Delivery room resuscitation and adverse outcomes among very low birth weight preterm infants.

OBJECTIVE: To evaluate risk factors and impact of delivery room cardiopulmonary resuscitation (DR-CPR) on very low birth weight (VLBW) preterm infants. STUDY DESIGN: A national, population-based, observational study evaluating risk factors and short-term neonatal outcomes associated with DR-CPR among VLBW, extremely preterm infants (EPIs, 24 to 27 weeks' gestation) and very preterm infants (VPI, 28 to 31 weeks' gestation) born in 1995 to 2010. RESULTS: Among 17 564 VLBW infants, 636 (3.6%) required DR-CPR. In the group of 6478 EPI, 412 (6.4%) received DR-CPR compared with 224 of 11 086 infants (2.0%) in the VPI group. EPI who underwent DR-CPR had higher odds ratios (ORs (95% confidence interval)) for mortality compared to EPI not requiring DR-CPR (OR 3.32 (2.58, 4.29)), grades 3 to 4 intraventricular hemorrhage (IVH) (OR 1.59 (1.20, 2.10)) and periventricular leukomalacia (OR 1.81 (1.17, 2.82)). DR-CPR among VPI was associated with higher ORs for mortality (OR 4.99 (3.59, 6.94)), early sepsis (OR 2.07 (1.05, 4.09)), grades 3 to 4 IVH (OR 3.74 (2.55, 5.50)) and grades 3 to 4 retinopathy of prematurity (ROP) (OR 2.53 (1.18, 5.41)) compared to VPI not requiring DR-CPR. Only 11% of infants in the EPI DR-CPR group had favorable outcomes compared with 44% in the VPI DR-CPR group. Significantly higher ORs for mortality, IVH and ROP were found in the VPI compared to the EPI group. CONCLUSION: Preterm VLBW infants requiring DR-CPR were at increased risk of adverse outcomes compared to those not requiring CPR. This effect was more pronounced in the VPI group.

Perinatal health services organization for preterm births: a multinational comparison.

OBJECTIVE: To explore population characteristics, organization of health services and comparability of available information for very low birth weight or very preterm neonates born before 32 weeks' gestation in 11 high-income countries contributing data to the International Network for Evaluating Outcomes of Neonates (iNeo). STUDY DESIGN: We obtained population characteristics from public domain sources, conducted a survey of organization of maternal and neonatal health services and evaluated the comparability of data contributed to the iNeo collaboration from Australia, Canada, Finland, Israel, Italy, Japan, New Zealand, Spain, Sweden, Switzerland and UK. RESULTS: All countries have nationally funded maternal/neonatal health care with >90% of women receiving prenatal care. Preterm birth rate, maternal age, and neonatal and infant mortality rates were relatively similar across countries. Most (50 to >95%) between-hospital transports of neonates born at non-tertiary units were conducted by designated transport teams; 72% (8/11 countries) had designated transfer and 63% (7/11 countries) mandate the presence of a physician. The capacity of 'step-down' units varied between countries, with capacity for respiratory care available in <10% to >75% of units. Heterogeneity in data collection processes for benchmarking and quality improvement activities were identified. CONCLUSIONS: Comparability of healthcare outcomes for very preterm low birth weight neonates between countries requires an evaluation of differences in population coverage, healthcare services and meta-data.

Hypertensive disorders of pregnancy and outcomes of preterm infants of 24 to 28 weeks' gestation.

