Prenatal factors associated with autism spectrum disorder (ASD).

Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal and postnatal etiologies. We discuss the known associated prenatal factors affecting the fetus throughout pregnancy; whenever relevant, also summarize some animal data. Among the maternal diseases in pregnancy associated with ASD are pregestational and/or gestational diabetes mellitus (PGDM, GDM), maternal infections (i.e. rubella, cytomegalovirus (CMV)), prolonged fever and maternal inflammation, which cause changes in a variety of inflammatory cytokines. Among the drugs are valproic acid, thalidomide, and possibly misoprostol and serotonin reuptake inhibitors (SSRIs). Associations were described with ethanol, and possibly cocaine, heavy metals heavy smoking and Folic acid deficiency. Heavy exposure to pesticides and air pollution during pregnancy was recently associated with ASD. We need more epidemiologic data to establish many of these associations; if proven, they might be promising avenues for prevention.

Dynamics of pleural fluid effusion and chylothorax in the fetus and newborn: role of the lymphatic system.

Pleural fluid effusion particularly chylothorax is a relatively rare occurrence in the newborn, but when it occurs it is often life-threatening. In this article, we describe and illustrate the morphologic features of the visceral and parietal pleura including pleural lymphatics and the physiology and pathophysiology of pleural fluid balance. The role and function of the lymphatic system in controlling the volume and composition of pleural liquid are detailed and a conceptual scheme presented. Finally, the crucial role of inadequate lymphatic drainage (either functional overload from an imbalance in Starling forces or mechanical insufficiency from lymphatic dysplasia) is emphasized.

Clinical outcome of umbilical artery catheter-related thrombosis - a cohort study.

OBJECTIVE: To reveal the incidence of umbilical artery catheter-related thrombosis (UACRT), the associated risk factors and the natural history of clot formation and regression. STUDY DESIGN: A prospective cohort study. An umbilical artery catheter was inserted in 61 infants, who were evaluated and followed by serial duplex ultrasound studies for the development of UACRT, renal artery resistance index (RI) and clot resolution. Maternal and infant clinical variables were correlated with the characteristics of thrombi. RESULT: Nineteen infants developed UACRT, all resolved spontaneously without sequella; most had maximal length at the first evaluation. No correlation was found between the thrombus length and time to resolution. The RI did not differ between the infants with and without UACRT. After adjusting for possible confounding, catheter days was the only covariate associated with UACRT. CONCLUSION: Asymptomatic UACRT in our cohort was a self-resolving disease; it was associated with catheter days and did not necessitate medical treatment.

Gastrointestinal colonization with ESBL-producing Klebsiella in preterm babies--is vancomycin to blame?

In this study, we examine the possible association between treatment with vancomycin and colonization with extended-spectrum beta-lactamase (ESBL)-producing Klebsiella in our neonatal intensive care unit (NICU). Variables compared between newborns which developed rectal colonization and those who did not include: gestational age, birth weight, gender, and total length of hospital stay until positive stool culture or discharge, treatment with vancomycin, and positive blood culture for coagulase-negative Staphylococcus. We found that lower birth weight, younger gestational age, and treatment with vancomycin were statistically significant risk factors for gastrointestinal colonization with ESBL-producing Klebsiella. When applying a multivariate model, treatment with vancomycin, both for a full 10-day course and for a short 3-day empirical treatment, remained statistically significant. Treatment with vancomycin is a risk factor for gastrointestinal colonization with ESBL-producing Klebsiella in premature babies.

Congenital fetal and neonatal visceral chylous effusions: neonatal chylothorax and chylous ascites revisited. A multicenter retrospective study.

