSSION: More severe intervillous infiltrates in CHI placentas is associated with a lower birth weight and placental weight. Furthermore, this study proposes thrombomodulin as a possible new severity marker of placental damage. More research is needed to better understand the pathophysiology of CHI.

Clinical outcomes in chronic intervillositis of unknown etiology.

INTRODUCTION: Chronic intervillositis of unknown etiology (CIUE) is a histopathological lesion of the placenta that is frequently accompanied by unfavourable pregnancy outcomes, e.g. miscarriage, fetal growth restriction (FGR) and intrauterine fetal death. Earlier described case series and cohorts have been based on diverse diagnostic criteria of CIUE. To improve our understanding of clinical outcomes associated with CIUE, we report the obstetric and perinatal outcomes in a cohort based on the recently described diagnostic criteria. METHODS: CIUE is defined as an infiltrate occupying 5% or more of the intervillous space with approximately 80% of mononuclear cells positive for CD68 in the absence of an infection. Thirty-eight cases were included. Also previous and subsequent pregnancies were described. RESULTS: Pregnancies accompanied by CIUE frequently resulted in FGR (51.6%) and pre-term birth (55.3%). Twenty-nine out of 38 pregnancies (76.3%) with CIUE resulted in a living baby. Women with CIUE frequently have had a miscarriage (16/38; 42%). Four-teen subsequent pregnancies in 8 women resulted in 2 miscarriages, 2 terminations of pregnancy for FGR, 1 early neonatal death and 9 living babies (9/14; 64.3%). Histopathologically confirmed CIUE recurred in 5 out of 10 subsequent pregnancies. Two pregnancies with recurrent CIUE were terminated, one pregnancy ended in a late miscarriage and another resulted in term birth complicated by FGR. Recurrent CIUE can also be accompanied by an uncomplicated pregnancy (1/5; 20%). CONCLUSION: This study provides additional insight into the clinical phenotype of CIUE and emphasises the need for further research to understand the pathophysiology behind different pregnancy outcomes in CIUE.

Symmetrical Thalamic Lesions in the Newborn: A Case Series.

Although bilateral injury to the thalami is often seen in (near)term infants with hypoxic ischemic encephalopathy (HIE), symmetrical thalamic lesions (STL) is a different, very rare condition, seen both in full-term and preterm infants often after an antenatal insult, although the history is not always clear. These lesions are usually first detected using cranial ultrasound (cUS). They may not always be seen on the first (admission) scan, but become apparent in the course of the 1st week after birth. Clinically, these infants present with hypo- or hypertonia, absence of sucking and swallowing reflexes, and they may have contractures and facial diplegia. Neuropathology commonly demonstrates a thalamic lesion with additional and variable involvement of basal ganglia and brainstem. The prognosis is very poor, the condition often leads to severe disabilities and/or death within the first years of life. The clinical course and neuroimaging findings of 13 patients with symmetrical thalamic lesions (STL) are reported.

Correction to: Cardiovascular causes of sudden unexpected death in children and adolescents (0-17 years) : A nationwide autopsy study in the Netherlands.

Correction to:Neth Heart J 2018 https://doi.org/10.1007/s12471-018-1152-y In the version of the article originally published online, there was an error in the 'Methods and results' section of the Abstract. It is stated that 'In the 10-14 year group, hypertrophic cardiomyopathy (n = 1) and ruptured ….

Cardiovascular causes of sudden unexpected death in children and adolescents (0-17 years) : A nationwide autopsy study in the Netherlands.