OBJECTIVE: To examine the relationship between hypertensive disorders of pregnancy (HDPs) and mortality and major morbidities in preterm neonates born at 24 to 28 weeks of gestation. STUDY DESIGN: Using an international cohort, we retrospectively studied 27 846 preterm neonates born at 240 to 286 weeks of gestation during 2007 to 2010 from 6 national neonatal databases. The incidence of HDP was compared across countries, and multivariable logistic regression analyses were conducted to examine the association of HDP and neonatal outcomes including mortality to discharge, bronchopulmonary dysplasia, severe brain injury, necrotizing enterocolitis and treated retinopathy of prematurity. RESULTS: The incidence of HDP in the entire cohort was 13% (range 11 to 16% across countries). HDP was associated with reduced odds of mortality (adjusted odds ratio (aOR) 0.77; 95% confidence interval (CI) 0.67 to 0.88), severe brain injury (aOR 0.74; 95% CI 0.62 to 0.89) and treated retinopathy (aOR 0.82; 95% CI 0.70 to 0.96), but increased odds of bronchopulmonary dysplasia (aOR 1.16; 95% CI 1.05 to 1.27). CONCLUSIONS: In comparison with neonates born to mothers without HDP, neonates of HDP mothers had lower odds of mortality, severe brain injury and treated retinopathy, but higher odds of bronchopulmonary dysplasia. The impact of maternal HDP on newborn outcomes was inconsistent across outcomes and among countries; therefore, further international collaboration to standardize terminology, case definition and data capture is warranted.

Risk factors associated with post-hemorrhagic hydrocephalus among very low birth weight infants of 24-28 weeks gestation.

OBJECTIVE: Post-hemorrhagic hydrocephalus (PHH) is associated with morbidity and mortality among very low birth weight (VLBW) infants. This study aimed to determine risk factors for PHH among VLBW infants with peri-intraventricular hemorrhage (PIVH). STUDY DESIGN: This is a population-based cohort of VLBW infants of 24 to 28 weeks gestation, born in Israel from 1995 to 2012. Infants in whom a brain ultrasound was not performed before 28 days or with major congenital malformations were excluded. Univariate and multivariable analyses identified risk factors associated with PHH. RESULTS: The final study cohort comprised 2811 infants with grade 2 or higher PIVH, of whom 610 (21.7%) developed PHH. PHH was independently associated with PIVH severity, with bilateral grade 3 PIVH and PIVH grade 3 and contralateral grade 4 having the highest risks (odds ratio (OR) 12.2, 95% confidence interval (CI) 8.56 to 17.4 and OR 13.7, 95% CI 9.4 to 20.1, respectively). Unilateral grade 3 or 4 PIVH's had moderately increased risks of PHH (OR 3.50, 95% CI 2.26 to 5.42 and OR 3.79, 95% CI 2.35 to 6.12, respectively). PHH was independently associated with increasing gestational age (GA) and with neonatal morbidities including patent ductus arteriosus (OR 1.47, 95% CI 1.15 to 1.88 if medically treated and OR 3.01, 95% CI 2.11 to 4.29 if surgically treated), sepsis (OR 1.79, 95% CI 1.44 to 2.22) and necrotizing enterocolitis (OR 1.60, 95% CI 1.18 to 2.17). CONCLUSIONS: Among VLBW infants with PIVH, PHH was independently associated with PIVH severity group, increasing GA and acute neonatal morbidities. Unilateral grade 3 or 4 PIVH was associated with a moderate risk of developing PHH compared with bilateral severe hemorrhages.

Antenatal corticosteroid treatment in singleton, small-for-gestational-age infants born at 24-31 weeks' gestation: a population-based study.

