Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a secondary analysis of the PITCHES trial.

OBJECTIVE: To evaluate whether a particular group of women with intrahepatic cholestasis of pregnancy (ICP), based on their presenting characteristics, would benefit from treatment with ursodeoxycholic acid (UDCA). DESIGN: Secondary analysis of the PITCHES trial (ISRCTN91918806). SETTING: United Kingdom. POPULATION OR SAMPLE: 527 women with ICP. METHODS: Subgroup analyses were performed to determine whether baseline bile acid concentrations or baseline itch scores moderated a woman's response to treatment with UDCA. MAIN OUTCOME MEASURES: Bile acid concentration and itch score. RESULTS: In women with baseline bile acid concentrations less than 40 µmol/l, treatment with UDCA resulted in increased post-randomisation bile acid concentrations (geometric mean ratio 1.19, 95% CI 1.00-1.41, P = 0.048). A test of interaction showed no significance (P = 0.647). A small, clinically insignificant difference was seen in itch response in women with a high baseline itch score (-6.0 mm, 95% CI -11.80 to -0.21, P = 0.042), with a test of interaction not showing significance (P = 0.640). Further subgroup analyses showed no significance. Across all women there was a weak relationship between bile acid concentrations and itch severity. CONCLUSIONS: There was no subgroup of women with ICP in whom a beneficial effect of treatment with UDCA on bile acid concentration or itch score could be identified. This confirms that its routine use in women with this condition for improvement of bile acid concentration or itch score should be reconsidered. TWEETABLE ABSTRACT: PITCHES: No group of women with ICP has been found in whom UDCA reduces bile acid concentrations or pruritus.

Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: a systematic review and critical analysis.

BACKGROUND: Early reports of COVID-19 in pregnancy described management by caesarean, strict isolation of the neonate and formula feeding. Is this practice justified? OBJECTIVE: To estimate the risk of the neonate becoming infected with SARS-CoV-2 by mode of delivery, type of infant feeding and mother-infant interaction. SEARCH STRATEGY: Two biomedical databases were searched between September 2019 and June 2020. SELECTION CRITERIA: Case reports or case series of pregnant women with confirmed COVID-19, where neonatal outcomes were reported. DATA COLLECTION AND ANALYSIS: Data were extracted on mode of delivery, infant infection status, infant feeding and mother-infant interaction. For reported infant infection, a critical analysis was performed to evaluate the likelihood of vertical transmission. MAIN RESULTS: Forty nine studies included information on mode of delivery and infant infection status for 655 women and 666 neonates. In all, 28/666 (4%) tested positive postnatally. Of babies born vaginally, 8/292 (2.7%) tested positivecompared with 20/374 (5.3%) born by Caesarean. Information on feeding and baby separation were often missing, but of reported breastfed babies 7/148 (4.7%) tested positive compared with 3/56 (5.3%) for reported formula fed ones. Of babies reported as nursed with their mother 4/107 (3.7%) tested positive, compared with 6/46 (13%) for those who were reported as isolated. CONCLUSIONS: Neonatal COVID-19 infection is uncommon, rarely symptomatic, and the rate of infection is no greater when the baby is born vaginally, breastfed or remains with the mother. TWEETABLE ABSTRACT: Risk of neonatal infection with COVID-19 by delivery route, infant feeding and mother-baby interaction.

Economic costs associated with moderate and late preterm birth: a prospective population-based study.

