Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis.

OBJECTIVE: To examine the role of indomethacin in neonatal gut injury. STUDY DESIGN: Infants born at gestational age 23 weeks and with birth weights 400-1200 g were included in this prospective prevalence study of neonatal gut injury. Infants with isolated intestinal perforation (IIP) confirmed at laparotomy or at autopsy or with necrotizing enterocolitis (NEC) were identified. Data were abstracted bi-weekly. RESULT: Among 992 study infants, 58 infants exposed solely to prenatal indomethacin did not show an increased rate of neonatal gut injury. Any postnatal indomethacin exposure (n=611) increased the odds of IIP (OR 4.17, CI, 1.24-14.08, P=0.02) but decreased the odds of NEC (OR 0.65, CI 0.43-0.97, P=0.04). There was a negative association between the timing of indomethacin-exposure and the odds of developing IIP (OR 0.30, CI 0.11-0.83, P=0.02). Compared with NEC, IIP occurred at an earlier age (P<0.05) and was more common (P<0.05) among infants who received early indomethacin (first dose at <12 h of age) to prevent intraventricular hemorrhage than among infants who were treated with late indomethacin for closure of a patent ductus arteriosus (PDA). Unlike the classic hemorrhagic ischemic lesions of NEC in which large areas of tissue were inflamed or necrotic, the IIP lesions were small and discrete. CONCLUSION: Early (<12 h) postnatal indomethacin exposure was associated with an increased odds of IIP in very low birth weight infants whereas its later use for closure of a PDA appeared to provide protection against NEC. The paradoxical effect of the timing of indomethacin on IIP versus on NEC may be related to the different pathogeneses of the two diseases. Our findings also suggest that PDA may contribute to NEC.

Early neutropenia is not associated with an increased rate of nosocomial infection in very low-birth-weight infants.

BACKGROUND: Evidence is contradictory whether very low-birth-weight (VLBW, birth weight <1500 g) infants with early neutropenia (NP), especially those born to mothers with preeclampsia experience a greater incidence of nosocomial infection (NI). OBJECTIVE: To investigate whether NP within the first 7 days of life is a risk factor for NI in VLBW infants. METHODS: Over a 42-month period, we identified all VLBW infants born at

Early neonatal hypotension in premature infants born to preeclamptic mothers.

BACKGROUND: Early neonatal hypotension (ENH) is common in premature infants and has been claimed to occur more frequently in infants born to mothers with severe preeclampsia. Previous studies that showed a relationship between maternal preeclampsia and neonatal hypotension did not control for potential confounding factors such as birth weight and maternal treatment with magnesium sulfate (MgSO4). OBJECTIVE: To determine whether maternal preeclampsia is an independent risk factor for ENH. STUDY DESIGN: We conducted a retrospective review of all viable singleton infants with gestational age of 23 to 30 weeks who were admitted to the neonatal intensive care unit over a 2-year period. ENH was defined as the persistence of the mean arterial pressure lower than the gestational age in weeks requiring volume expansion and inotropic support in the first 24 h of life. RESULTS: One hundred and eighty four infants were enrolled. Seventy-five (41%) infants met the diagnostic criteria for ENH. Maternal preeclampsia, the presence of labor, maternal treatment with MgSO4, Apgar scores, birth weight, gestational age and respiratory distress syndrome were significantly associated with ENH by univariate analysis. Only gestational age and maternal preeclampsia were significantly associated with ENH by multiple logistic regression. CONCLUSION: Gestational age and maternal preeclampsia were independent risk factors for ENH in our population of premature infants.

A model to study antioxidant regulation of endotoxemia-modulated neonatal granulopoiesis and granulocyte apoptosis.