OBJECTIVE: To assess the impact of antenatal corticosteroid therapy on mortality and severe morbidities in preterm, small-for-gestational-age (SGA) neonates compared with preterm non-SGA neonates. DESIGN: Population-based study. SETTING/POPULATION: Israel National Very Low Birth Weight infant database from 1995-2012. METHODS: Singleton infants of 24-31 weeks' gestation, without major malformations. Antenatal corticosteroids were considered either any treatment or no treatment. MAIN OUTCOME MEASURES: Univariate and multivariable logistic regression analyses were performed to assess the effect of antenatal corticosteroids on neonatal mortality and a composite adverse outcome of mortality or severe neonatal morbidity. RESULTS: Among the 10 887 study infants, 1771 were SGA. Of these, 70.4% of SGA and 66.7% of non-SGA neonates were exposed to antenatal corticosteroids. Among SGA neonates, antenatal corticosteroids were associated with decreased mortality (32.2 versus 19.3%, P < 0.0001) and composite adverse outcome (54.1 versus 43.4%, P < 0.0001), similar to the effect in non-SGA neonates (mortality 26.7 versus 12.2%, P < 0.0001; composite outcome 50.5 versus 34.6%, P < 0.0001). Multivariable logistic regression analyses demonstrated a 50% reduction in mortality risk among SGA and 57% reduction in non-SGA neonates exposed to corticosteroids [OR = 0.50, 95% confidence interval (95% CI) 0.39-0.64 and OR = 0.43, 95% CI 0.38-0.47, respectively], P-value for interaction = 0.08. Composite adverse outcome risk was significantly reduced in SGA (OR = 0.67, 95% CI 0.54-0.83) and non-SGA infants (OR = 0.57, 95% CI 0.52-0.63), P-value for interaction = 0.04. CONCLUSIONS: Antenatal corticosteroids significantly reduced mortality and severe morbidities among preterm SGA neonates, with slightly a less pronounced effect compared with non-SGA preterm infants. Antenatal corticosteroids should be given to fetuses suspected of intrauterine growth retardation, at risk for preterm delivery, in order to improve perinatal outcome. TWEETABLE ABSTRACT: Antenatal steroids reduced mortality and severe morbidities among singleton, preterm SGA neonates.

Perinatal factors associated with active intensive treatment at the border of viability: a population-based study.

OBJECTIVE: The aim of this national population-based study was to identify perinatal and neonatal factors associated with active intensive treatment (AIT) of infants born at the periviable period of 22 to 24 weeks of gestation. STUDY DESIGN: Data from the Israel national very low-birth weight infant database on 2207 infants born alive in 1995 to 2010 at gestational age (GA) 22 to 24 weeks were evaluated. AIT was defined as endotracheal intubation in the delivery room or mechanical ventilation in the neonatal intensive care unit. Multivariable logistic regression analyses were used to identify the independent effect of demographic and perinatal factors on AIT for each gestational week. RESULT: Of the 2207 infants born at 22 to 24 weeks GA, 1643 (74.4%) received AIT and 564 (25.6%) received comfort care. AIT increased from 25.5% at 22 weeks to 62.7 and 93.5% at 23 and 24 weeks GA, respectively, reflecting a 4.66 (95% confidence interval (CI) 3.32 to 6.54)- and 29.8 (95% CI 19.9 to 44.6)-fold odds for AIT at 23 and 24 weeks GA, respectively, compared with 22-week GA infants. Perinatal treatments associated with AIT included maternal tocolytic therapy (odds ratio (OR) 1.51, 95% CI 1.04 to 2.20), prenatal steroid therapy, both partial (OR 3.30, 95% CI 2.14 to 5.10) and complete (OR 3.17, 95% CI 1.91 to 5.26) and cesarean delivery (OR 2.68, 95% CI 1.88 to 3.83). Each unit increase in birth weight z-score was associated with an OR of 1.58 (95% CI 1.30 to 1.92) for AIT. At 22 weeks GA, maternal tocolytic treatment was associated with higher odds of AIT. In the 23 and 24-week GA infants, maternal infertility treatment, antenatal steroids, cesarean delivery and higher-birth weight z-scores were significantly associated with AIT. Among 23-week GA infants, AIT decreased significantly in the period 2006 to 2010 compared with 1995 to 2000 (OR 0.51, 95% CI 0.34 to 0.77). CONCLUSION: An active approach in obstetric management of pregnancies appears to impact the neonatologists' decision to undertake AIT treatment in infants born at the border of viability. The higher odds for AIT associated with obstetric interventions might contribute to the reported beneficial effect of antenatal steroids and cesarean delivery on the survival of infants born at the border of viability.

Congenital malformations in infants conceived following assisted reproductive technology in comparison with spontaneously conceived infants.