OBJECTIVE: We sought to determine the economic costs associated with moderate and late preterm birth. DESIGN: An economic study was nested within a prospective cohort study. SAMPLE: Infants born between 32(+0) and 36(+6)  weeks of gestation in the East Midlands of England. A sample of infants born at ≥37 weeks of gestation acted as controls. METHODS: Data on resource use, estimated from a National Health Service (NHS) and personal social services perspective, and separately from a societal perspective, were collected between birth and 24 months corrected age (or death), and valued in pounds sterling, at 2010-11 prices. Descriptive statistics and multivariable analyses were used to estimate the relationship between gestational age at birth and economic costs. MAIN OUTCOME MEASURES: Cumulative resource use and economic costs over the first two years of life. RESULTS: Of all eligible births, 1146 (83%) preterm and 1258 (79%) term infants were recruited. Mean (standard error) total societal costs from birth to 24 months were £12 037 (£1114) and £5823 (£1232) for children born moderately preterm (32(+0) -33(+6)  weeks of gestation) and late preterm (34(+0) -36(+6)  weeks of gestation), respectively, compared with £2056 (£132) for children born at term. The mean societal cost difference between moderate and late preterm and term infants was £4657 (bootstrap 95% confidence interval, 95% CI £2513-6803; P < 0.001). Multivariable regressions revealed that, after controlling for clinical and sociodemographic characteristics, moderate and late preterm birth increased societal costs by £7583 (£874) and £1963 (£337), respectively, compared with birth at full term. CONCLUSIONS: Moderate and late preterm birth is associated with significantly increased economic costs over the first 2 years of life. Our economic estimates can be used to inform budgetary and service planning by clinical decision-makers, and economic evaluations of interventions aimed at preventing moderate and late preterm birth or alleviating its adverse consequences. TWEETABLE ABSTRACT: Moderate and late preterm birth is associated with increased economic costs over the first 2 years of life.

Differences in post-mortem findings after stillbirth in women with and without diabetes.

AIMS: The reason for the fivefold increased risk of stillbirth in women with diabetes is not known. Further understanding of the underlying mechanisms may facilitate identification of pregnancies at increased risk. We have compared post-mortem reports in matched pairs of stillbirths in women with and without diabetes. METHODS: Post-mortem reports were provided by the Centre for Maternal and Child Enquiries. Stillbirths as a result of lethal congenital and genetic abnormalities were excluded. Whole body, placenta and organ weights and histo-pathological findings in cases and controls were compared and also related to published reference values. RESULTS: We analysed post-mortem reports on 23 matched pairs of stillbirths from 2009 to 2010. Mean placental weight in women with diabetes was 75 g less than in control subjects (95% CI -143 to -7 g; P = 0.032). In maternal diabetes, the thymus was often small and showed a 'starry sky' pattern on histology in 11 of 20 cases compared with four of 22 controls (P = 0.03). This histological finding was associated with a particularly low mean placental weight z-score -2.1 (1.1) standard deviations below a reference population corrected for gestational age. CONCLUSIONS: In over half of the stillbirths occurring in women with diabetes, there was a 'starry sky' appearance in the fetal thymus on histology, this being associated with a small placenta. These findings are consistent with a critical subacute metabolic disturbance being a prominent cause of the increased risk of stillbirth in pregnancies complicated by maternal diabetes.

Neonatal intensive care outcomes and resource utilisation of infants born <26 weeks in the former Trent region: 2001-2003 compared with 1991-1993.

OBJECTIVES: To provide survival data and rates of severe disability at 2 years of corrected age in infants born prior to 26 weeks' gestation in 2001-2003 and to compare these outcomes with an earlier cohort from 1991 to 1993. DESIGN: Population-based prospective cohort study. SETTING: Former Trent region of UK covering a population of approximately five million and around 55 000 births per annum. PARTICIPANTS: The authors identified a 3-year cohort of infants born before 26 weeks' gestation between 1 January 2001 and 31 December 2003 from The Neonatal Survey (TNS). Questionnaires based on the Oxford minimum dataset were completed. MAIN OUTCOME MEASURES: Survival, service use and disability levels were compared between the 2001- 2003 cohort and the cohort from 1991 to 1993. RESULTS: In 2001-2003, 0%, 18% and 35% of live born babies were alive at 2 years without any evidence of severe disability at 23, 24 and 25 weeks' gestation, respectively. Overall, of those children admitted to neonatal care, the proportion with no evidence of severe disability at 2 years corrected age improved from 14.5% in 1991-1993 to 26.5% in 2001-2003. There was an increase in the proportion of children with at least one severe disability, out of total admissions to neonatal unit (8% vs 17%) and of those assessed at 2 years (35% vs 39%). CONCLUSIONS: This study has shown an improvement in survival to discharge in babies admitted for neonatal care. However, this improved survival has been associated with an increase in the proportion of children with at least one severe disability at a corrected age of 2 years.

