Maternal versus fetal inflammation and respiratory distress syndrome: a 10-year hospital cohort study.

OBJECTIVES: To determine the impact of maternal and fetal intrauterine inflammatory responses (chorioamnionitis and umbilical vasculitis) on the development of neonatal respiratory distress syndrome (RDS) in preterm infants. DESIGN, SETTING AND SUBJECTS: The study included all infants <30 weeks' gestation born at the Royal Prince Alfred Hospital, Sydney, Australia, and admitted to neonatal intensive care from 1992 to 2001. Those without placental examination were excluded. Antenatal and perinatal data were extracted from prospectively kept hospital databases and correlated with the independent, central neonatal database. Placentae were examined prospectively using a standardised, semi-quantitative method. MAIN OUTCOME MEASURE: A diagnosis of neonatal RDS. RESULTS: There were 766 eligible babies and 724 (94.5%) had placental examination. The mean (SD) gestational age of the cohort was 27.1 (1.6) weeks. Antenatal maternal steroids were given to 93.6%. Histological chorioamnionitis alone was evident in 19.1% of infants, and chorioamnionitis with umbilical vasculitis in 30.2%. Regression analysis showed that increasing gestational age (adjusted odds ratio (OR) 0.72, 95% CI 0.64 to 0.81), chorioamnionitis (adjusted OR 0.49, 95% CI 0.31 to 0.78), and chorioamnionitis with umbilical vasculitis (adjusted OR 0.23, 95% CI 0.15 to 0.35) were associated with a significant reduction in RDS. Factors associated with increased odds of RDS were multiple gestation (twin or triplet pregnancies), pregnancy-induced hypertension and an Apgar score <4 at 1 minute. CONCLUSIONS: Maternal and fetal intrauterine inflammatory responses are both protective for RDS. The presence of chorioamnionitis with umbilical vasculitis is associated with a markedly greater reduction of RDS than chorioamnionitis alone.

Resuscitation beyond 10 minutes of term babies born without signs of life.

OBJECTIVE: To obtain population-based data on babies who were admitted to a neonatal intensive care unit despite having Apgar scores of 0 up to and including 10 min, and to document their outcomes. We aimed also to review other studies where outcomes following a 10-min Apgar score of 0 were described, and to combine them with own results. Current recommendations regarding the discontinuation of resuscitation will be reconsidered in light of these results. METHODS: In order to obtain population-based data for babies born in New South Wales (NSW), a request was made to the NSW Neonatal Intensive Care Unit Study (NICUS) directors to allow identification of babies in the NICUS database with Apgar scores of 0 at both 1 and 5 minutes. Individual directors were then asked to determine from their hospital records, which of these babies had a 10-minute Apgar of 0, and to provide the results of follow-up assessments of any survivors in this subgroup. RESULTS: Twenty-nine full-term newborns with a 10-minute Apgar score of 0 were identified. Twenty of the 29 babies died before leaving hospital. Of the 9 who were discharged alive, eight had severe disability and one had moderate disability. Thus death or severe disability occurred in 28/29 (97%), and death or any disability in 100%. Combining with other published studies, death or severe disability occurred in 63/64 (98%). CONCLUSION: The above findings strongly support the discontinuation of resuscitation if a baby remains asystolic at 10 minutes.

How well do diagnosis-related groups perform in the case of extremely low birthweight neonates?

OBJECTIVE: To determine how well diagnosis related groups (DRG) perform for extremely low birthweight neonates, by examining length of stay (LOS) data for babies with birthweight of 750-999 g and managed in the seven New South Wales maternity hospital neonatal intensive care units (NICU). METHODOLOGY: Neonates with an admission weight of 750-999 g and admitted to one of the seven NICU were studied. Those who died or were transferred in the first 5 days were excluded, leaving the group of neonates defined by DRG P62Z. In order to allow comparisons between the different NICU, neonates whose care was split between two or more NICU were also excluded, leaving those who either died, were transferred to a nursery closer to their home or were discharged directly to their home. The relationship between LOS and a number of perinatal factors was studied for the total group, and LOS data were compared for individual hospitals. RESULTS: Length of stay was most strongly associated with mode of separation. It was also significantly associated with gestational age, time ventilated, oxygen need at 36 weeks postconceptual age, and retinopathy of prematurity. Neonatal intensive care units with the highest proportion of neonates being transferred had the lowest average LOS, and vice versa. CONCLUSIONS: The LOS of neonates in DRG P62Z is more strongly related to mode of separation (died, transferred or discharged home) than to factors that reflect best practice. A funding model that rewards NICU for a short LOS may unfairly disadvantage some units while favouring others.