OBJECTIVE: To evaluate the risk for congenital malformations diagnosed at birth following assisted reproductive technology (ART) treatments compared with live births conceived spontaneously. METHODS: A retrospective cohort study including 9042 live births following ART and 213 288 spontaneously conceived (SC) live births during the period 1997-2004.The cohort was linked to the national live birth registry to determine the outcome of the pregnancies including congenital malformations. RESULTS: An increased adjusted risk for all congenital malformations was observed in ART compared with SC infants [2.4% versus 1.9%; ORadj = 1.45; 95% CI: 1.26, 1.68]. The increased risk was observed in singleton births [2.4% versus 1.8%; ORadj = 1.41; 95% CI: 1.14, 1.71] but not in the ART conceived multiple births [2.5% versus 2.6%.; ORadj = 1.15; 95% CI: 0.90, 1.46]. Significantly increased adjusted risks for nervous, circulatory, digestive and genital system malformations were evident in the ART singleton group compared to SC infants. In addition, increased risks were also observed in separate comparisons of IVF births versus SC [ORadj = 1.28; 95% CI: 1.00, 1.63] and ICSI births versus SC [ORadj = 1.56; 95% CI: 1.31, 1.84]. Data regarding pregnancy termination or congenital malformation diagnosed later in life were not included. CONCLUSION: Infants born following ART were at significantly increased risk for congenital malformations compared to live birth conceived spontaneously.

Maternal and neonatal health outcomes following assisted reproduction.

This study assessed the risk for maternal complications in women and neonatal outcomes in children conceived following assisted reproductive treatment as compared with spontaneously conception and also separately evaluated conventional IVF and intracytoplasmic sperm injection (ICSI). The prospective cohort included 1161 women with singleton pregnancies: 561 who conceived following assisted reproduction (223 following IVF and 338 following ICSI) and 600 who conceived spontaneously. No differences were observed in pregnancy complications (including spontaneous abortion, pregnancy-induced hypertension, gestational diabetes and Caesarean delivery) except for significantly increased risk for excess vaginal bleeding in assisted reproduction pregnancies (21.4% versus 12.9%; OR 1.67, 95% CI 1.18-2.37), which was prominent in women who reported polycystic ovary syndrome. Neonates born following assisted reproduction had increased risk for prematurity (10.6% versus 5.3%; OR 1.72, 95% CI 1.04-2.87), and IVF, but not ICSI, was associated with significantly increased risk for prematurity (OR 2.36, 95% CI 1.28-4.37) and low birthweight (OR 1.89, 95% CI 1.03-3.46). In conclusion, this study observed only an increased risk for excess vaginal bleeding as a pregnancy-associated complication in singleton pregnancies following assisted compared with spontaneous conception. However, singleton neonates born following IVF, but not ICSI, were at increased risk for prematurity.

Primary aortoduodenal fistula in combination with aortoiliac occlusive disease: report of a rare case.

Most of the cases of aortoenteric fistula are due to aneurysm of the aorta, although infection, tumor, radiotherapy, gastric ulcers and foreign body ingestion have also been described in the literature. We report the case of a 62-year-old woman presenting with massive gastrointestinal bleeding with hematemesis and melaena. This case is unique in that the primary aortoduodenal (PADF) fistula formed as a result of complex atherosclerotic disease of the abdominal aorta and both iliacal arteries, also known as Leriche's syndrome, and not primarily due to an aneurysm. We will give a brief summary of the difficulties and challenges which the surgeon faced during the operation and a surprisingly uneventful postoperative course.

Management of problems related to the new morbidity by community-based paediatricians in Israel.

OBJECTIVES: To assess community-based paediatricians' management of clinical situations, particularly those related to the new morbidity (NM), such as chronic disease, developmental, behavioural, and psychosocial problems, and to identify the main associated factors. METHODS: The study population included all community-based paediatricians employed by Israel's two largest health maintenance organizations in the central and southern regions of the country (n= 574; 74% response rate). Using a self-administered questionnaire including 20 vignettes describing common clinical situations (14 related to NM; 6 related to classic paediatrics (CP)), physicians reported how they would manage each situation and how they perceived their role in managing such problems. RESULTS: Paediatricians were less likely to take an active role in managing NM-related problems than CP-related problems (68.3% vs. 93.2%; P < 0.001). In most NM situations, when paediatricians regarded the problem as part of their role, they were more likely to either manage the problem by themselves or with the help of other professionals. A multivariable linear regression model, adjusting for demographic, practice and training characteristics indicated the following predictive factors for taking an active role in managing NM (P < 0.001): practicing in the periphery, consulting with non-medical community-based professionals and combining community and hospital practice. CONCLUSIONS: To assure comprehensive paediatric care, simultaneous modification of paediatricians' residency training, practice environment and role perception are required.