Neonates with septicemia tend to develop granulocytopenia, which may, in part, be due to septic mediators such as oxygen free radicals and tumor necrosis factor alpha (TNF-alpha). Granulocytopenia may be caused by a decrease in granulocyte growth and/or an increase in granulocyte destruction. In the present study, we investigated antioxidant regulation of endotoxin-modulated neonatal granulopoiesis and granulocyte apoptosis. Using human umbilical cord blood (HUCB), we found that simulating endotoxemia in vitro elicited significant superoxide production within a few minutes. Endotoxin exposure suppressed colony-forming unit-granulocyte and monocyte formation in a dose-dependent fashion. Addition of antioxidants such as N-acetyl-cysteine could reverse the endotoxin suppression of colony-forming unit-granulocyte and monocyte formation (13 +/- 5 versus 75 +/- 5 colony-forming units/mL). Spontaneous in vitro granulocyte apoptosis in 6 h, as reflected by phosphatidylserine expression on the cell surface, was higher in granulocytes from HUCB than in those from adult blood (10.8 +/- 1.0% versus 5.6 +/- 1.2%). The addition of endotoxin or IL-8 to the cells in the in vitro model did not promote granulocyte apoptosis, but TNF-alpha, a major mediator of the effects of endotoxin, significantly induced granulocyte apoptosis in HUCB (control versus TNF-alpha: 8.9 +/- 1.2% versus 35.9 +/- 2.9%). Addition of the antioxidant N-acetyl-cysteine effectively blocked TNF-alpha-induced granulocyte apoptosis as demonstrated by DNA fragmentation. Results from these studies indicate that oxygen radicals are directly involved in endotoxin suppression of granulopoiesis, and indirectly promote granulocyte apoptosis, presumably through TNF-alpha-mediated action. Thus, under certain conditions, modulation of oxygen radical production in the blood may benefit neonates with granulocytopenia.

Superoxide reacts with nitric oxide to nitrate tyrosine at physiological pH via peroxynitrite.

Tyrosine nitration is a widely used marker of peroxynitrite (ONOO(-)) produced from the reaction of nitric oxide with superoxide. Pfeiffer and Mayer (Pfeiffer, S., and Mayer, B. (1998) J. Biol. Chem. 273, 27280-27285) reported that superoxide produced from hypoxanthine plus xanthine oxidase in combination with nitric oxide produced from spermine NONOate did not nitrate tyrosine at neutral pH. They suggested that nitric oxide and superoxide at neutral pH form a less reactive intermediate distinct from preformed alkaline peroxynitrite that does not nitrate tyrosine. Using a stopped-flow spectrophotometer to rapidly mix potassium superoxide with nitric oxide at pH 7.4, we report that an intermediate spectrally and kinetically identical to preformed alkaline cis-peroxynitrite was formed in 100% yield. Furthermore, this intermediate nitrated tyrosine in the same yield and at the same rate as preformed peroxynitrite. Equivalent concentrations of nitric oxide under aerobic conditions in the absence of superoxide did not produce detectable concentrations of nitrotyrosine. Carbon dioxide increased the efficiency of nitration by nitric oxide plus superoxide to the same extent as peroxynitrite. In experiments using xanthine oxidase as a source of superoxide, tyrosine nitration was substantially inhibited by urate formed from hypoxanthine oxidation, which was sufficient to account for the lack of tyrosine nitration previously reported. We conclude that peroxynitrite formed from the reaction of nitric oxide with superoxide at physiological pH remains an important species responsible for tyrosine nitration in vivo.

Granulocyte colony-stimulating factor in the cord blood of premature neonates born to mothers with pregnancy-induced hypertension.

OBJECTIVES: To estimate the cord blood levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in preterm infants and to study the relationship of these levels to pregnancy-induced hypertension (PIH) and absolute neutrophil counts. STUDY DESIGN: G-CSF and GM-CSF levels in the cord blood of preterm neonates (n = 74) either with or without maternal PIH were estimated by enzyme-linked immunosorbent assay. RESULTS: Infants in the PIH group had lower white blood cell, absolute neutrophil, absolute lymphocyte, and monocyte counts. The levels of G-CSF in cord blood were significantly lower in infants whose mothers had PIH (P =.04) and in infants with neutropenia (P =. 01). G-CSF levels were positively correlated with both absolute neutrophil count (P =.02) and total white blood cell count (P =.01). GM-CSF was undetectable in all subjects. According to logistic regression with neutropenia as the dependent variable, only maternal PIH (P <.001), gestational age (P <.001), and G-CSF (P =.01) were independently related. CONCLUSION: In this study maternal PIH and low gestational age were significantly associated with neutropenia in premature infants. Low G-CSF levels may contribute to the neutropenia that is commonly seen in infants born to mothers with PIH.