This retrospective study was carried out at eight Neonatal Intensive Care Units (NICU) Centers worldwide on 33 newborns presenting at birth with pleural, pericardial, or abdominal chylous effusions. Diagnosis of chylous effusion is based on findings of fluid with a milk-like appearance, a concentration of triglycerides in pleural effusion >1.1 mmol/l, and a total cell count >1,000 cells/ml with a predominance of >80% lymphocytes. Thirty-three newborns met the inclusion criteria and were studied. Six subjects who presented at birth with fetal effusion were treated by in-utero pleuro-amniotic shunt. Five of these patients are alive at follow-up. At birth, pleural drainage was performed in 29/33 patients and abdominal drainage was carried out in 3/33. Total parenteral nutrition (TPN) was given to 32/33 patients; 19/23 patients were fed a medium-chain triglycerides (MCT). No adverse effects were observed. Eight patients were treated with Octreotide at dosages ranging from 1 to 7 mcg/kg/hour for 8 to 35 days. All patients showed decreased chylous production. Two patients were treated by pleurodesis. Twenty-two babies are alive after at least 6 months follow-up, 9/33 are deceased, and 2 were lost to follow-up. Clinical conditions of survivors are basically good except for lung involvement [chronic lung disease (CLD) or lung lymphangiectasia] and lymphedema. All patients were using a MCT diet at follow-up with good control of chylous effusion. Visceral chylous effusions of the fetus and neonate are rare disorders, and there currently is only partial agreement on decision-making strategies. We suggest the need for an international prospective trial in an effort to establish the efficacy and effectiveness of diagnostic and therapeutic options described in this article.

The embryotoxicity of sera from patients with autoimmune diseases on post-implantation rat embryos in culture persists during remission and is not related to oxidative stress.

We evaluated the embryolethality and embryotoxicity of sera from patients suffering from autoimmune diseases during remission on post-implantation rat embryos cultured on these sera and determined the association between the patients' clinical history, high blood levels of specific antibodies, medications, and oxidative stress parameters. One hundred and eighty, 10.5-day-old rat embryos were cultured in their yolk sacs in 33 sera of systemic lupus erythematosus (SLE)/antiphospholipid syndrome (APS) patients, and compared with 84 embryos cultured in rat sera and 88 embryos cultured in control human sera. The sera proved to be lethal and embryotoxic but not teratogenic resulting in smaller yolk sacs and embryos, lower protein level and lower developmental score. Significantly less embryos cultured in 'toxic' SLE/APS sera had peak 2 of low molecular weight antioxidants (LMWA) wave, implying a delayed maturation of the antioxidant defense. Lower peak 1 of LMWA correlated with a history of recurrent abortions. Embryonic levels of superoxide dismutase (SOD) and catalase (CAT) did not correlate with sera toxicity, patients' clinical history or specific antibodies. We conclude that SLE/APS patients' clinical remission did not prevent death or developmental delay accompanied by later appearance of peak 2 of LMWA in post-implantation rat embryo cultures. The normal levels of the antioxidant enzymes evaluated may indicate that sera toxicity is not related to oxidative stress.

Elimination of vancomycin-resistant enterococci from a neonatal intensive care unit following an outbreak.

A policy of weekly faecal cultures for vancomycin-resistant enterococci (VRE) was instituted following the investigation of an outbreak of VRE in our neonatal intensive care unit in 2005. We found that 11 of 18 patients were infected or colonised during the outbreak, including three cases of bloodstream infection and one case of meningitis. This report describes the utility of the surveillance policy in maintaining a VRE-free environment. The outbreak investigation showed that all VRE isolated were Enterococcus faecium of the vanA type. Pulsed-field gel electrophoresis suggested that the outbreak was caused by a single strain. Control of the outbreak was achieved by enhanced contact isolation precautions, cohorting of patients and staff, improved environmental decontamination and closure of the unit to new admissions. The patients with bloodstream infections and meningitis were treated successfully with linezolid. Approximately one year after the outbreak, weekly surveillance detected two patients with faecal carriage of VRE whose periods of admission overlapped. Early intensive intervention was associated with disappearance of the organism from the neonatal intensive care unit. No further cases of colonisation or disease have occurred in the unit in the two and a half years since then.

Effect of publication of the "Practice Parameter for the management of hyperbilirubinemia" on treatment of neonatal jaundice.

