Evaluation of women referred to the two-week wait gynaecology clinic with suspected ovarian cancer.

OBJECTIVES: Ovarian cancer is the leading cause of death from gynaecological cancer in the UK, making early diagnosis key. The two-week wait pathway aims to facilitate rapid referrals from primary to secondary care for suspected cancer thus increasing rates of early diagnosis. The objective of this study was to evaluate referrals made via the two-week wait pathway for suspected ovarian cancer. STUDY DESIGN: A retrospective analysis of 215 women referred on the two-week wait pathway to a tertiary centre in the United Kingdom with suspected ovarian cancer in 2018. RESULTS: Only 16% of women referred were subsequently diagnosed with gynaecological malignancy. Of those diagnosed with ovarian cancer, 78% had late stage disease at diagnosis. Pre-menopausal women made up 29% of those referred, but only 6% of those diagnosed with cancer. CONCLUSION: Despite its goal of increasing early stage diagnosis of cancer, the majority of women referred via the two-week wait pathway do not have cancer, and the majority of those who do are referred with late stage disease. These results highlight the need for an effective screening programme for ovarian cancer.

Antenatal predictors and body composition of large-for-gestational-age newborns: perinatal health outcomes.

OBJECTIVE: To compare body composition of large-for-gestational-age (LGA) with appropriate-for-gestational-age (AGA) newborns and to identify antenatal predictors of LGA. STUDY DESIGN: This cross-sectional study included 536 term, singleton infants. Anthropometric measurements were performed within 48 h of birth and included determination of body fat percentage (%BF) by air displacement plethysmography. Associations were investigated using logistic regression. RESULT: LGA infants had greater %BF (P<0.001) compared with AGA infants. Significant predictors of LGA infants included parity (odds ratio (OR)=1.98, (95% confidence interval (CI) 1.00, 4.02)), paternal height (OR=1.08, (95% CI 1.03, 1.14)), maternal pregravid weight (65 to 74.9 kg: OR=2.77, (95% CI 1.14, 7.06)) and gestational weight gain (OR=1.09, 95% CI (1.03, 1.16)). Gestational diabetes mellitus was not associated with LGA infants (P=0.598). CONCLUSION: Paternal height, parity, maternal pregravid weight and gestational weight gain were strongly associated with LGA infants. These results may allow early prediction and potential modification, thereby optimising clinical outcomes.

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.

Viruses and other infections in stillbirth: what is the evidence and what should we be doing?

In Australia, as in other developed countries, approximately 40-50% of stillbirths are of unknown aetiology. Emerging evidence suggests stillbirths are often multifactorial. The absence of a known cause leads to uncertainty regarding the risk of recurrence, which can cause extreme anguish for parents that may manifest as guilt, anger or bewilderment. Further, clinical endeavours to prevent recurrences in future pregnancies are impaired by lack of a defined aetiology. Therefore, efforts to provide an aetiological diagnosis of stillbirth impact upon all aspects of care of the mother, and inform many parts of clinical decision making. Despite the magnitude of the problem, that is 7 stillbirths per 1000 births in Australia, diagnostic efforts to discover viral aetiologies are often minimal. Viruses and other difficult to culture organisms have been postulated as the aetiology of a number of obstetric and paediatric conditions of unknown cause, including stillbirth. Reasons forwarded for testing stillbirth cases for infectious agents are non-medical factors, including addressing all parents' need for diagnostic closure, identifying infectious agents as a sporadic cause of stillbirth to reassure parents and clinicians regarding risk for future pregnancies, and to reduce unnecessary testing. It is clear that viral agents including rubella, human cytomegalovirus (CMV), parvovirus B19, herpes simplex virus (HSV), lymphocytic choriomeningitis virus (LCMV), and varicella zoster virus (VZV) may cause intrauterine deaths. Evidence for many other agents is that minimal or asymptomatic infections also occur, so improved markers of adverse outcomes are needed. The role of other viruses and difficult-to-culture organisms in stillbirth is uncertain, and needs more research. However, testing stillborn babies for some viral agents remains a useful adjunct to histopathological and other examinations at autopsy. Modern molecular techniques such as multiplex PCR, allow searches for multiple agents. Now that such testing is available, it is important to assess the clinical usefulness of such testing.