The human tail.

The human tail is a congenital anomaly with a protruding lesion from the lumbosacrococcygeal region. A newborn with a tail-like structure over the coccygeal area observed since birth is presented. Lipoma accompanied by tethered spinal cord were found. In reviewing the literature from 1960 to 1997, 59 cases were described. Higher incidences of spinal dysraphism (49.15%) and tethered spinal cord (20.34%) compared with previous reports were evident. This fact plays an important role in understanding the disturbance of development and regression of human tails. A new classification according to whether the anomaly appears in combination with spinal dysraphism is proposed for clinical usage. Preoperative detailed image studies are needed to clarify the possibility of tethered spinal cord syndrome developing in the future and thus prevent it. Magnetic resonance imaging is the modality of choice if available. Long-term follow-up for possible sequelae after operation, especially in cases with spinal dysraphism, is necessary.

Perinatal candidiasis and transient maternal candidemia: report of one case.

A premature infant who contracted candida pneumonia and candidemia early in the postnatal period was reported. Fungal hyphae was found in the pus-like gastric aspirate soon after birth, giving the first clue to the diagnosis and prompting an early institution of antifungal therapy. Maternal candidemia was documented in the immediate postpartum period, which resolved spontaneously without specific antifungal treatment.

Comparison of the outcome of extremely-low-birth-weight infants between two periods.

A comparison was made of the outcome of 73 neonates born with their birth weight of 500-999 gm in National Taiwan University Hospital during the period between January 1, 1993 and December 31, 1996 (Period II), with the outcome of 21 such neonates born between April 1, 1988 and October 31, 1992 (Period I). Exclusion criteria included parental refusal for resuscitation, and major anomalies. Data were collected via a predetermined record sheet. The incidences of the extremely-low-birth-weight infants were 23/10,173 (0.23%) and 81/13,835 (0.59%) in Periods I and II, respectively. Early neonatal mortality rate was significant decreased in Period II (43% versus 14%). The limit of viability was improved from gestational age of 26 weeks or 700 gm to gestational age of 24 weeks or 600 gm. The incidence of neonatal morbidity (80% versus 50%) and total survival rate (48% versus 60%) have not changed significantly as seen in this limited number of cases. This study concluded that, with the introduction of exogenous surfactant and modern neonatal care, early neonatal survival rate and the limit of viability were improved.

Optimal timing of retina examinations for premature infants.

Developments in modern neonatal intensive care have resulted in increased survival of very premature infants. Along with this increase in survival, there has been a concomitant increase in the frequency of retinopathy of prematurity (ROP). We investigated the relationship between the severity and the time course of ROP as well as the optimal time for retinal examinations of premature infants of various birth weights and gestational ages. A total of 80 premature infants were enrolled for analysis. The mean postnatal age of infants at the time of diagnosis was 7.3 +/- 3.4 weeks for stage 1 retinopathy, 9.2 +/- 5.8 for stage 2 retinopathy, 9.5 +/- 3.8 for stage 3 retinopathy, 10.7 +/- 3.7 for threshold disease, and 11.7 +/- 3.2 for stage 4 retinopathy. The mean postconceptional age of infants at the time of diagnosis was 35 +/- 3 for stage 1 retinopathy, 36.4 +/- 3 for stage 2 retinopathy, 37.6 +/- 3.5 for stage 3 retinopathy, 38.4 +/- 3.5 for threshold disease, and 40 +/- 3.7 for stage 4 retinopathy. The age at the time of the initial detection of ROP was from the ninth to 10th week among infants weighing less than 1,000 g at birth and from the fifth to seventh week among those weighing 1,000 g or more at birth. However, the postconceptional age at the time of initial detection of ROP for the whole group was 36 weeks and was not influenced by birth weight or gestational age. Therefore, we suggest that postconceptional age, rather than postnatal age, should be used to decide the timing of retinal examinations for premature infants.