UNLABELLED: The aim of this study was to evaluate the change in the treatment of neonatal jaundice following introduction of the "American Academy of Pediatrics' Practice Parameter for the management of hyperbilirubinemia in the healthy term newborn". In a historical control observation cohort study, we examined the rate of phototherapy and exchange transfusions among full-term (> or = 37 wk gestation) and near-term (gestational age between 35 and 37 wk and birthweight > 2000 g) infants in two community hospitals. The study included all consecutive infants born during two 15-mo study periods immediately before and after the introduction of the new guidelines. Data were prospectively recorded in a computerized database. The rate of phototherapy significantly decreased in the second study period from 7.9% (514/6499) to 2.9% (251/8650) (p < 0.0001) among full-term infants, and from 20.9% (102/489) to 9.4% (47/502) (p < 0.0001) in near-term infants. The use of exchange transfusion was significantly higher (p < 0.001) in the first compared to the second period: 0.2% (15/6499) vs 0.03% (3/8650). A significant decrease was found when the data from each hospital were analyzed separately. CONCLUSION: A significant decrease in the use of phototherapy and exchange transfusion occurred after the publication of the new practice parameters. This trend was observed for both term and preterm newborns, although the new guidelines were not intended for infants born before term.

A new blue light-emitting phototherapy device: a prospective randomized controlled study.

OBJECTIVE: To evaluate the efficacy of a new phototherapy light source with a narrow luminous blue spectrum. The device, made with high-intensity gallium nitride light-emitting diodes (LEDs), was compared with conventional phototherapy at similar light intensities. SETTING: Two university-affiliated community hospitals in Jerusalem. DESIGN: Prospective open randomized study. PARTICIPANTS: Sixty-nine jaundiced, but otherwise healthy, term infants who met the entry criteria for phototherapy set by the American Academy of Pediatrics' Practice Parameter. MAIN OUTCOME MEASURES: The duration of phototherapy and the rate of decrease in total serum bilirubin (TSB) concentration. RESULTS: The mean TSB concentrations at initiation and termination of treatment did not differ between newborns receiving LED and those receiving conventional phototherapy. The duration of phototherapy and the rate of decrease in TSB concentration were not statistically different in the 2 groups. The average rate of decrease in TSB after adjustment by a linear regression analysis for confounding factors was -3.16 micromol/L/h (95% confidence limits -4.81, -1.51) in newborns receiving LED phototherapy compared with -2.19 micromol/L/h (-3.99, -0.40) in those treated with conventional phototherapy (P <.14). No side effects were noted in any of the newborns. CONCLUSIONS: The blue gallium nitride LED device is as effective as conventional phototherapy and is readily accepted by nursing staff. Future LED phototherapy devices can provide much higher irradiance, and thus greater efficacy, and offer a new highly versatile approach to the treatment of jaundice.

Agenesis of tibia with ectrodactyly/Gollop-Wolfgang complex associated with congenital heart malformations and additional skeletal abnormalities.

We report on a child with bifid femur, absent tibiae, hypoplastic hallux, bilateral club feet, congenital heart defects, and segmentation anomalies of the spine and ribs. Parents are consanguineous, from a region where other consanguineous families with similarly affected individuals have been reported. Clinical and genetic controversies of the tibial aplasia-ectrodactyly syndrome/Gollop-Wolfgang complex are discussed.

Predicting the risk of jaundice in full-term healthy newborns: a prospective population-based study.

OBJECTIVE: The need to recognize infants that are at high risk for developing significant jaundice is apparent in the era of routine early discharge. The aim of the present study was to prospectively determine the ability to predict severe hyperbilirubinemia in term healthy newborns (defined as total serum bilirubin of > 10.0 mg/dl at day 2, > 14.0 mg/dl at day 3, and > 17.0 mg/dl at days 4 and 5 of life). DESIGN: Prospective study of 1177 healthy term newborns. SETTING: Two university-affiliated community hospitals in Jerusalem. RESULTS: Using a multiple logistic regression analysis, neonatal jaundice was best predicted (p < 0.0001) by day 1 serum bilirubin (adjusted odds ratio of 3.1 [per mg/dl] [95% confidence limits of 2.4 to 4.1]) and by a change in serum bilirubin from the first to the second day of life (2.4 [per mg/dl] [1.9 to 3.0]). Maternal blood type 0 (2.9 [1.5 to 5.8]), age (1.1 [per year] [1.0 to 1.2]), schooling (0.8 [per year] [0.7 to 0.9]), and full breastfeeding (0.4 [0.2 to 0.9]) were also associated with jaundice (p < 0.005). Other factors considered in the regression model but not found to be significantly related to jaundice included maternal ethnic origin, smoking, hypertension, diabetes mellitus, intranatal administration of oxytocin, meperidine, anesthesia, premature rupture of the membranes, parity, newborn sex, birth weight, gestational age, presentation. Apgar scores, blood type, hematocrit, cephalohematoma, and history of jaundice in other siblings. A model for predicting neonatal jaundice based on the above factors had a sensitivity of 81.8%, a specificity of 82.9%, a false positive rate of 80.2%, and a false negative rate of 1.1%. CONCLUSION: Individual risk assessment on discharge in association with day 1 total serum bilirubin is of value in identifying infants at greater risk for neonatal jaundice.