BACKGROUND: Little is known about the causes of unexpected death in minors (0-17 years). In young adults an important cause is cardiovascular disease, with primary arrhythmogenic disorders, atherosclerotic events, cardiomyopathies and myocarditis as main contributors. The aim of this autopsy study was to determine the contribution of cardiovascular disease to unexpected death in minors. METHODS AND RESULTS: In the Netherlands, systematic investigation of all cases of unexplained death in minors was compulsory in a nationwide governmental project during a 15-month period. Autopsies were performed according to a standardised protocol (autopsy rate 85%). A cardiovascular cause of death was found in 13/56 cases (23%). In the group <1 year, the main cardiovascular causes were various congenital defects (n = 3) and myocarditis (n = 2). In the 1-9 year group, no cardiovascular causes were found. In the 10-14 year group, coronary anomalies (n = 2) and arrhythmogenic cardiomyopathy (n = 1) were observed. In the 15­17 year group, hypertrophic cardiomyopathy (n = 1) and ruptured ascending aortic aneurysm (n = 1) were among the observed cardiovascular causes [corrected]. In 14/56 (25%) cases autopsy revealed no structural abnormalities that could explain the sudden death, mostly in the group <1 year. CONCLUSION: This national cohort with a high autopsy rate reveals a high incidence (23%) of cardiovascular diseases as the pathological substrate of sudden unexpected death in children. Another high percentage of minors (25%) showed no structural abnormalities, with the possibility of a genetic arrhythmia. These findings underline the importance of systematic autopsy in sudden death in minors, with implications for cardiogenetic screening of relatives.

Dutch guideline for clinical foetal-neonatal and paediatric post-mortem radiology, including a review of literature.

Clinical post-mortem radiology is a relatively new field of expertise and not common practice in most hospitals yet. With the declining numbers of autopsies and increasing demand for quality control of clinical care, post-mortem radiology can offer a solution, or at least be complementary. A working group consisting of radiologists, pathologists and other clinical medical specialists reviewed and evaluated the literature on the diagnostic value of post-mortem conventional radiography (CR), ultrasonography, computed tomography (PMCT), magnetic resonance imaging (PMMRI), and minimally invasive autopsy (MIA). Evidence tables were built and subsequently a Dutch national evidence-based guideline for post-mortem radiology was developed. We present this evaluation of the radiological modalities in a clinical post-mortem setting, including MIA, as well as the recently published Dutch guidelines for post-mortem radiology in foetuses, neonates, and children. In general, for post-mortem radiology modalities, PMMRI is the modality of choice in foetuses, neonates, and infants, whereas PMCT is advised in older children. There is a limited role for post-mortem CR and ultrasonography. In most cases, conventional autopsy will remain the diagnostic method of choice. CONCLUSION: Based on a literature review and clinical expertise, an evidence-based guideline was developed for post-mortem radiology of foetal, neonatal, and paediatric patients. What is Known: • Post-mortem investigations serve as a quality check for the provided health care and are important for reliable epidemiological registration. • Post-mortem radiology, sometimes combined with minimally invasive techniques, is considered as an adjunct or alternative to autopsy. What is New: • We present the Dutch guidelines for post-mortem radiology in foetuses, neonates and children. • Autopsy remains the reference standard, however minimal invasive autopsy with a skeletal survey, post-mortem computed tomography, or post-mortem magnetic resonance imaging can be complementary thereof.

Towards standardized criteria for diagnosing chronic intervillositis of unknown etiology: A systematic review.

Chronic intervillositis of unknown etiology (CIUE) is a poorly understood, relatively rare condition characterized histologically by the intervillous infiltration of mononuclear cells in the placenta. Clinically, CIUE is associated with poor pregnancy outcome (e.g., impaired fetal growth, preterm birth, fetal death) and high risk of recurrence in subsequent pregnancies. Because CIUE is not defined consistently, it is essential to clearly define this condition. We therefore review the published definitions of CIUE. In addition, we provide an overview of the reviewed histopathological and maternal characteristics, obstetric features, and pregnancy outcomes. Medical publication databases were searched for articles published through February 2017. Eighteen studies were included in our systematic review. The sole inclusion criterion used in all studies was the presence of intervillous infiltrates. Overall, CIUE was characterized by adverse pregnancy outcome. Miscarriage occurred in 24% of cases, with approximately half of these miscarriages defined as late. Impaired growth was commonly observed, 32.4% of pregnancies reached term, and the live birth rate was 54.9%. The high recurrence rate (25.1%) of the intervillous infiltrates in subsequent pregnancies underscores the clinical relevance of CIUE, the need for increased awareness among pathologists and clinicians, and the need for further research. Criteria for the diagnosis of CIUE are proposed and a Delphi study could be used to resolve any controversy regarding these criteria. Future studies should be designed to characterize the full clinical spectrum of CIUE.

Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions.

The genetic basis of the many progressive, multi systemic, mitochondrial diseases that cause a lack of cellular ATP production is heterogeneous, with defects found both in the mitochondrial genome as well as in the nuclear genome. Many different mutations have been found in the genes encoding subunits of the enzyme complexes of the oxidative phosphorylation system. In addition, mutations in genes encoding proteins involved in the assembly of these complexes are known to cause mitochondrial disorders. Here we describe two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits. Whole exome sequencing revealed a homozygous nonsense mutation resulting in a premature stop codon in the gene encoding Pet117, a small protein that has previously been predicted to be a complex IV assembly factor. PET117 has not been identified as a mitochondrial disease gene before. Lentiviral complementation of patient fibroblasts with wild-type PET117 restored the complex IV deficiency, proving that the gene defect is responsible for the complex IV deficiency in the patients, and indicating a pivotal role of this protein in the proper functioning of complex IV. Although previous studies had suggested a possible role of this protein in the insertion of copper into complex IV, studies in patient fibroblasts could not confirm this. This case presentation thus implicates mutations in PET117 as a novel cause of mitochondrial disease.

Hyaluronic Acid-Based Hydrogel Coating Does Not Affect Bone Apposition at the Implant Surface in a Rabbit Model.

BACKGROUND: Uncemented orthopaedic implants rely on the bone-implant interface to provide stability, therefore it is essential that a coating does not interfere with the bone-forming processes occurring at the implant interface. In addition, local application of high concentrations of antibiotics for prophylaxis or treatment of infection may be toxic for osteoblasts and could impair bone growth. QUESTIONS/PURPOSES: In this animal study, we investigated the effect of a commercially available hydrogel, either unloaded or loaded with 2% vancomycin. We asked, does unloaded hydrogel or hydrogel with vancomycin (1) interfere with bone apposition and timing of bone deposition near the implant surface; and (2) induce a local or systemic inflammatory reaction as determined by inflammation around the implant and hematologic parameters. METHODS: In 18 New Zealand White rabbits, an uncoated titanium rod (n = 6), a rod coated with unloaded hydrogel (n = 6), or a rod coated with 2% vancomycin-loaded hydrogel (n = 6) was implanted in the intramedullary canal of the left tibia. After 28 days, the bone volume fraction near the implant was measured with microCT analysis, inflammation was semiquantitatively scored on histologic sections, and timing of bone apposition was followed by semiquantitative scoring of fluorochrome incorporation on histologic sections. Two observers, blinded to the treatment, scored the sections and reconciled their scores if there was a disagreement. The hematologic inflammatory reaction was analyzed by measuring total and differential leukocyte counts and erythrocyte sedimentation rates in blood. With group sizes of six animals per group, we had 79% power to detect a difference of 25% in histologic scoring for infection and inflammation. RESULTS: No differences were found in the amount of bone apposition near the implant in the No Gel group (48.65% ± 14.95%) compared with the Gel group (59.97% ± 5.02%; mean difference [MD], 11.32%; 95% CI, -3.89% to 26.53%; p = 0.16) or for the Van2 group (56.12% ± 10.06%; MD, 7.46; 95% CI, -7.75 to 22.67; p = 0.40), with the numbers available. In addition, the scores for timing of bone apposition did not differ between the No Gel group (0.50 ± 0.55) compared with the Gel group (0.33 ± 0.52; MD, -0.17; 95% CI, -0.86 to 0.53; p = 0.78) or the Van2 group (0.83 ± 0.41; MD, 0.33; 95% CI, -0.36 to 1.03; p = 0.42). Furthermore, we detected no differences in the histopathology scores for inflammation in the No Gel group (2.33 ± 1.67) compared with the Gel group (3.17 ± 1.59; MD, 0.83; 95% CI, -0.59 to 2.26; p = 0.31) or to the Van2 group (2.5 ± 1.24; MD, 0.17; 95% CI, -1.26 to 1.59; p = 0.95). Moreover, no differences in total leukocyte count, erythrocyte sedimentation rate, and neutrophil, monocyte, eosinophil, basophil, and lymphocyte counts were present between the No Gel or Van2 groups compared with the Gel control group, with the numbers available. CONCLUSION: The hydrogel coated on titanium implants, unloaded or loaded with 2% vancomycin, had no effect on the volume or timing of bone apposition near the implant, and did not induce an inflammatory reaction in vivo, with the numbers available. CLINICAL RELEVANCE: Antibiotic-loaded hydrogel may prove to be a valuable option to protect orthopaedic implants from bacterial colonization. Future clinical safety studies will need to provide more evidence that this product does not impair bone formation near the implant and prove the safety of this product.