Predicting the need for ventilatory support in neonates 30-36 weeks' gestational age.

OBJECTIVES: To determine antenatal factors associated with the need for ventilatory support in babies born between 30 and 36 weeks gestational age and use this information to help referring obstetricians decide which mothers need antenatal transfer. METHODS: Babies born at Royal Prince Alfred Hospital at 30-36 weeks' gestation inclusive between January 1992 to December 1999 were identified in the obstetric and neonatal databases. Information for a wide range of antenatal factors and respiratory outcomes was extracted. Babies with major congenital anomalies were excluded. Statistical analysis using spss for Windows was then undertaken. RESULTS: Data were available for 3102 babies. On univariate analysis, seven factors were significant. Lower gestational age, absence of labour, Caesarean section, antepartum haemorrhage, breech presentation and hypertensive disease of pregnancy were associated with increased risk, while threatened premature labour was protective. On logistic regression analysis, gestational age and absence of labour dominated the model. Other significant factors in the model had a relatively minor impact. CONCLUSIONS: The risk of needing ventilatory support according to antenatal risk factors is described for infants born between 30 and 36 weeks. Gestational age and absence of labour were found to be the major determinants of risk. Delivery without labour increased the risk by the equivalent of about 2 weeks of gestation. For example, to avoid a risk > 20%, the cut off is 33 weeks for mothers who labour, but is increased to 35 weeks when there is no labour. Our results should be interpreted with caution, as the patients in a tertiary obstetric unit may not be typical of the wider community.

Risk of hepatitis C virus infection in multiply transfused premature neonates.

BACKGROUND: Reports from around the world indicate that multiply transfused patients are at increased risk of hepatitis C virus (HCV) infection, with reported rates of between 4% and 44%. Such reports are mostly of haematological and renal patients. As recipients of blood products in the newborn period, premature infants share this risk, but there is little information regarding their risk. AIM: To assess the risk of HCV infection in children who, as premature neonates, received multiple blood products prior to the introduction of screening of donated blood for HCV. METHODS: Premature infants born between January 1985 and January 1990 who had attended our high-risk follow-up clinic were selected on the basis of the number of transfusions of blood, platelets or fresh frozen plasma they received in the newborn period. Ethical approval to offer HCV testing to parents was obtained from the Central Sydney Area Health Service Ethics Review Committee. Parents of infants who received three or more transfusions were then contacted by mail with the approved letter explaining the study, and offered HCV testing. Detection of anti-HCV antibodies was undertaken using second, and later third generation enzyme immunoassay kits. Samples which were found to be 'indeterminate' were tested using a Wellcozyme HCV western blot assay (Murex Diagnostics Ltd, Datford, UK). Hepatitis C virus-ribonucleic acid (RNA) was detected using an 'in-house' polymerase chain reaction (PCR) assay. Alanine transaminase (ALT) was also measured, with values above 55 U/L considered abnormal. RESULTS: Consent was obtained for 45 children (25 males, 20 females). The mean (+/- SEM) gestational age and weight of the children at birth was 26.7 +/- 0.2 weeks and 938 +/- 27 g, respectively. The children received 198 transfusions of blood products, an average of 4.4 U per child. All of the infants except for one were negative for anti-HCV antibodies. One infant was 'indeterminate' (low positive on third generation test but negative on second generation test), but proved negative subsequently on both western blot and PCR testing. HCV-RNA was not detected in any of the infants on PCR testing. All of the samples had normal ALT values, the mean being 16 U/L (range 8-52). CONCLUSION: None of the children consenting to this study had evidence of current HCV infection. Because of the sample size, we were not able to estimate the true risk of infection from this study, except that the upper limit for the risk is about 1/200 per transfused blood sample.

Hepatitis C in injecting drug-using women during and after pregnancy.