Sedatives for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using a sedative compared to a non-opiate control for NAS due to withdrawal from opiates, and to determine which type of sedative is most effective and safe. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This update included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), MEDLINE 1966-March 2005 and abstracts of conference proceedings. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to sedative or control. Control could include another sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included treatment failure (failure to achieve symptom control or use of additional drug treatment), seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Six studies enrolling a total of 305 patients met inclusion criteria (Coyle 2002; Finnegan 1984; Kahn 1969; Kaltenbach 1986; Khoo 1995; Madden 1977); however, two (Finnegan 1984; Kaltenbach 1986) may be sequential reports that include some identical patients. Methodological concerns included the use of quasi-random allocation methods in four studies, and sizeable, largely unexplained differences in reported numbers allocated to each group in three studies. Phenobarbitone compared to supportive care alone has not been shown to reduce treatment failure or time to regain birthweight (one study). However, the duration of supportive care given to infants was significantly reduced (MD -162.1 mins/day, 95% CI -249.2, -75.1). Comparing phenobarbitone to diazepam, meta-analysis of two studies found phenobarbitone produced a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). There was no significant difference in duration of treatment or hospital stay. Comparing phenobarbitone with chlorpromazine, one study found no significant difference in treatment failure rate. No data for neurodevelopment reported by treatment group of allocation were available. No trials were eligible that assessed clonidine for NAS. In infants treated with an opiate, a small quasi-random study reported a reduced severity of withdrawal. Infants were weaned from an opiate more quickly which allowed earlier hospital discharge and reduced hospital costs. These findings may reflect the low dose of opiate used for initial treatment and the policy of discharging infants home on phenobarbitone but not morphine. AUTHORS' CONCLUSIONS: In newborn infants with NAS, there is no evidence that phenobarbitone compared with supportive care alone reduces treatment failure; however, phenobarbitone may reduce the daily duration of supportive care needed. Phenobarbitone, compared to diazepam, reduces treatment failure. In infants treated with an opiate, the addition of phenobarbitone may reduce withdrawal severity. Further trials are required to determine if this finding is applicable when a higher initial dose of opiate is used, and determine the effects of phenobabritone on infant development. There is insufficient evidence to support the use of chlorpromazine or clonidine in newborn infants with NAS. Clonidine and chlorpromazine should only be used in the context of a randomised clinical trial. This review should be taken in conjunction with the review "Opiate treatment for opiate withdrawal in newborn infants" (Osborn 2002a) which indicates that an opiate is the preferred initial therapy for NAS.

Opiate treatment for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using an opiate, compared to a sedative or non-pharmacological treatment, for treatment of NAS due to withdrawal from opiates. SEARCH STRATEGY: The previous review was updated with additional searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), MEDLINE (1966-December 2004) and EMBASE (1980-December 2004) supplemented by searches of conference abstracts and citation lists of published articles. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to opiate or control. Control could include an opiate, sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included control of symptoms, seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using relative risk (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Seven studies enrolling a total of 585 infants met inclusion criteria (Carin 1983; Finnegan 1984; Jackson 2004; Kaltenbach 1986; Kandall 1983; Khoo 1995; Madden 1977); however, two (Finnegan 1984; Kaltenbach 1986) may be sequential reports that include some identical patients. The studies enrolled infants of mothers who had used opiates with or without other drugs during pregnancy. Methodological concerns included the use of quasi-random rather than random patient allocation methods in three studies; sizeable, largely unexplained differences in reported numbers allocated to each group in four studies; and imbalances in group characteristics after randomisation in one study. Opiate (morphine) vs supportive care only: One study (Khoo 1995) found no significant effect on treatment failure (RR 1.29, 95% CI 0.41, 4.07), a significant increase in hospital stay (MD 15.0 days, 95% CI 8.9, 21.1) and significant reductions in time to regain birthweight (MD -2.8 days, 95% -5.3, -0.3) and duration of supportive care (MD -197.2 minutes/day, 95% CI -274.2, -120.3). Opiate vs phenobarbitone: Meta-analysis of four studies found no significant difference in treatment failure (typical RR 0.76, 95% CI 0.51, 1.11). One of these studies (Finnegan 1984) reported that opiate treatment resulted in a significant reduction in treatment failure among infants of mothers who had used only opiates; however, as this was a post-hoc analysis, this result should be interpreted with caution. One study (Jackson 2004) reported a significant reduction in duration of treatment and admission to the nursery for infants receiving morphine compared to phenobarbitone. One study (Kandall 1983) reported a reduction in seizures, of borderline statistical significance, with the use of opiate. Opiate vs diazepam: Meta-analysis of two studies found a significant reduction in treatment failure (RR 0.43, 95% CI 0.23, 0.80) with the use of opiate. No study reported neurodevelopment by allocated treatment group. AUTHORS' CONCLUSIONS: Opiates, as compared to supportive care only, appear to reduce the time to regain birth weight and reduce the duration of supportive care, but increase the duration of hospital stay; there is no evidence of effect on treatment failure. When compared to phenobarbitone, opiates may reduce the incidence of seizures but, overall, there is no evidence of effect on treatment failure. One study reported a reduction in duration of treatment and nursery admission for infants on morphine. When compared to diazepam, opiates reduce the incidence of treatment failure. A post-hoc analysis generates the hypothesis that treatment effects may vary according to whether the population includes infants born to all opiate users (i.e. with or without other drug exposure) or is restricted to infants of mothers who used opiates only. In view of the methodologic limitations of the included studies the conclusions of this review should be treated with caution.