Prevalence of overweight in kindergarten children in the centre of Israel - association with lifestyle habits.

OBJECTIVES: (1) To determine the prevalence of overweight and at risk for overweight in a sample of 4- to 6-year-old Israeli children; and (2) to delineate factors which may be associated with excess of overweight such as food intake, food habits physical and sedentary activity, family and socio-economic factors. METHODS: In a cross-sectional survey in six kindergartens in the centre of Israel, 204 children (104 boys), mean age 5.5 years were studied. RESULTS: In total, 40% of the children were either at risk for overweight (25%) or overweight (15%). Parents of one-third of all children reported their children ate unbalanced meals; however, caloric intake was not different between the weight groups. Overweight children were reported to eat according to mood status and preferred eating candies. Knowledge of dietary requirements was fairly good and similar in all three weight groups. Screen viewing time was more than twofold greater than the recommended in all weight groups. The rate of parental obesity was not different in the weight groups. CONCLUSIONS: A high rate of overweight was documented among pre-schoolers in the centre of Israel. Poor lifestyle habits were noted in about one-third of all children; however, no association was found between the poor lifestyle habits and overweight but more overweight children eat according to mood status and preferred eating candies as a snack.

Less postnatal steroids, more bronchopulmonary dysplasia: a population-based study in very low birthweight infants.

OBJECTIVE: To study the association between reduced use of postnatal steroids for bronchopulmonary dysplasia (BPD) in very low birthweight (VLBW) infants and oxygen (O(2))-dependency at 28 days of age and at 36 weeks postmenstrual age. DESIGN: Large national database study. SETTING: The Israel National VLBW Neonatal Database. PATIENTS: The sample included infants born between 1997 and 2004, of gestational age 24-32 weeks, who required mechanical ventilation or O(2) therapy. Four time periods were compared: 1997-8 (era 1, peak use), 1999-2000 (era 2, intermediate), 2001-2 (era 3, expected reduction) and 2003-4 (era 4, lowest). The outcome variable "oxygen dependency" was based on clinical criteria. Multivariate regression models were used to account for confounding variables. RESULTS: Steroid use fell significantly from 23.5% in 1997-8 to 11% in 2003-4 (p<0.005). After adjustment for relevant confounding variables, the odds ratio for O(2) therapy at 28 days in era 4 versus era 1 was 1.75, 95% confidence interval (CI) 1.47 to 2.09 and 1.41, 95% CI 1.15 to 1.73 at 36 weeks postmenstrual age. The mean duration of O(2) therapy increased from 25.3 days (95% CI 23.3 to 26.3) in era 1, to 28.0 days (95% CI 26.6 to 29.4) in era 4. Survival increased from 78.5% in era 1 to 81.6% in era 4 (p<0.005). CONCLUSIONS: The use of steroids has fallen considerably since the awareness of the adverse effects of this treatment. This change has been temporally associated with increased O(2) dependency at 28 days of age and at 36 weeks postmenstrual age. The prolongation of O(2) therapy was modest in degree.