BACKGROUND: A high proportion of female injecting drug users (IDU) have evidence of hepatitis C virus (HCV) infection. We undertook a prospective study of patients attending a clinic for pregnant IDU to determine the impact of pregnancy on the course of HCV infection and whether pregnancy is affected by HCV infection. METHODS: One hundred and thirty-one IDU were recruited and followed up with liver function tests, HCV serology and HCV-RNA tests. RESULTS: Of 131 patients, 125 had HCV antibodies (anti-HCV positive) at delivery, and of these 62% were HCV-RNA positive. The anti-HCV-negative women were younger and had a shorter duration of drug use than the anti-HCV-positive women. There were no differences between viraemic and non-viraemic women with respect to age, ethnicity, duration of injecting drug use, methadone maintenance dose, hepatitis B exposure or reported high-risk behaviour. Alanine aminotransferase (ALT) levels were higher and the proportion with ALT > 55 IU/L higher in viraemic women. Viraemia persisted in all 55 women who were viraemic at term. Eleven had an ALT flare post-partum that was unrelated to viral load and was clinically unsuspected. Four had concurrent elevated gamma-glutamyltranspeptidase and were considered to be drinking alcohol at hazardous levels. Four of 23 women who were HCV-RNA negative at term became positive during follow up. CONCLUSIONS: Pregnancy does not adversely affect the course of hepatitis C. A modest rebound in ALT levels, but not HCV-RNA, occurs after delivery in some viraemic women. This supports the theory that immune mechanisms rather than direct viral cytopathology are involved in hepatocyte injury during HCV infection. Hepatitis C infection did not influence pregnancy complications and outcomes.

Short- and long-term neurological outcomes following neonatal chest physiotherapy.

OBJECTIVE: To test the hypothesis that chest physiotherapy in extremely premature infants is associated with abnormal neurological outcomes. METHODS: All babies born during the years 1992-1994 at gestations of 24-29 weeks who survived to 28 days were included in the study cohort (n=213). Chest physiotherapy was provided by trained physiotherapists for babies with secretions causing obstruction to the airway or for babies with evidence of collapse and/or consolidation. The relationship between chest physiotherapy and cystic brain lesions at discharge, or cerebral palsy (CP) and developmental quotient (DQ) at 1 year corrected age, were then explored. RESULTS: Ninety-seven babies (45% of the cohort) received physiotherapy. No baby had a brain lesion similar to that described as encephaloclastic porencephaly. Babies receiving physiotherapy had significantly lower birthweights and gestational ages. Of the 13 babies found to have either periventricular leucomalacia or porencephalic cysts, seven (7%) were in the physiotherapy group, and six (5%) were in the nonphysiotherapy group. Of the babies surviving to 1 year corrected age, 189 (92%) had multidisciplinary follow-up. Eleven (13%) of the babies who received physiotherapy had suspected CP, and 14 (13%) of those not receiving physiotherapy had CP. The DQ of those who received physiotherapy was 96.0+/-16.6, and 101.6+/-16.6 for those who did not. Following adjustment for gestational age and other unequal risk factors using logistic regression, none of the above outcomes was significantly associated with the number of physiotherapy treatments. CONCLUSION: We could find no evidence that chest physiotherapy, as given in our unit, was associated with abnormal neurological outcomes in extremely preterm infants.

Transmission of hepatitis C virus to infants of human immunodeficiency virus-negative intravenous drug-using mothers: rate of infection and assessment of risk factors for transmission.

The risk of perinatal transmission of hepatitis C virus (HCV) from a cohort of 95 human immunodeficiency virus (HIV)-negative intravenous drug users (IVDU) is described, 89 of whom were positive for antibodies to HCV (anti-HCV). Infection, defined as the presence of HCV RNA in a serum sample collected from an infant at any time during follow-up, was detected in six of 63 (9.5%) infants born to HCV antibody-positive viraemic mothers. No mother who was HCV RNA negative at delivery transmitted HCV to her infant. Hepatitis C virus antibodies became undetectable in uninfected infants by 15 months, but persisted in all HCV-infected infants throughout follow-up. An abnormal alanine aminotransferase (ALT) level was observed on at least one occasion in all HCV-infected infants and in six occasions in uninfected infants. Two of the six HCV-infected infants became HCV RNA negative during follow-up by 27 and 29 months. Both of these infants had a large ALT elevation (mean peak ALT 398U l-1) at around 12 months of age. Analysis of a range of potential risk factors revealed that maternal HCV RNA load was important in predicting transmission, but suggested that other factors play a role in perinatal transmission from mother to child. No difference was found between mothers who transmitted HCV to their infants and those who did not for HCV genotype, duration of drug use, duration of methadone use, methadone dose, history of alcohol abuse, past hepatitis B virus (HBV) infection, mode of delivery, maternal and gestational age, birth weight and incidence of breast-feeding. Mothers who transmitted HCV to their infants had a longer duration between membrane rupture and delivery than the mothers who did not transmit (P = 0.03). HCV RNA was not detected in breast milk and colostrum samples from 38 viraemic mothers, including two who transmitted HCV to their infant.