Antibiotic regimens for suspected late onset sepsis in newborn infants.

BACKGROUND: Late onset neonatal sepsis (systemic infection after 48 hours of age) continues to be a significant cause of morbidity and mortality. Early treatment with antibiotics is essential as infants can deteriorate rapidly. It is not clear which antibiotic regimen is most suitable for initial treatment of suspected late onset sepsis. OBJECTIVES: To compare the effectiveness and adverse effects of different antibiotic regimens for treatment of suspected late onset sepsis in newborn infants. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This includes electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2004), MEDLINE (1966 - Dec 2004), EMBASE (1980 - Dec 2004) and CINAHL (1982 - Dec 2004), electronic abstracts of Pediatric Academic Society meetings (1996 - Dec 2004) and previous reviews including cross references (all articles referenced). SELECTION CRITERIA: Randomised and quasi randomised controlled trials comparing different initial antibiotic regimens in neonates with suspected late onset sepsis were evaluated. DATA COLLECTION AND ANALYSIS: Both reviewer authors screened abstracts and papers against the inclusion criteria, appraised the quality of and extracted data from papers. For dichotomous outcomes, treatment effect was expressed as relative risk and risk difference with 95% confidence intervals. NNT was calculated for outcomes for which there was a statistically significant reduction in risk difference. MAIN RESULTS: Thirteen studies were identified as possibly eligible for inclusion. The majority of studies were excluded as they did not separate data for early and late onset infection. Two studies are still awaiting assessment. Only one small study, in 24 neonates, was included in this review. It compared beta-lactam therapy with a combination of beta lactam plus aminoglycoside. The study did not meet our prespecified criteria for good methodological quality. In babies with suspected infection there was no significant difference in mortality (RR 0.17, 95% CI 0.01 to 3.23) or treatment failure (RR 0.17, 95% CI 0.01 to 3.23). Antibiotic resistance was assessed and there were no cases in either group. AUTHORS' CONCLUSIONS: There is inadequate evidence from randomised trials in favour of any particular antibiotic regimen for the treatment of suspected late onset neonatal sepsis. The available evidence is not of high quality. Although suspected sepsis and antibiotic use is common, quality research is required to specifically address both narrow and broad spectrum antibiotic use for late onset neonatal sepsis. Future research also needs to assess cost effectiveness and the impact of antibiotics in different settings such as developed or developing countries and lower gestational age groups.

Measurement of movement is an objective method to assist in assessment of opiate withdrawal in newborns.

OBJECTIVE: To develop an objective and reliable method to assess drug withdrawal in newborns by quantitatively estimating the amount of movement rather than scoring individual withdrawal signs. DESIGN: In this cross sectional study, a commercial portable motion detector with computer memory, similar to a wrist watch (the actigraph) was used to measure movement. The measurements were compared with a clinical decision based on the neonatal abstinence syndrome (NAS) score. Movement was analysed, using non-parametric tests, in three groups: a control group of 10 infants, 13 opiate exposed newborns not treated for NAS, and 30 newborns treated for NAS (17 before treatment, eight within 24 hours of treatment, five when stabilised). RESULTS: There were significant differences in the median activity score, expressed as counts per minute (cpm), in the pretreatment group (124 cpm) compared with the control (42 cpm, p < 0.0001), non-treated (74 cpm, p = 0.001), and stabilised treatment (75 cpm, p = 0.007) groups. The accuracy of the actigraph in the identification of newborns requiring treatment from those who did not was high compared with the clinical scores; sensitivity 94%; specificity 85%; positive and negative predictive values 88% and 92% respectively. CONCLUSIONS: The measure of movement is comparable to the clinical score in the identification of newborns who require treatment and in determining the severity of withdrawal. The clear advantage of this method is its objectivity, reliability, and efficiency as a simple, non-invasive, bedside measure. Further evaluation in a randomised, controlled trial would establish comparative benefits, potential harms, safety, and acceptability.