Antenatal umbilical Doppler abnormalities: an independent risk factor for early onset neonatal necrotizing enterocolitis in premature infants.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) emergency seen in neonatal units. Many factors have been considered as potentially important aetiologically, including gut ischaemia, sepsis and feeding. However, evidence remains equivocal. OBJECTIVE: This study investigated whether preterm babies born to mothers with abnormal antenatal umbilical Dopplers (absent or reversed end diastolic flow--AREDF), that is exposed to antenatal gut ischaemia, are at an identical risk of developing NEC early in life, compared to babies born to mothers with normal Dopplers. METHODS: All preterm (

Geographically based investigation of the influence of very-preterm births on routine mortality statistics from the UK and Australia.

BACKGROUND: Comparisons of national perinatal and neonatal mortality often neglect the underlying causes. OBJECTIVE: To assess effects of very-preterm births in the UK and Australia. SETTING: Two geographically defined populations: the former Trent Health Region of the UK and New South Wales (NSW)/the Australian Capital Territory (ACT), Australia. METHOD: All births 22(+0) to 31(+6) weeks in 2000, 2001 and 2002 were identified by established surveys of perinatal care. Rates of birth and death were compared. RESULTS: The population of NSW/ACT was 35% higher and there were 66% more births than in Trent (273 495 vs 164 824). The proportion of liveborn infants between 22 and 31 weeks gestation was about 25% higher in Trent (NSW/ACT 2945, rate per 1000 live births 10.82 (95% CI 10.43 to 11.22); Trent 2208, rate per 1000 live births 13.47 (95% CI 12.92 to 14.05)). The proportion of these infants admitted to a neonatal unit was also higher in Trent (91.2% vs 94.4%; OR 1.63 (95% CI 1.30 to 2.05)). Unadjusted mortality in infants admitted to a neonatal unit was similar: NSW/ACT 332/2686 (12.4%); Trent 284/2085 (13.6%); unadjusted OR 1.12 (95% CI 0.94 to 1.33; p = 0.21). CONCLUSIONS: The higher rates of very premature birth and more ready admission to neonatal intensive care for infants in the UK may help to explain why perinatal and neonatal mortality are higher there than in Australia. Efforts to understand why the rate of premature birth in the UK is so high should be a national priority.

Socioeconomic inequalities in very preterm birth rates.

AIMS: To investigate the extent of socioeconomic inequalities in the incidence of very preterm birth over the past decade. METHODS: Ecological study of all 549 618 births in the former Trent health region, UK, from 1 January 1994 to 31 December 2003. All singleton births of 22(+0) to 32(+6) weeks gestation (7 185 births) were identified from population surveys of neonatal services and stillbirths. Poisson regression was used to calculate incidence of very preterm birth (22-32 weeks) and extremely preterm birth (22-28 weeks) by year of birth and decile of deprivation (child poverty section of the Index of Multiple Deprivation). RESULTS: Incidence of very preterm singleton birth rose from 11.9 per 1000 births in 1994 to 13.7 per 1000 births in 2003. Those from the most deprived decile were at nearly twice the risk of very preterm birth compared with those from the least deprived decile, with 16.4 per 1000 births in the most deprived decile compared with 8.5 per 1000 births in the least deprived decile (incidence rate ratio 1.94; 95% CI (1.73 to 2.17)). This deprivation gap remained unchanged throughout the 10-year period. The magnitude of socio-economic inequalities was the same for extremely preterm births (22-28 weeks incidence rate ratio 1.94; 95% CI (1.62 to 2.32)). CONCLUSIONS: This large, unique dataset of very preterm births shows wide socio-economic inequalities that persist over time. These findings are likely to have consequences on the burden of long-term morbidity. Our research can assist future healthcare planning, the monitoring of socio-economic inequalities and the targeting of interventions in order to reduce this persistent deprivation gap.