Neurobehavioral development at term in very low-birthweight infants and normal term infants in Taiwan.

We compared the neurobehavioral performance at term between very low-birthweight (VLBW) infants and term infants in Taiwan, and investigated the relationships between neonatal factors and neurobehavioral performance in VLBW infants. Sixty VLBW infants and 58 healthy term infants were examined using the Neonatal Neurobehavioral Examination-Chinese version (NNE-C) at 40 weeks postmenstrual age. Medical records of the VLBW infants were reviewed to assess neonatal factors. The mean total score of the preterm infants (67.4+/-5.0) was significantly lower than that of the term infants (73.8+/-3.0) (t = 8.51, P < 0.0001). Furthermore, respiratory illness had a marginal effect on the rate of low neurobehavioral score (defined as 2SD below the mean score of term infants) in the preterm infants after adjustment for gestational age (odds ratio = 7.67, chi2 = 3.36, P = 0.067). Our findings indicate that preterm infants have lower neurobehavioral scores at term than their healthy term counterparts. Furthermore, respiratory illness may be a potential risk factor for low neurobehavioral score at term in preterm infants when gestational age is adjusted for.

Early outcome of extremely low birth weight infants in Taiwan.

We retrospectively evaluated the outcome and the risk factors for mortality among extremely low birth weight (ELBW) infants born at National Taiwan University Hospital. The records of all live-born infants with body birth weight of less than 1,000 g from January 1, 1993, to December 31, 1996, were evaluated. Infants with major anomalies or whose parents refused resuscitation were excluded from the analysis. There were 81 ELBW infants (0.59%) among a total of 13,835 live births during the study period, and 73 cases were enrolled for study. The mean gestational age (GA) was 27.2 (range, 24-34) weeks. Sixty-six percent of the ELBW infants were born by cesarean delivery. Respiratory distress syndrome occurred in 64% of infants and exogenous surfactant therapy was given to 47%, while intermittent mandatory ventilation was given to 85%. Symptomatic patent ductus arteriosus occurred in 34% of infants, septicemia in 30%, chronic lung disease in 48%, grade III to IV intraventricular hemorrhage in 27%, stage III to V retinopathy of prematurity in 33%, and necrotizing enterocolitis in 8%. Neonatal survival was 74%, survival to discharge was 60%, and intact survival was 50%. The survival rate was 40% for infants with a birth body of weight less than or equal to 750 g, and 68% for those with a birth body weight of greater than 750 g. While survival was 27% for infants with a GA of less than 26 weeks, it was 75% for those with a GA of greater than or equal to 26 weeks. The survival rate improved year by year for those with a GA less than 28 weeks. Cox regression analysis of survival showed that Apgar score at 1 minute (p = 0.0063), pulmonary hypertension (p = 0.012), and severe intraventricular hemorrhage (p = 0.0031) were the most important factors associated with mortality. Though the outcome of ELBW infants in our institute seems poorer than in some more developed countries, it is improving. The prognosis for ELBW infants of 24 to 25 weeks' GA remains guarded under our present care.