Sedatives for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using a sedative compared to a non-opiate control for NAS due to withdrawal from opiates, and to determine which type of sedative is most effective and safe. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002) and MEDLINE 1966-2002. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to sedative or control. Control could include another sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included treatment failure (failure to achieve symptom control or use of additional drug treatment), seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Five studies enrolling a total of 285 patients met inclusion criteria (Finnegan 1984, Kahn 1969, Kaltenbach 1986, Khoo 1995, Madden 1977); however, two (Finnegan 1984, Kaltenbach 1986) may be sequential reports that include some identical patients. Methodological concerns included the use of quasi-random rather than random patient allocation methods in three studies, and sizeable, largely unexplained differences in reported numbers allocated to each group in three studies. Phenobarbital compared to supportive care alone has not been shown to reduce treatment failure or time to regain birthweight (one study). However, the duration of supportive care required to be given to infants each day was significantly reduced (MD -162.1 minutes/day, 95% CI -249.2, -75.1). Comparing phenobarbital to diazepam, meta-analysis of two studies found that phenobarbital produced a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). There was no significant difference in duration of treatment or duration of hospital stay. Comparing phenobarbital with chlorpromazine, one study found no significant difference in treatment failure rate. No data for neurodevelopment were available, reported by treatment group as allocated. No trials were eligible that assessed clonidine for NAS. REVIEWER'S CONCLUSIONS: In newborn infants with NAS, there is no evidence that phenobarbital, compared with supportive care alone, reduces treatment failure; however, phenobarbital may reduce the daily duration of supportive care needed. Phenobarbital, compared to diazepam, reduces treatment failure. There is insufficient evidence to support the use of chlorpromazine or clonidine in newborn infants with NAS. Clonidine and chlorpromazine should only be used in the context of a randomised clinical trial. The results of this review, taken in conjunction with the related review, Opiate treatment for opiate withdrawal in newborn infants (Osborn 2002), indicate that treatment with opiates is the preferred initial therapy for NAS. It is hypothesised that this is particularly true for infants whose mothers have used only opiates during pregnancy. If a sedative is used, phenobarbital is preferred to diazepam. The results of an ongoing trial of the addition of phenobarbital to an opiate are awaited.

Opiate treatment for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using an opiate, compared to a sedative or non-pharmacological treatment, for treatment of NAS due to withdrawal from opiates. The evidence for use of different opiates was assessed in subgroup analyses. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group including searches (up to March 2002) of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002), MEDLINE (1966-March 2002), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to opiate or control. Control could include an opiate, sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included control of symptoms, seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using relative risk (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Six studies enrolling a total of 511 infants met inclusion criteria (Carin 1983, Finnegan 1984, Kaltenbach 1986, Kandall 1983, Khoo 1995, Madden 1977); however, two (Finnegan 1984, Kaltenbach 1986) may be sequential reports that include some identical patients. The studies enrolled infants of mothers who had used opiates with or without other drugs during pregnancy. Methodological concerns included the use of quasi-random rather than random patient allocation methods in three studies, and sizeable, largely unexplained differences in reported numbers allocated to each group in four studies. Opiate (morphine) vs supportive care only: One study (Khoo 1995) found no significant effect on treatment failure (RR 1.29, 95% CI 0.41, 4.07), a significant increase in hospital stay (MD 15.0 days, 95% CI 8.9, 21.1) and significant reductions in time to regain birthweight (MD -2.8 days, 95% -5.3, -0.3) and duration of supportive care (MD -197.2 minutes/day, 95% CI -274.2, -120.3). Opiate vs phenobarbital: Meta-analysis of three studies found no significant difference in treatment failure (typical RR 0.78, 95% CI 0.46, 1.32). One of these studies (Finnegan 1984) reported that opiate treatment resulted in a significant reduction in treatment failure among infants of mothers who had used only opiates; however, as this was a post-hoc analysis, this result should be interpreted with caution. One study (Kandall 1983) reported a reduction in seizures, of borderline statistical significance, with the use of opiate. Opiate vs diazepam: Meta-analysis of two studies found a significant reduction in treatment failure (RR 0.43, 95% CI 0.23, 0.80) with the use of opiate. No study reported neurodevelopment by allocated treatment group. REVIEWER'S CONCLUSIONS: Opiates, as compared to supportive care only, appear to reduce the time to regain birth weight and reduce the duration of supportive care, but increase the duration of hospital stay; there is no evidence of effect on treatment failure. When compared to phenobarbital, opiates may reduce the incidence of seizures but, overall, there is no evidence of effect on treatment failure. When compared to diazepam, opiates reduce the incidence of treatment failure. A post-hoc analysis generates the hypothesis that treatment effects may vary according to whether the population includes infants born to all opiate users (i.e. with or without other drug exposure) or is restricted to infants of mothers who used opiates only. In view of the methodologic limitations of the included studies the conclusions of this review should be treated with caution. Further research is needed.