Placental pathology and outcome after perinatal asphyxia and therapeutic hypothermia.

OBJECTIVE: To assess the relationship between placental pathology, pattern of brain injury and neurodevelopmental outcome in term infants with perinatal asphyxia receiving therapeutic hypothermia. STUDY DESIGN: Studies were performed in 76 infants. Death or survival with impairments at 18 to 24 months was used as a composite adverse outcome. Multivariable analysis was performed. RESULTS: Among the 75 infants analyzed, the predominant pattern of brain injury was: no injury (n=27), a white matter/watershed pattern (n=14), basal-ganglia-thalamic injury (n=13) or near-total brain injury (n=21). An adverse outcome was seen in 35 of the 76 infants. Elevated nucleated red blood cells were associated with white matter involvement. Small placental infarcts were more common among infants without brain injury. All other placental abnormalities were not related to both outcome measures. CONCLUSION: In our population of term infants receiving therapeutic hypothermia, no type of placental pathology was related to extensive brain injury or adverse neurodevelopmental outcome.

Biopsy techniques to study the human placental bed.

BACKGROUND: The physiologic transformation of uterine spiral arteries in the human placental bed is essential for a healthy pregnancy. Failure of this transformation due to deficient trophoblast invasion is widely believed to underlie pregnancy complications such as preeclampsia, foetal growth restriction, miscarriage and preterm labour. Understanding of invasive behaviour and remodelling properties of trophoblasts in the uterine wall is essential in elucidating the aetiology of these pregnancy complications. However, there is a lack of satisfactory specimens of the placental bed to enhance our knowledge on the mechanisms that control trophoblast invasion. Several techniques can be used to obtain biopsies from the placental bed and sample handling can be executed differently depending on the research question. METHODS: This systematic review provides an overview of all studies investigating the placental bed and sampling techniques used. Papers that described surgical techniques, specimen handling, complications and/or success rate of the placental bed biopsy procedures were included. Placental bed biopsies are an essential and feasible technique to study abnormalities in the placental bed associated with pregnancy complications. RESULTS: Depending on the technique used the likelihood of sampling a spiral artery and trophoblast from the placental bed is 51%-78% per case, without significant complications. CONCLUSIONS: Caution is needed when interpreting data if the placental bed is subjected to labour. We propose a uniform sampling technique and conservation protocol for the study of the placental bed and provide tools for selection of the appropriate technique for future placental bed collections.

Placental pathology in early intrauterine growth restriction associated with maternal hypertension.

INTRODUCTION: To identify key pathological characteristics of placentas from pregnancies complicated by early intrauterine growth restriction, and to examine their relations with maternal hypertensive disease and umbilical artery Doppler waveform abnormalities. METHODS: Single-center retrospective cohort study of singleton pregnancies with abnormal umbilical artery Doppler flow patterns resulting in a live birth <34 weeks of a baby with a weight <10th percentile for gestational age. Umbilical artery end diastolic flow was classified as being either present or absent/reversed (AREDF). Data were stratified into intrauterine growth restriction with or without hypertensive disease and pathological characteristics were compared between these various conditions according to predefined scoring criteria. RESULTS: Among 164 placentas studied, we found high rates of characteristic histopathological features that were associated with intrauterine growth restriction, including infarction (>5% in 42%), chronic villitis (21%), chronic chorioamnionitis (36%), membrane necrosis (20%), elevated nucleated red blood cells (89%), increased syncytial knotting (93%), increased villous maturation (98%), fetal thrombosis (32%) and distal villous hypoplasia (35%). Chronic inflammation of fetal membranes and syncytial knotting were more common in women with concomitant hypertensive disease as compared to women with normotensive IUGR (p < 0.05). Placentas from women with umbilical artery AREDF were more likely to show increased numbers of nucleated red blood cells and distal villous hypoplasia (p < 0.05). DISCUSSION: Placentas of women with early IUGR show high rates of several histological aberrations. Further, concomitant maternal hypertension is associated with characteristic inflammatory changes and umbilical artery AREDF with signs of chronic hypoxia.