Bronchopulmonary dysplasia in very low birth weight infants is associated with prolonged hospital stay.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with prolonged hospital length of stay (LOS) and delayed discharge home. OBJECTIVES: To evaluate the association between BPD and LOS and to assess the contribution of concomitant major morbidities on LOS among infants with BPD. STUDY DESIGN: A population-based observational study of very low birth weight (VLBW) infants born from 1995 through 2003. Multivariate analyses, adjusted for perinatal variables, assessed the association between BPD and concomitant morbidities on LOS. RESULTS: Of 10 134 survivors, 1926 (19.0%) had BPD. The adjusted LOS for infants with and without BPD was 84.1 days (95% CI, 82.8, 85.6) and 58.1 days (95% CI, 57.2, 59.0), respectively. Addition of a single concomitant morbidity increased mean LOS by 4 to 13 days. CONCLUSIONS: BPD is a major cause of increased length of hospitalization among VLBW infants. Preventive or therapeutic modalities are required to reduce the significant burden of this condition.

Health-related quality of life among children and adolescents: associations with obesity.

OBJECTIVE: To assess the impact of obesity on health-related quality of life (HRQOL) of children, and to compare HRQOL scores of obese children in a hospital versus community setting. DESIGN: A cross-sectional study in two clinical samples. SUBJECTS: A total of 182 children and adolescents recruited from the community pediatric clinics and a hospital-based obesity clinic. MEASUREMENTS: Obesity was defined as body mass index (BMI) >95th percentile for age and gender. Subjects were divided into quartiles of BMI Z-scores each containing 45 or 46 children. The first two quartiles correspond to normal BMI, 3rd and 4th quartiles represent moderate and severe obesity, respectively. HRQOL was assessed by the Pediatric Quality of Life Inventory (PedsQL) questionnaire submitted by both children and their parents. RESULTS: Obese children reported significantly lower HRQOL in physical, social and school domains compared with normal weight children (P<0.01). Analyzing results of HRQOL by BMI quartiles showed that the emotional and school domains scores of the moderately obese children were similar to the normal BMI quartiles. Only in the 4th quartile, that of children with severe obesity, were scores significantly lower. In contrast, in both physical and social domains scores decreased progressively with increased BMI Z-scores. In the obese group, parents' scores were lower than the children's in all domains. HRQOL scores of obese children assessed in the hospital clinic were similar to that of obese children assessed in the community. CONCLUSIONS: Moderately obese children had similar emotional and school HRQOL scores as normal weight children, whereas in the physical domain, a significant difference was documented even in moderate obesity. Parents of obese children perceived their child's HRQOL lower than the children themselves. We believe that intervention programs aimed at improving HRQOL should be directed to both parents and children. Understanding the resilience of moderately obese children in school and emotional domains may assist us in the management of childhood obesity.

Effect of birth order on neonatal morbidity and mortality among very low birthweight twins: a population based study.

OBJECTIVE: To study the effect of birth order on the risk for respiratory distress syndrome (RDS), chronic lung disease (CLD), adverse neurological findings, and death in very low birthweight (VLBW; < 1500 g) twins. METHODS: A population based study of VLBW infants from the Israel National VLBW Infant Database. The sample included all complete sets of VLBW twin pairs admitted to all 28 neonatal intensive care units between 1995 and 1999. Outcome variables were compared by birth order and stratified by mode of delivery and gestational age, using General Estimating Equation models, with results expressed as odds ratio (OR) with 95% confidence interval (CI). RESULTS: Second twins were at increased risk for RDS (OR 1.51, 95% CI 1.29 to 1.76), CLD (OR 1.36, 95% CI 1.11 to 1.66), and death (OR 1.24, 95% CI 1.02 to 1.51) but not for adverse neurological findings (OR 1.20, 95% CI 0.91 to 1.60). Mode of delivery did not significantly influence outcome. The odds ratio for RDS in the second twin was inversely related to gestational age, and the increased risk for RDS and CLD was found in both vaginal and caesarean deliveries. CONCLUSIONS: VLBW second twins are at increased risk for acute and chronic lung disease and neonatal mortality, irrespective of mode of delivery.

Effect of ethnicity on mortality of very low birthweight infants in Israel.