Sleep deprivation, disorganization and fragmentation during opiate withdrawal in newborns.

OBJECTIVE: To determine specific sleep characteristics in neonatal opiate withdrawal, referred to as the Neonatal Abstinence Syndrome (NAS), by measuring sleep efficiency, deprivation, disorganization and fragmentation in three groups: (i) healthy term neonates; (ii) opiate-exposed neonates who were treated for opiate withdrawal; and (iii) a group of opiate-exposed neonates who did not require treatment. METHODS: A cohort study recording sleep patterns of neonates at 2-10 days of age (after 36 or more weeks of gestation) was carried out. Twenty-one neonates were exposed to opiates during pregnancy and 15 neonates were healthy controls. Sleep characteristics were predefined, and treated newborns were divided into early and stabilized treatment groups. Polygraphic recordings of sleep, movement and breathing were made continuously after a daytime feed. RESULTS: Sleep deprivation, disorganization and fragmentation were found in newborns with NAS and were associated with the severity of the withdrawal. Neonates treated for NAS displayed increased wakefulness during early treatment (deprivation), but were similar to controls once stabilized. Both treated and non-treated groups had reduced amounts of quiet sleep (deprivation). Treated newborns showed an increase in indeterminate sleep (disorganization) and arousals-to-wakefulness (fragmentation). CONCLUSION: This study determined the exact nature and degree of sleep disturbances in newborns during acute opiate withdrawal. The findings contribute to a further understanding of the physiology underlying neonatal opiate withdrawal and suggest that some changes in sleep are due to opiate withdrawal but others may reflect opiate dependency in utero.

Airway protection following simulated gastro-oesophageal reflux in sedated and sleeping neonatal piglets during active sleep.

1. In infants, promethazine has been implicated in the pathogenesis of sleep apnoea, apparent life threatening events (ALTE) and the Sudden Infant Death syndrome (SIDS). The aim of the present study was to investigate, in a neonatal animal, the effects of a commonly used promethazine-containing medication on airway protective mechanisms and cardiorespiratory reflexes following simulated gastro-oesophageal reflux (GER) to different levels in the oesophagus and pharynx. 2. Physiological and radiographic recordings were made in 21 naturally sleeping (controls) and 21 sedated (1.5 mg/kg, p.o., promethazine) piglets. On 3 consecutive days physiological recordings were made in all piglets during active sleep. Gastro-oesophageal reflux was simulated by the injection of boluses of 0.5 mL HCl, pH 2 or 3, or NaCl (0.9%) at 37 degrees C into the pharynx, upper or lower oesophagus. 3. In healthy neonatal piglets, minimal sedation with promethazine, which did not affect behaviour during wakefulness, revealed previously unreported findings during active sleep. 4. The most significant effects were observed following simulated GER to the pharynx, with no effect observed in the lower oesophagus. In sedated piglets, compared with naturally sleeping piglets, there was a significant reduction in swallowing (P < 0.01), delayed radiological clearance of fluid (P < 0.05), a reduction in breathing rate, oxygen saturation and heart rate and an increase in apnoea. 5. These findings are consistent with a low dose of promethazine producing a significant attenuation of airway protective mechanisms and, thus, stimulation of the laryngeal chemoreflex. The results suggest a mechanism for the association observed between promethazine use and the occurrence of ALTE and SIDS. The results support continued caution and suggest the need for greater regulation of promethazine-containing medications in infants.