Isolated abdominal wall defect with complete liver herniation without a covering or remnant membrane: an ominous sign: case report and review of literature.

Complete liver herniation in abdominal wall defects without a membrane is rare and its prognosis is not well documented. We present a case diagnosed at 12 weeks of gestation. At 27 weeks, a C-section was performed for fetal distress. The infant proved impossible to ventilate and died. In literature, 16 similar cases are described of whom 14 died in the neonatal period and two in infancy. This suggests that herniation of the complete liver in isolated abdominal wall defects without a remnant membrane is lethal and counselling should be provided accordingly.

Patterns of placental pathology in preterm infants with a periventricular haemorrhagic infarction: association with time of onset and clinical presentation.

BACKGROUND: A periventricular haemorrhagic infarction (PVHI) is a complication of preterm birth with serious consequences. While various risk factors are recognized, little is known about the role of the placenta in the pathogenetic pathway of this type of white matter injury. AIM: To evaluate prenatal, maternal and neonatal risk factors and describe placental pathology in infants with typical and atypical timing and presentation of PVHI. METHODS: PVHI was defined as typical when the onset was within 6-96 h after birth in the context of established risk factors. PVHI was determined to be atypical when presumed antenatal (<6 h after birth) OR late in the postpartum course (>96 h). Maternal, prenatal and neonatal risk factors were collected retrospectively from patient charts. Microscopic placental pathology was described in 38/45 (84%) preterm infants (GA <34 wks) with a typical PVHI and 14/19 (74%) with an atypical presentation of PVHI. RESULTS: Using univariate analysis clinical factors significantly associated with a typical PVHI were mechanical ventilation (p = 0.00), while fetal heart rate abnormalities (p = 0.00), a planned caesarean section (p = 0.00) and hypertensive disorders (p = 0.01) were associated with an atypical PVHI. Placental pathology was different between the typical vs atypical group with respect to chorioamnionitis (p = 0.04), funisitis (p = 0.05), fetal thrombosis (p = 0.01) and placental infarction (p = 0.00). CONCLUSION: Chorioamnionitis and funisitis were significantly more common in infants with a typical PVHI. Fetal thrombosis and placental infarction were significantly more often associated with an atypical PVHI. Placental pathology in infants with PVHI reflects underlying disease processes and clinical conditions which may interact with the pathogenic mechanism of PVHI.

A known and a novel mutation in the glycine decarboxylase gene in a newborn with classic nonketotic hyperglycinemia.

A term neonate displayed typical features of nonketotic hyperglycinemia (NKH). Conventional magnetic resonance imaging showed corpus callosum hypoplasia and increased signal intensity of the white matter. Magnetic resonance proton spectroscopy revealed high cerebral glycine levels. The liquor/plasma glycine ratio was increased. Genetic testing detected a known and a novel mutation in the glycine decarboxylase gene, leading to the classic form of glycine encephalopathy. Prenatal genetic testing in the subsequent pregnancy showed that this fetus was not affected. As features of neonatal NKH may not be very specific, recognition of the disease may be difficult. An overview of clinical, electroencephalography, and neuroimaging findings is given in this article.

Osteogenesis Imperfecta: A Review with Clinical Examples.

