Measurement of the cardiac time intervals of the fetal ECG utilising a computerised algorithm: A retrospective observational study

.ObjectiveEstablish whether the reliable measurement of cardiac time intervals of the fetal ECG can be automated and to address whether this approach could be used to investigate large datasets.DesignRetrospective observational study.SettingTeaching hospitals in London UK, Nottingham UK and New York USA.ParticipantsSingleton pregnancies with no known fetal abnormality.MethodsArchived fetal ECG's performed using the MonicaAN24 monitor. A single ECG (PQRST) complex was generated from 5000 signal-averaged beats and electrical cardiac time intervals measured in an automated way and manually.Main Outcome measureValidation of a newly developed algorithm to measure the cardiac time intervals of the fetal ECG.Results188/236 (79.7%) subjects with fECGs of suitable signal:noise ratio were included for analysis comparing manual with automated measurement. PR interval was measured in 173/188 (92%), QRS complex in 170/188 (90%) and QT interval in 123/188 (65.4%). PR interval was 107.6 (12.07) ms [mean(SD)] manual vs 109.11 (14.7) ms algorithm. QRS duration was 54.72(6.35) ms manual vs 58.34(5.73) ms algorithm. QT-interval was 268.93 (21.59) ms manual vs 261.63 (36.16) ms algorithm. QTc was 407.5(32.71) ms manual vs 396.4 (54.78) ms algorithm. The QRS-duration increased with gestational age in both manual and algorithm measurements.ConclusionAccurate measurement of fetal ECG cardiac time intervals can be automated with potential application to interpretation of larger datasets

Determination of Haloperidol and Reduced Haloperidol in the Plasma and Blood of Patients on Depot Haloperidol

We developed a sensitive HPLC assay to measure haloperidol (HA) and its metabolite, reduced haloperidol (RH), in plasma and whole blood. The conditions under which HA might be converted to RH during collection and analysis of blood were examined. Provided the blood was kept at 0° C, erythrocyte ketone reductase activity was insignificant. The solid phase extraction method did not generate RH. We studied ten patients taking 25–400 mg/month of HA decanoate and one patient for 4 weeks after the daily oral dose of 120 mg HA was ceased. In the patients on depot HA, the plasma and blood concentrations of HA were not significantly different (P>0.1). For the first time, RH was detected in plasma patients on depot drug, but only in three cases. In contrast, RH was present in the blood of eight of these patients. The accumulation of RH in red blood cells was also evident in the patient on oral HA, in whom the mean ratio of RH concentrations in whole blood to plasma was 3.6±1.1. Plasma concentrations of HA correlated highly with total neuroleptic activity measured by a radioreceptor assay. Compared to plasma, analysis of concentrations of HA and RH in blood has the advantages of greater sensitivity, of using smaller volumes of blood and of avoiding the efflux of HA and RH during separation of plasma and red cells

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis

Background: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 \u3bcmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67\ub78%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0\ub77%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0\ub76%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1\ub704, 95% CI 0\ub735\u20133\ub707; p=0\ub795). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0\ub729, 95% CI 0\ub704\u20132\ub742; p=0\ub725). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1\ub728, 95% CI 0\ub786\u20131\ub791; p=0\ub722), but was associated with a reduced composite outcome when considering only randomised controlled trials (0\ub760, 0\ub739\u20130\ub791; p=0\ub7016). Interpretation: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. Funding: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy

Background: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35–3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04–2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86–1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39–0·91; p=0·016). Interpretation: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. Funding: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.</p