PIP: A review of the records of all live-born neonates with a birth weight below 1000 g born in 1993-96 at National Taiwan University Hospital was conducted, with emphasis on outcomes and risk factors for mortality. There were 81 extremely-low-birth-weight infants (0.59%) among the 13,835 live births recorded during the 3-year study period and, after exclusion of infants with major anomalies, 73 cases were enrolled for study. The mean gestational age was 27.2 weeks (range, 24-34 weeks). The most common complications of pregnancy leading to premature delivery were antepartum hemorrhage (44%) and pregnancy-induced hypertension. Respiratory distress syndrome occurred in 64%; exogenous surfactant therapy was provided to 47% and 85% received intermittent mandatory ventilation. Symptomatic patent ductus arteriosus occurred in 34% of infants, septicemia in 30%, chronic lung disease in 48%, grade III-IV intraventricular hemorrhage in 27%, stage III-V retinopathy of prematurity in 33%, and necrotizing enterocolitis in 8%. 54 infants (74%) survived the neonatal period and 44 (60.3%) survived until discharge. The survival rate was 40% for infants with a birth weight of 501-750 g and 68% for those weighing 751-999 g. Survival was 27% for infants with a gestational age under 26 weeks compared with 75% for those with a gestational age of 26 weeks and above. Cox regression analysis of survival indicated that Apgar scores at 1 minute, pulmonary hypertension, and severe intraventricular hemorrhage were the most significant contributing factors to mortality.

Long QT syndrome manifested as fetal ventricular tachycardia and intermittent AV block.

A case of long QT syndrome diagnosed in the early neonatal period is described. This full-term female baby had intermittent atrioventricular (AV) block and ventricular tachycardia detected antenatally at the gestational age of 26 weeks. Sinus rhythm with prolonged QT interval (QTc = 0.636 sec) was found soon after birth. She developed variable degree of AV block with alternating left and right bundle branch block, which suggested the presence of multilevel AV block. Her mother had no lupus autoantibodies. Auditory brain stem evoked potential was normal. Family study revealed QT prolongation in her grandmother. Her condition improved after pacemaker implantation and oral beta-blocker usage.

Successful arterial switch operation in a low-birth-weight neonate who had transposition of the great arteries and advanced necrotizing enterocolitis.

A low-birth-weight (LBW; 1,940 g) girl was born at the gestational age of 36 weeks without any perinatal insult. Transposition of the great arteries (TGA) with a large patent ductus arteriosus (PDA) and interatrial shunt was detected. Stage IIIB necrotizing enterocolitis (NEC) developed 46 hours after birth. She received ileostomy and drainage. Arterial switch operation was successfully performed at 23 days of age when her weight was 1,900 g. The enterostomy was successfully repaired at 104 days of age.

Jacobsen distal 11q deletion syndrome with a myelodysplastic change of hemopoietic cells.

We describe a male infant with unusual facial appearance, relative pancytopenia, bilateral simian creases, and an accessory nipple. Cytogenetic analysis showed deletion of the long arm of chromosome 11 [46,XY,del(11)(pter-->q23.2:)]. Bone-marrow study showed a myelodysplastic change of hemopoietic cells compatible with peripheral blood findings. Pachygyria of the temporal and frontal lobes was demonstrated by magnetic resonance image (MRI) of the brain. We present our findings in order to contribute to the information on 11q23 deletion.

Etiology and outcome of hydrops fetalis.

Hydrops fetalis is a morbid condition caused by a wide variety of diseases. Although treatment for some underlying pathologies is becoming available, the prognosis remains poor. To analyze the etiology and outcome of hydrops fetalis, we reviewed the records of 79 fetuses encountered at the National Taiwan University Hospital between January 1993 and October 1996. The mean +/- standard deviation gestational age at presentation was 24.9 +/- 6.3 weeks. One case was due to RhE incompatibility. Seventy-eight fetuses were diagnosed as having nonimmune hydrops fetalis; this was idiopathic in 20 fetuses. In the other 58, the causes and associated conditions were classified into eight groups: hematologic (25), cardiovascular (15), chromosomal (5), gastrointestinal (4), cystic hygroma (3), pulmonary (2), infection (2), and miscellaneous (3). One fetus with cystic hygroma also had a chromosomal abnormality (Turner's syndrome). The most common cause of nonimmune hydrops fetalis was homozygous alpha-thalassemia (31%). Twenty-nine fetuses were lost to follow-up after initial evaluation and 50 fetuses were delivered at our hospital. Of these, there were eight cases of antepartum death, 24 cases of intrapartum death, and 18 live births. Seventeen of the live-born infants were treated at our neonatal intensive care unit, of whom only seven survived.