Successful outcome of idiopathic nonimmune hydrops fetalis treated by maternal digoxin.

Nonimmune hydrops fetalis (NIHF), occurring in 1 in 2,500-3,000 live births has a reported mortality rate of 50-98%. A similar mortality rate for intrauterine death of fetuses with NIHF probably exists. Many fetal pathological entities have been implicated as causing the condition, but to date, treatment has only been found for cases of fetal tachycardia complicated with hydrops. During a routine ultrasonographic survey of a woman at 32 weeks of gestation, we detected a fetus with severe ascites. There was no apparent etiology, and although no tachycardia was evident, low dosage transplacental digoxin therapy was immediately initiated. The hydropic condition completely resolved within 17 days and at 39 weeks of gestation, a perfectly normal baby was born after a spontaneous and uneventful labor. This is the first report of successful treatment of idiopathic NIHF with maternal digoxin.

Hospital readmission due to neonatal hyperbilirubinemia.

Severe neonatal hyperbilirubinemia can occur without apparent reason in term healthy breast-fed infants and some develop kernicterus. The aim of our study was to assess the incidence of severe hyperbilirubinemia in term healthy newborns discharged from the hospital. From January 1 through December 31, 1994, 6705 infants were delivered at Bikur-Cholim and Misgav-Ladach Community Hospitals. All 1448 newborns discharged with a serum bilirubin level > 10.0 mg/dL were instructed to return to the hospital within 3 days for follow-up, as well as bilirubin determination. Twenty-one newborns with a bilirubin level > 18.0 mg/dL were identified and readmitted at mean +/- standard deviation (SD) 5.5 +/- 1.8 (range, 5 to 10 days of life). This represents 1.7% of the 1220 infants who returned for follow-up examination. Mean +/- SD serum bilirubin levels at readmission were 19.6 +/- 2.5 mg/dL. All but one of the infants were breast-fed. No cases of ABO incompatibility were found and two newborns were glucose-6-phosphate dehydrogenase (G6PD)-deficient. Sepsis work-up and direct Coomb's tests were negative in all cases. None had hemolysis or were found to have any cause for hyperbilirubinemia other than breast-feeding. Phototherapy was provided in all but two cases, and an exchange transfusion was performed in one case. Three additional infants, with bilirubin levels < 10 mg/dL at discharge, were readmitted due to hyperbilirubinemia. One was diagnosed with neonatal hepatitis. We conclude that, based on our study population, 0.36% of term infants may subsequently develop severe neonatal hyperbilirubinemia in the first postnatal week.(ABSTRACT TRUNCATED AT 250 WORDS)

Homozygosity for Waardenburg syndrome.

In a large kindred including many individuals affected with Waardenburg (WS) type 1 (WS1) syndrome, a child affected with a very severe form of WS type 3 was born. This child presented with dystopia canthorum, partial albinism, and very severe upper-limb defects. His parents were first cousins, both affected with a mild form of WS1. Molecular analysis of PAX3, the gene that was determined by linkage to cause the disorder in the family, demonstrated a novel missense mutation (S84F) in exon 2 of PAX3 within the paired box. While individuals affected with WS1 were heterozygous for the mutation, the child with WS3 was homozygous for S84F. The observation that the PAX3 homozygote in humans may allow life at least in early infancy and does not cause neural tube defects was unexpected, since, in all the mutations known in mice (splotch), homozygosity has led to severe neural tube defects and intrauterine or neonatal death.

Carboxyhemoglobin levels in neonatal immune hemolytic jaundice treated with intravenous gammaglobulin.