BACKGROUND: Multiple demographic, genetic, and environmental factors differ between Muslim and Jewish infants in Israel. OBJECTIVE: To evaluate whether, after adjustment for perinatal factors associated with mortality, excess mortality occurs in very low birthweight (VLBW) Muslim compared with Jewish infants. DESIGN: The Israel National VLBW infant database includes data on 99% of all VLBW births in Israel. The study population comprised 5015 Jewish and 1549 Muslim VLBW infants of more than 23 weeks gestation, born between 1995 and 1999. The Mantel-Haenszel test was used for stratified analysis and logistic regression analysis to assess the effect of ethnic origin on mortality. RESULTS: The death rate was significantly higher among Muslim infants (22.7% v 17.2%; crude odds ratio 1.42; 95% confidence interval 1.24 to 1.63). Excess mortality in Muslims occurred mainly in the 32-33 week (8.0% v 2.8%) and >33 week (14.7% v 4.7%) gestational age groups, and in birthweight groups of 1000-1249 g (17.6% v 9.3%) and 1250-1500 g (9.1% v 3.6%). In VLBW infants without congenital malformations, there was a significantly higher risk of mortality among Muslim infants (odds ratio 1.28; 95% confidence interval 1.04 to 1.57) compared with Jewish infants, after adjustment for gestational age, birth weight, small for gestational age, prenatal care, prenatal steroid treatment, plurality, mode of delivery, and Apgar score. CONCLUSIONS: Excess mortality was present among Muslim VLBW infants without congenital malformations. Perinatal factors associated with increased risk of mortality were more prevalent in the Muslim VLBW population. The pattern of disparities suggests inadequate access to, or utilisation of, effective perinatal technology in the Muslim population in Israel.

Excess risk of mortality in very low birthweight triplets: a national, population based study.

BACKGROUND: Neonatal morbidity and mortality differ between singletons, twins, and triplets. OBJECTIVE: To evaluate whether plurality is associated with excess risk of neonatal morbidity and poor outcome (death, chronic lung disease, or adverse neurological findings) in very low birthweight (VLBW) infants from a national, population based cohort. METHODS: The Israel national VLBW infant database has prospectively collected extensive perinatal and neonatal data on all liveborn VLBW infants since 1995. The study sample (n = 5594) consisted of all singletons (n = 3717) and all complete sets of twins (n = 1394) and triplets (n = 483) born during 1995-1999. To account for differences in case-mix, both univariate and multivariate comparisons that included confounding variables such as antenatal steroid treatment and mode of delivery were performed for each of the outcome variables. RESULTS: There was a small inverse correlation between gestational age (GA) and birth weight (BW) and the number of fetuses (singletons: GA 28.9 (2.6) weeks, BW 1096 (269) g; twins: GA 28.4 (2.3) weeks, BW 1062 (271) g; triplets: GA 28.5 (2.4) weeks, BW 1049 (259) g). Triplets were significantly more likely to have been conceived following fertility treatments, to have received antenatal steroids, and to be delivered by caesarean section. Respiratory distress syndrome was significantly more common in twins and triplets in spite of the increased exposure to antenatal steroids. Multivariate logistic regression analysis using all significant perinatal covariates showed that triplets were at increased risk of death (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.13 to 2.11), but not of adverse neurological outcome (OR 1.29, 95% CI 0.91 to 1.85) or chronic lung disease (OR 0.69, 95% CI 0.46 to 1.02). CONCLUSION: Despite considerable differences in the incidence of confounding variables between the groups, VLBW triplets are at increased risk of death compared with twins and singletons. In addition, VLBW twins and triplets more often have respiratory distress syndrome but not chronic lung disease or adverse neurological findings.

Effect of maternal tocolysis on the incidence of severe periventricular/intraventricular haemorrhage in very low birthweight infants.