New South Wales population-based birthweight percentile charts.

OBJECTIVE: To derive newborn percentile charts using NSW population and hospital-based data. METHODOLOGY: Birthweight data for liveborn singleton infants were obtained from the New South Wales Midwives Data Collection (MDC) from 1990 to 1994 inclusive (n = 422139). Data were also collected from King George V Hospital (KGV) for liveborn singleton infants less than 35 weeks of gestation for 1982-89 inclusive, and for all gestations for 1990-95 inclusive (n = 30610). Birthweight percentiles were derived using the MDC data separately for males and females. Head circumference (n = 29090) and birth length percentiles (n = 26973) were derived from the KGV data. RESULTS: The charts derived from MDC data had generally higher percentiles than previously published charts. These represent the largest Australian population-based study published to date. CONCLUSIONS: Periodic review of newborn growth charts is recommended because of changing ethnic and socio-economic factors.

Predictive value of umbilical artery pH in preterm infants.

Compared with term infants, little information is available about the usefulness of the umbilical artery pH in relation to outcome in extremely preterm infants. This prospective study evaluates the relation between umbilical artery pH (UapH), Apgar scores, perinatal events, and outcome in infants born at less than 32 weeks' gestation. Six hundred and twenty three infants of < 32 weeks' gestation were studied. The median UapH was 7.25, with a range of 6.78-7.49. A low UapH was significantly associated with male sex, hyaline membrane disease, grade 3 or 4 intraventricular haemorrhage, and neonatal death. It was also associated with lower birth weight and lower birthweight centile. The relations between the UapH and outcomes of neonatal death, cerebral palsy, and developmental quotient at 1 year, and other perinatal risk factors were then examined using multiple logistic regression. After adjusting for other risk factors, UapH was not significantly associated with any outcome. In contrast, a low one minute Apgar (< 4) remained a significant risk factor, with odds ratios of 2.7 (95% confidence interval (CI) 1.5 to 5.2) for neonatal death and 3.8 (95% CI 1.4 to 10.4) for cerebral palsy.

Risk factors for necrotising enterocolitis: the influence of gestational age.

Over a 7 year study period, 82 infants were identified who had necrotising enterocolitis (NEC). A case-control study of the 74 preterm infants was performed to determine those factors which contributed to the development of NEC. The 35 infants with NEC and gestation between 30-36 weeks, when compared with control infants matched for gestational age, had significantly lower birthweight centiles, cord pH, and 1 minute Apgar scores. By contrast, there were no significant differences between the 39 infants with NEC and controls in the 25-29 week group, except that fewer babies with NEC had received breast milk. The eight term babies all appeared to have an obvious predisposing event. We thus propose a model in which susceptibility to NEC is dependent on gestational age. In the 25-29 week range all babies are at risk on the basis of extreme prematurity. In the 30-36 week range asphyxiated and growth retarded babies are at increased risk, while at term a major predisposing event appears to be required.

3-(3-Substituted prop-1-enyl)cephalosporins.

The synthesis of cephalosporin derivatives possessing a 3-substituted prop-1-enyl group at the 3 position is described. This was achieved using the reaction of vinylmagnesium chloride with the 3-formyl derivatives 1 to give a vinylcarbinol which readily underwent allylic rearrangements to give the desired side chains. The new derivatives exhibited potent in vitro and in vivo antibacterial activity.

Synthesis of cephalosporin-4-aldehydes.

The first reported synthesis of cephalosporin-4-aldehyde derivatives has been achieved via Moffatt oxidation of the corresponding 4-hydroxymethylcephalosporins. The aldehyde 1 was converted into a number of polar derivatives, in particular the acrylic acid derivative 13 which is the 4-vinylogue of sodium cephalothin. None of the new cephalosporin derivatives possessed useful antibacterial activity.