Osteogenesis imperfecta (OI) is characterized by susceptibility to bone fractures, with a severity ranging from subtle increase in fracture frequency to prenatal fractures. The first scientific description of OI dates from 1788. Since then, important milestones in OI research and treatment have, among others, been the classification of OI into 4 types (the 'Sillence classification'), the discovery of defects in collagen type I biosynthesis as a cause of most cases of OI and the use of bisphosphonate therapy. Furthermore, in the past 5 years, it has become clear that OI comprises a group of heterogeneous disorders, with an estimated 90% of cases due to a causative variant in the COL1A1 or COL1A2 genes and with the remaining 10% due to causative recessive variants in the 8 genes known so far, or in other currently unknown genes. This review aims to highlight the current knowledge around the history, epidemiology, pathogenesis, clinical/radiological features, management, and future prospects of OI. The text will be illustrated with clinical descriptions, including radiographs and, where possible, photographs of patients with OI.

The presence of extracellular matrix degrading metalloproteinases during fetal development of the intervertebral disc.

Matrix metalloproteinases (MMPs) regulate connective tissue architecture and cell migration through extracellular matrix (ECM) degradation and are associated with both physiological and pathological processes. Although they are known to play a role in skeletal development, little is known about the role of MMPs in intervertebral disc (IVD) development. Sixteen fetal human lumbar spine segments, obtained at autopsy, were compared with five normal, non-fetal L4-L5 IVDs. Intensity and/or localization of immunohistochemical staining for MMP-1, -2, -3 and -14 were evaluated by three independent observers. MMP-2 production and activation was quantified by gelatin zymography. MMP-1 and -14 were abundantly present in the nucleus pulposus (NP) and notochordal (NC) cells of the fetal IVDs. In non-fetal IVDs, MMP-1 and -14 staining was significantly less intense (p = 0.001 and p < 0.001, respectively). MMP-3 was found in almost the entire IVD with no significant difference from non-fetal IVDs. MMP-2 staining in the NC and NP cells of the fetal IVD was moderate, but weak in the non-fetal IVD. Gelatin zymography showed a negative correlation of age with MMP-2 activity (p < 0.001). MMP-14 immunostaining correlated positively with MMP-2 activity (p = 0.001). For the first time, the presence of MMP-1, -2, -3 and -14 in the fetal human IVD is shown and the high levels of MMP-1, -2 and -14 suggest a role in the development of the IVD. In particular, the gradual decrease in MMP-2 activation during gestation pinpoints this enzyme as key player in fetal development, possibly through activation by MMP-1 and -14.

Predictors of outcome at 2 years of age after early intrauterine growth restriction.

OBJECTIVE: To examine the relative importance of antenatal and perinatal variables on short- and long-term outcome of preterm growth restricted fetuses with umbilical artery (UA) Doppler abnormalities. METHODS: This was a cohort study of 180 neonates with birth weight < 10(th) percentile, gestational age at delivery < 34 weeks and abnormal Doppler ultrasound examination of the UA. Various antenatal and perinatal variables were studied in relation to short- and long-term outcome. RESULTS: Neonatal and overall mortality (up to 2 years of age) were predicted by low gestational age at delivery. Neonatal mortality was additionally predicted by absent or reversed UA end-diastolic flow, while the presence of severe neonatal complications and placental villitis were additional predictors of both infant (between 28 days and 1 year of postnatal life) and overall mortality. Placental villitis was found to be the only predictor of necrotizing enterocolitis. Low gestational age at delivery, male sex, abnormal cardiotocography, absent or reversed UA end-diastolic flow and the HELLP syndrome predicted respiratory distress syndrome. Abnormal neurodevelopmental outcome at 2 years was predicted by low birth weight (< 2.3(rd) percentile), fetal acidosis (UA pH < 7.00), and placental villitis. CONCLUSION: Less advanced gestation at delivery remains an important predictor of short-term outcome in growth-restricted fetuses. In addition, the presence of placental villitis may aid neonatologists in the early identification of infants at increased risk of necrotizing enterocolitis, death and abnormal neurodevelopment at 2 years of age. Abnormal neurodevelopment was related to low weight and acidosis at birth, indicating that the severity of malnutrition and fetal acidosis affect long-term outcome.