AIM: To examine the relation between grade III-IV periventricular/intraventricular haemorrhage (PVH/IVH) and antenatal exposure to tocolytic treatment in very low birthweight (VLBW) premature infants. STUDY DESIGN: The study population consisted of 2794 infants from the Israel National VLBW Infant Database, of gestational age 24-32 weeks, who had a cranial ultrasound examination during the first 28 days of life. Infants of mothers with pregnancy induced hypertension or those exposed to more than one tocolytic drug were excluded. Of the 2794 infants, 2013 (72%) had not been exposed to tocolysis and 781 (28%) had been exposed to a single tocolytic agent. To evaluate the effect of tocolysis and confounding variables on grade III-IV PVH/IVH, the chi(2) test, univariate analysis, and a logistic regression model were used. RESULTS: Of the 781 infants (28%) exposed to tocolysis, 341 (12.2%) were exposed to magnesium sulphate, 263 (9.4%) to ritodrine, and 177 (6.3%) to indomethacin. The overall incidence of grade III-IV PVH/IVH was 13.4%. In the multivariate logistic regression analysis, the following factors were related significantly and independently to grade III-IV PVH/IVH: no prenatal steroid treatment, low gestational age, one minute Apgar score 0-3, respiratory distress syndrome, patent ductus arteriosus, mechanical ventilation, and pneumothorax. Infants exposed to ritodrine tocolysis (but not to the other tocolytic drugs) were at significantly lower risk of grade III-IV PVH/IVH after adjustment for other variables (odds ratio = 0.3; 95% confidence interval 0.2 to 0.6). CONCLUSION: This study suggests that antenatal exposure of VLBW infants to ritodrine tocolysis, in contrast with tocolysis induced by magnesium sulphate or indomethacin, was associated with a lower incidence of grade III-IV PVH/IVH.

5-year results of dose-intensive sequential adjuvant chemotherapy for women with high-risk node-positive breast cancer: A phase II study.

PURPOSE: We conducted a phase II pilot study of dose-intensive adjuvant chemotherapy with doxorubicin followed sequentially by high-dose cyclophosphamide to determine the safety and feasibility of this dose-dense treatment and to estimate the disease-free and overall survival in breast cancer patients with four or more involved axillary lymph nodes. PATIENTS AND METHODS: Seventy-three patients received adjuvant treatment with four cycles of doxorubicin 75 mg/m(2) as an intravenous bolus every 21 days, followed by three cycles of cyclophosphamide 3,000 mg/m(2) every 14 days with granulocyte colony-stimulating factor support. RESULTS: Seventy-one patients were assessable, and all but two completed all planned chemotherapy. There was no treatment-related mortality. The most common toxicity was neutropenic fever, which occurred in 39% of patients. Median disease-free survival is 66 months (95% confidence interval, 34 to 98 months), and median overall survival has not yet been reached. At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. There is no long-term treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSION: Our pilot study of doxorubicin followed by cyclophosphamide demonstrates the safety and feasibility of the sequential dose-dense plan. Long-term follow-up, although noncomparative, is promising. However, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose and schedule of doxorubicin and cyclophosphamide, and therefore it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials testing the dose-dense approach have been completed but not yet reported. Because the sequential plan can decrease overlapping toxicities, it is an appropriate platform for the addition of newer active agents, such as taxanes or monoclonal antibodies.

Unexplained fever in neonates may be associated with hepatitis B vaccine.

AIM: To investigate whether hepatitis B vaccination has increased the number of cases of unexplained neonatal fever. METHOD: The files of all infants born from 1 January 1991 to 31 December 1992, in whom a diagnosis of "injected antibiotic" or "disease of temperature regulation" was recorded, were reviewed. Those who had unexplained fever of 38 degrees C or higher during the first three days of life were divided into two groups: infants who did not receive the hepatitis B vaccine (1991) and infants who did (1992). RESULTS: In 1992 the incidence of unexplained fever in hepatitis B vaccinated neonates was significantly higher than in the 1991 group of pre-vaccination neonates (35 out of 5819 (0.6%) vs 14 out of 5010 neonates (0.28%) respectively, p=0.013). CONCLUSIONS: The increase in the number of cases of unexplained neonatal fever seems to be associated with the introduction of routine hepatitis B vaccination on the first day of life. The possibility that an excess number of neonates will undergo unnecessary procedures and treatment to diagnose unexplained fever justifies planning a controlled study to determine whether these preliminary findings point to a significant problem.