Follow up of infants following discharge from the neonatal unit: structure and process.

Reviewing high risk infants after discharge to provide ongoing clinical care and to monitor later outcomes is an important role for neonatologists and paediatricians. Clinical need is the primary reason for such follow up but the process does provide additional opportunities, for example collecting information on later outcomes is vital for health care commissioning, and to determine the longer term effects of new medical treatments. Parents welcome the early identification of any problems in their infant and the opportunity for early intervention may improve outcomes in some circumstances. However, depending on the model adopted, follow up can be costly and this expenditure must be justified by considering the benefits obtained.

Data collection from very low birthweight infants in a geographical region: methods, costs, and trends in mortality, admission rates, and resource utilisation over a five-year period.

AIMS: 1. To determine the survival and morbidity of infants at discharge with a birthweight of less than 1500 g in the geographically defined population of East Anglia. 2. To demonstrate a cost-effective method of regional data collection. 3. To determine whether there were any changes in the demand for neonatal care. STUDY DESIGN AND SUBJECTS: A prospective cohort analysis using a single database to collect data on 1244 very low birthweight infants from eight neonatal units in one Region from 1993 to 1997. RESULTS: Estimated ascertainment of VLBW infants to the study was 96%. Over the 5 years survival rates were stable (75-79%). 52% of deaths in infants admitted for neonatal care occurred on day 1, with just 15% of deaths occurring after 28 days of life. Mortality risk significantly decreased with increasing gestational age at birth. Compared to 22-25-week old infants, the mortality risk decreased by 65% for 26-27-week old infants (OR 0.35 95% CI (0.21, 0.59)) and by 92% for 32-39-week old infants (OR 0.08 95% CI (0.03, 0.21)) with intermediate odds ratios of 0.22 (0.12, 0.42) and 0.13 (0.06, 0.28) for the 28-29 and 30-39 weeks gestation, respectively. Higher birthweight, after adjusting for gestation also decreased the mortality risk (OR 0.78 per 100 g difference, 95% CI (0.71, 0.86)). No change was seen in the number of extremely preterm infants admitted for intensive care or resource utilisation, although a significant increase was seen in the number of infants dying in delivery rooms. There was a reduction in the reported incidence of pulmonary interstitial emphysema (10-4%) but no change in the number of ventilation days or the rate of chronic lung disease. The mean maternal age increased from 27.7 years to 28.9 years during the study. Maternal steroid administration increased (30% to 59%) and was associated with a decreased risk of mortality (OR 0.44, 95% CI: 0.31-0.62). CONCLUSIONS: It is possible to collect useful data from the neonatal period at a reasonable cost from a geographically defined population. This information was used for informing clinicians, counselling parents and in the era of managed clinical networks will be useful in guiding the provision of effective health care resources.

Outcome at 2 years for very low birthweight infants in a geographical population: risk factors, cost, and impact of congenital anomalies.

AIM: To determine the type and rate of disability at 2 years of age in infants born in the geographically defined population of East Anglia with a birthweight less than 1500 g and to assess the risk factors for disability. STUDY DESIGN: A prospective cohort analysis from all eight neonatal units in East Anglia from 1993-1997 using a single database. METHODS: Local paediatricians assessed children at 2 years using the Health Status Questionnaire and data collection was centrally coordinated. RESULTS: Outcomes for 947 children, 99% of survivors, were available, 74 (7.8%) had severe disability and this was significantly associated with gestational age (p<0.0005), birthweight (p<0.0005) and sex (p=0.046). Major congenital abnormality contributed 27% of all severe disability. The overall cerebral palsy rate was 6.2%, nine children were blind and five had sensorineural hearing loss requiring aids. These children had a high level of use of community services with 19% of the cohort being referred to one or more community service. ELBW infants or those born <30 weeks gestation were 1.5 times and twice as likely to have moderate or severe disability and 2.3 and 5.4 times as likely to have cerebral palsy as those weighing 1000 to 1500 g or >30 weeks gestation. Boys were at higher risk of adverse outcome. CONCLUSIONS: The study was able to define the increased risk associated with being born at lower gestational age or lower birthweight and demonstrates successful ascertainment of outcomes for large local populations at a reasonable cost.