The role of swallowing during active sleep in the clearance of reflux in term and preterm infants.

OBJECTIVES: To investigate swallowing and peristalsis in sleep and during gastroesophageal reflux (GER) in both healthy term and preterm infants at term equivalent age. STUDY DESIGN: Multichannel recordings were made in 12 healthy term and 11 preterm infants, under the same conditions, after feeding. Sleep state, cardiorespiratory variables, esophageal pH, and pharyngeal swallowing and peristalsis were measured. GER was defined as pH <4 for > or = 15 seconds, and swallows were classified as pharyngeal only, primary peristalsis (propagated, dropped, interrupted), or secondary peristalsis. RESULTS: Spontaneous swallowing rate was not significantly different between term and preterm infants and was sleep state-related, occurring in active sleep but rarely in quiet sleep. In response to acid GER, term infants significantly increased pharyngeal swallowing from a median of 0.7 (25th-75th interquartile range, 0.5-0.9) to 1.7 (1.0-3.0) swallows/min and secondary peristalsis from a median of 0.5 (25th-75th interquartile range, 0.3-0.8) to 1.1 (0.8-2.0) waves/min (P <.05). In contrast, the preterm infants demonstrated a significantly higher proportion of fully propagated peristaltic swallows compared with the term infants (53% and 27%, respectively) (P <.05). CONCLUSION: The occurrence of swallowing is sleep state-related. In active sleep, term infants clear GER by increasing swallowing and secondary peristalsis, whereas preterm infants at term equivalent age clear GER by increasing propagated peristalsis. This method of clearance would explain the mechanism by which preterm infants have significantly shorter episodes of reflux than term infants.

Targeted early rescue surfactant in ventilated preterm infants using the click test.

OBJECTIVE: To determine whether use of the click test, a rapid bedside test of surfactant function, results in earlier and more appropriate surfactant administration in ventilated preterm infants than does usual early rescue treatment. STUDY DESIGN: Ventilated preterm infants (n = 126) with inspired oxygen >/=25% and mean airway pressure >/=7 cm H(2)O were randomized in gestational strata (<28 weeks and 28-36 weeks) to have surfactant therapy determined by the click test or by usual clinical and chest radiograph criteria. The treatment group had the click test performed on a tracheal aspirate as soon as possible after intubation and, if negative or equivocal (surfactant deficient), surfactant was given. The control group had surfactant given as soon as possible based on clinical and chest radiograph diagnoses of respiratory distress syndrome. RESULTS: In infants of <28 weeks' gestation, use of the click test resulted in significantly earlier surfactant therapy (median time: 50 vs 159 minutes) and a reduction in the number of infants receiving surfactant (48% vs 79%). In infants of 28 to 36 weeks' gestation, there was no difference in time to surfactant (median time: 300 vs 268 minutes) or in the number of infants receiving surfactant. Neonatal morbidity and mortality were similar in click test and control groups. CONCLUSIONS: Use of the click test in ventilated, extremely premature infants results in significantly earlier and more appropriately targeted administration of surfactant than does early rescue therapy based on clinical and radiograph criteria. A randomized trial of targeted early rescue surfactant therapy versus prophylactic surfactant therapy in infants of <28 weeks' gestation is warranted. The click test has the potential to improve clinical outcomes and reduce costs.

Sedation with promethazine profoundly affects spontaneous airway protection in sleeping neonatal piglets.

1. Phenothiazine use in infants has been implicated in apparent life-threatening events, sleep apnoea and Sudden Infant Death Syndrome. 2. The aim of this study was to investigate the cumulative effects of a commonly used antihistamine medication containing promethazine on airway protective mechanisms and cardiorespiratory responses in 42 healthy neonatal piglets (21 naturally sleeping, 21 sedated sleeping). 3. Sedated piglets were given 1.5 mg/kg, p.o., promethazine 2 h prior to each recording session. Control animals slept naturally with no sedative given. On three consecutive days in all piglets, physiological recordings were made during sleep; on at least one of these days, simultaneous physiological and radiological observations were made. 4. Following sedation, sleep time and time in active sleep were increased significantly (P < 0.01). The spontaneous occurrence of swallowing, arousal, body movement, gastrooesophageal reflux and apnoea was compared between naturally and sedated sleeping piglets. Sedation with promethazine significantly decreased the spontaneous occurrence of swallowing (P < 0.05) and arousal (P < 0.05) and increased the occurrence of both central (P < 0.05) and obstructive sleep apnoea (P < 0.0001). 5. By the third day, a cumulative effect of promethazine was seen; the rate of swallowing and body movement significantly decreased (P < 0.01). 6. In summary, a low dose of promethazine profoundly altered sleep characteristics, airway protective mechanisms and cardiorespiratory responses in normal healthy sleeping piglets. Continued use of promethazine over several days may attenuate airway protective mechanisms to a potentially life-threatening degree. Our findings support continued caution in the use of promethazine-containing medications for the sedation of infants.