Correlation between urinary epidermal growth factor excretion and serum thyroid hormone in premature and term neonates.

Eighty neonates, including 14 full-term, 31 premature, 27 twin or triplet, 6 small-for-gestational-age, and 2 infants with hyperthyroidism, were evaluated. The urinary epidermal growth factor/creatinine ratio (EGF/Cr) on the 1st postnatal day was not statistically different among full-term, premature, multiple-pregnancy, and small-for-gestational-age infants (F = 1.06, p = 0.6). There was no difference in urinary EGF/Cr between the 1st postnatal day and the 7th day (p = 0.4 by paired t test). The urinary EGF/Cr was not correlated with the serum thyroid-stimulating hormone level (r = -0.162, n = 60, p = 0.21), but showed a positive correlation with serum total T3 (r = 0.526, n = 60, p < 0.001) and with serum total T4 (r = 0.460, n = 60, p < 0.001). The correlation between urinary EGF/Cr and serum free T4 was even much better (r = 0.727, n = 25, p < 0.001). These results implicate that thyroid hormone may play a role in regulating urinary EGF excretion.

Retinopathy of prematurity in very-low-birthweight neonates: epidemiology and risk factors.

A retrospective study of 143 very-low-birthweight infants cared in a level III neonatal intensive care unit who had survived for at least 28 days. Initial eye ground evaluation was done at the postnatal age between 4 and 6 weeks. Follow-up evaluation was done every one to two weeks at the discretion of the ophthalmologists. Thirty-four variables were reviewed for each case. Statistical analysis was done for each variable, with the development of retinopathy of prematurity (ROP), severity of ROP and development of threshold ROP as the dependent variables, by Mann-Whitney U test or X2 test when adequate. Variables with P-valu < 0.05 were included in multiple regression. One hundred and thirty-eight cases were survived for more than 28 days with their eyes been checked. Twenty-six (18.8%) of them developed ROP. The prevalence of stage I was 2.2% (3/138), stage II was 3.6% (5/138), stage III was 12.3% (17/138), and stage V was 0.7% (1/138). Threshold disease, stage 3 (+) and above, was found in 5 cases (3.6%). Seventeen variables were found to be correlated with the development of ROP. Only the duration of continuous positive airway pressure (CPAP) was significantly correlated to the development of ROP in multivariate logistic regression. Fifteen variables were correlated with the severity of ROP, but only peak direct bilirublin level, peak total bilirubin level and duration of CPAP could entered multiple stepwise linear regression. Thirteen variables were correlated with the development of threshold ROP, but only episodes of septicemia enter the multivariate logistic regression. We postulate that the longer duration of CPAP in ROP cases may reflect the severity of apnea and episodes of hypoxic attacks. Reducing episodes of apnea may prevent the development of ROP. The number of episodes of septicemia was the only significant variable for threshold ROP so that infection control is important for the prevention of threshold disease.

Congenital short bowel syndrome with left acheiria: report of one case.

A case of congenital short bowel syndrome with left acheiria, hemivertebra and dextrocardia is described. Dilatation of the fetal bowel was observed at the 24th week of gestation during a routine ultrasonic scan of a healthy 23-year-old primigravida from a non-consanguineous marriage. Amniocentesis and chorionic villus sampling were denied. The baby was delivered at 38 weeks of gestational age. After delivery, multiple anomalies were noted: left acheiria, congenital short bowel syndrome (15 cm in length of the ileum), pseudo-obstruction of intestine, dextrocardia, and hemivertebrae. We suspected these abnormalities might be due to a vascular accident or failure of lateralization during the early gestational period. To our knowledge, these combinations have not been reported previously in English literature.