Feeding growth restricted preterm infants with abnormal antenatal Doppler results.

Absence or reversal of end diastolic flow (AREDF) in the umbilical artery is associated with poor outcome, and elective premature delivery is common. Feeding these infants is a challenge. They often have poor tolerance of enteral feeding, and necrotising enterocolitis may develop. This review explores current practice to see if there is evidence on which to base guidelines. The incidence of necrotising enterocolitis is increased in infants with fetal AREDF, especially when complicated by fetal growth restriction. Abnormalities of splanchnic blood flow persist postnatally, with some recovery during the first week of life, providing justification for a delayed and careful introduction of enteral feeding. Such a policy exposes babies to the risks of parenteral nutrition, with no trials to date showing any benefit of delayed enteral nutrition. Trials are required to determine the optimum timing for introduction of enteral feeds in growth restricted infants with fetal AREDF.

Neonatal disease severity scoring systems.

Illness severity scores have become widely used in neonatal intensive care. Primarily this has been to adjust the mortality observed in a particular hospital or population for the morbidity of their infants, and hence allow standardised comparisons to be performed. However, although risk correction has become relatively commonplace in relation to audit and research involving groups of infants, the use of such scores in giving prognostic information to parents, about their baby, has been much more limited. The strengths and weaknesses of the existing methods of disease severity correction in the newborn are presented in this review.

Kinetics of fusion of the cytoplasmic granules with phagocytic vacuoles in human polymorphonuclear leukocytes. Biochemical and morphological studies.

This study on human neutrophils was conducted to measure the kinetics of degranulation of the different cytoplasmic granules into phagocytic vacuoles, and to relate the timing of these events to the burst of respiration that accompanies phagocytosis by these cells. Purified neutrophils were incubated with latex particles opsonized with human immunoglobulin (Ig)G, and phagocytosis was stopped at timed intervals. The cells were examined by electron microscopy to document the sequence of degranulation of the cytoplasmic granules. The azurophil granules and lyosomes were identified by histochemical staining for peroxidase and acid phosphatase, respectively. Phagocytic vacuoles were separated from cell homogenates by floatation on sucrose gradients and assayed for contained lactoferrin, myeloperoxidase, and acid hydrolases. The conclusions drawn from the biochemical and morphological studies were in agreement and indicated: particle uptake and vacuole closure can be completed within 20 s; both the specific and azurophil granules fuse with the phagocytic vacuole much earlier than is generally appreciated, with half-saturation times of 39 s (99% confidence limits, 15-72); oxygen consumption has kinetics similar to those of the fusion of these granules with the phagosome; degranulation of the acid hydrolases beta-glucuronidase, N-acetyl-beta-glucosaminidase (biochemical assays), and acid phosphatase (biochemical assay and electron microscopic cytochemistry) have kinetics of degranulation that are similar to each other but totally different from and much slower than that of myeloperoxidase with half-saturation times of between 354 and 682 s (99% confidence limits, 246-883). This suggests that the acid hydrolases are not co-located with myeloperoxidase in the azurophil granule but are contained in distinct lysosomes, or "tertiary granules".

Where do those slides go?

The Foundation for Teaching Aids at Low Cost (TALC) distributes about 1000 lecture units of slides and scripts each month. This paper reports on the results of a postal enquiry to a stratified sample of those who receive these lecture units. The response to the enquiry was good, and showed a wide and varied use of this material, each set may be seen by around 140 students in the year after despatch.

Halothane does not inhibit human neutrophil function in vitro.

Various indices of function of neutrophils from normal healthy volunteers have been examined after in vitro exposure to halothane. Random free movement on glass was unaffected, but random migration through millipore filters was slightly increased. There was no significant change in migration in response to casein chemotaxis. Phagocytosis, degranulation and the enhanced non-mitochondrial respiration associated with phagocytosis were unaffected. Electron-microscopic appearance at 30 s after exposure to latex particles was normal in all respects.