Why the prone position is a risk factor for sudden infant death syndrome.

INTRODUCTION: The laryngeal chemoreflex may explain why prone sleeping increases the risk of sudden infant death syndrome (SIDS). Swallowing and arousal are crucial to prevent laryngeal chemoreflex stimulation. Our aim was to examine these reflexes and breathing responses in healthy neonates after pharyngeal infusion of water in the supine versus the prone position, controlling for sleep state. METHODS: A total of 10 term infants were recruited after parental consent and ethics approval. Polygraphic recordings included sleep state (active and quiet sleep by electroencephalogram, eye movements, breathing, and behavior), cardiorespiratory measurements (nasal airflow, chest wall movements, heart rate, and oxygen saturation), swallowing, and esophageal activity (solid state pressure catheter). Initial sleeping position was assigned randomly. Measurements were made for 1 minute before and after 0.4 mL of water was instilled into the oropharynx. To detect a 30% decrease in swallowing, power analysis indicated that >/=10 babies were required. Analysis, blinded to position, was made using nonparametric statistics. RESULTS: Of the 164 infusions, the most commonly evoked airway protective responses to pharyngeal infusion were swallowing (95%) and arousal (54%). After infusion in active sleep, there was a significant reduction in swallowing and breathing when the prone position was compared with the supine position (prone: 21.3 [1.0] swallows/min and -9.6 [2.1] breaths/min; and supine: 32 (2.2) and -2. 9 (1.5), respectively). However, there was no difference in the occurrence of arousal after water infusion. CONCLUSION: These data suggest that airway protection is compromised in the prone sleeping position during active sleep, even in healthy infants exposed to minute pharyngeal fluid volumes of 0.4 mL. This is because swallowing rate is reduced significantly, and there is no compensatory increase in arousal. The reduction in airway protective reflexes when in the prone position and in active sleep may be the mechanism for the increased risk of SIDS in the prone position.

Early onset group B streptococcal neonatal infection in Oxford 1985-96.

Of 74,920 babies live born in Oxford between 1985 and 1996, 41 (0.5 per 1000 95% CI 0.4-0.7) developed definite, culture confirmed, early onset (< 48 hours) group B streptococcal infection and 32 (0.4 per 1000 95% CI 0.3-0.6) developed probable infection (sepsis plus colonisation). There was no significant variation in incidence with time. The mortality from definite infection was 19.5%, and from probable infection 6%. These data suggest that the incidence of group B streptococcal infection in Oxford is considerably lower than that reported in the USA.

Airway protection in sleeping infants in response to pharyngeal fluid stimulation in the supine position.

This study was designed to evaluate upper airway protective mechanisms in response to pharyngeal fluid stimulation in healthy term and preterm infants at term equivalent age. Five term and seven preterm infants were studied and the following recorded: sleep state, cardiorespiratory function, and swallowing. Infusions of 0.9% saline and sterile water of volumes of 0.04, 0.2, and 0.35 mL were made during active (AS) and quiet sleep (QS). The effect of these variables on apnea (> or = 2 and > or = 5 s), swallowing, and arousal was examined. After pharyngeal infusion, apnea of > or = 2 and > or = 5 s did not change from spontaneous rates for both term and preterm infants. The most common response to pharyngeal infusion was swallowing. In AS, swallowing occurred after 65 and 73% and in QS after 40 and 64% of infusions in term and preterm infants, respectively. Swallowing was volume-related and occurred significantly more often in term infants after larger infusions of 0.35 and 0.2 mL (83 and 67%) compared with the 0.04 mL (19%) and after 0.2 mL compared with 0.04 mL for preterm infants (94 and 44%). At 0.2 mL, this was significantly higher in preterm compared with term infants (p < 0.01) and was the only significant difference between these infants. In response to pharyngeal fluid stimulation, airway defense in both full-term and preterm infants is maintained primarily by swallowing with no evidence of apnea.