In order to examine the effect of intravenous immunoglobulin (IVIG) on the rate of hemolysis in immune hemolytic hyperbilirubinemia, we measured the carboxyhemoglobin levels of 5 newborn infants who were subjected to IVIG treatment. The pretreatment rate of hemolysis, in the 5 patients with isoimmune hemolytic jaundice (3 patients with Rh hemolytic disease of the newborn and 2 patients with ABO hemolytic disease of the newborn), as reflected by carboxyhemoglobin levels was higher than the rate of hemolysis in normal newborn infants. In 4 out of the 5 patients treated with IVIG, there was a rapid decline ( > 30%) of carboxyhemoglobin levels, a pattern which was different from that observed in normal newborn infants with no hemolytic jaundice and in 3 untreated patients with ABO hemolytic disease of the newborn. None of the treated patients required an exchange transfusion. Our preliminary results support the theory that the attenuation of jaundice observed following IVIG treatment in patients with immune hemolytic hyperbilirubinemia is caused, at least in part, by the reduction in hemolysis.

Neonatal limb ischemia following maternal indomethacin treatment in twin pregnancies.

The prenatal administration of indomethacin in obstetric management has been implicated as a cause of neonatal cardio-pulmonary, gastrointestinal and renal complications. The present report describes two cases of twin pregnancy resulting in premature delivery at the 33rd and 30th week following prolonged maternal indomethacin treatment for 9 and 4 weeks respectively. Neonatal cardiovascular and renal complications were observed and an unusual severe ischemia of a lower limb occured in each of the first twins following insertion of an umbilical arterial line. It is suggested that prolonged antenatal exposure to the drug may increase the systemic arterial constrictive reactivity in some newborn infants and that special caution should be exercised during arterial catheterization of susceptible cases.

Basal ganglia and thalamic calcification following intrauterine intravascular transfusion.

In recent years intrauterine intravascular transfusion has become the method of choice for the treatment of severe fetal erythroblastosis. Despite the association of the procedure with fetal complications such as bradycardia and overtransfusion, later neonatal neurological consequences have been only rarely reported. A case is described of a neonate who underwent repeated intrauterine intravascular transfusion for treatment of erythroblastosis and who later developed calcification in the thalamus and the basal ganglia. The possible pathogenetic mechanisms are discussed.

Hyperbilirubinemia in premature infants: relevance to blood transfusion.

The rate of hemolysis of transfused adult red blood cells in the premature circulation may be higher than in the native circulation and produce a significant bilirubin load on the immature liver during the first days of life with consequent hyperbilirubinemia. The association between the transfusion of packed red blood cells and consequent change of serum bilirubin level was evaluated in 35 premature infants with birth weight of < 1,250 g during the first 10 days of life, using the analysis of variance method. There was a significant increase of bilirubin level with a mean of 24.3 mumol/l following packed red blood cells transfusion. Birth weight had a significant negative effect and mechanical ventilation for > 2 days had a significant positive effect on bilirubin levels; however, the changes were of small magnitude. The results of our study indicate that a rise of bilirubin level following blood transfusion to very low birth weight infants during the early neonatal period should be anticipated.

Intravenous immunoglobulin therapy in neonatal immune hemolytic jaundice.

Nine cases of newborn patients who developed hyperbilirubinemia due to blood group incompatibility and were treated with high dose (1 gram/Kg) intravenous immunoglobulin (IVIG) are described. In 7 of the 9 patients the rise of bilirubin level was attenuated and exchange transfusion was not required following treatment with IVIG. Of the two patients who did require an exchange transfusion despite IVIG treatment, one had the exchange performed immediately following the IVIG infusion, allowing no time for observation of the therapy effect. Our results suggest that IVIG administration may be efficacious in the treatment of immune hemolytic hyperbilirubinemia of the newborn but further studies are required to validate the efficacy of this treatment.

Nonketotic hyperglycinemia presenting with pin-point pupils and hyperammonemia.

We describe two siblings who presented with lethargy, decreased sucking, respiratory failure and seizures in their first days of life. Pin-point pupils were noted in both siblings. Amino acid analysis revealed elevated concentrations of glycine in plasma and cerebrospinal fluid (CSF), with abnormal CSF/plasma ratios, compatible with hyperglycinemia. Urine organic acid analysis was unremarkable. Hyperammonemia was found in both siblings, but this subsided within 24-72 h. We suggest that pin-point pupils may be an additional presenting sign of nonketotic hyperglycinemia and, if looked for early enough, hyperammonemia may be found in this disorder.