Library

Notes: The failure of tocolytics to improve neonatal outcomes in placebo-controlled trials has wrongly been interpreted as evidence that they do not work. While delivery is unequivocally prolonged by 24 hours, 48 hours and 7 days, the time gained was not exploited to optimise neonatal outcome. These trials typically studied women at relatively advanced gestational ages with predictably good outcomes, enrolled them in tertiary centres where they could not benefit from in-utero transfer, and had low levels of corticosteroid administration. No study has been powered to detect clinically meaningful differences that might be expected to accrue from 1–7 days prolongation of gestation. Despite this, Bayesian interpretation suggests that tocolytics do improve neonatal outcome. The largest placebo-controlled study showed clear trends towards better survival in fetuses 〈28 weeks, lower rates of cerebral palsy and higher Bayley mental scores. Meta-analysis of neonatal morbidity in the beta-agonist trials suggests a near-significant reduction in respiratory distress syndrome (RDS), together with trends towards reduced intraventricular haemorrhage, necrotising enterocolitis, and patent ductus arteriosus. Finally, there is the Orwellian analogy that tocolytics don't work, but some work better than others. Although calcium antagonists have not been evaluated against placebo, meta-analysis of comparative trials with beta-agonists demonstrate a significantly lower incidence of RDS and neonatal jaundice, presumably mediated through the reduced chance of delivery within 48 hours and 7 days. Development of tocolytics that are safe for mother and baby should facilitate adequately-powered placebo-controlled studies, which both focus on women most likely to benefit and capitalise on the 1–7 days gained.

Notes: Objectives To document the duration of fetal cardiac time intervals in uncomplicated singleton pregnancies using a novel non-invasive fetal electrocardiography (fECG) system and to demonstrate this technique's ability to acquire recordings in twin and triplet pregnancies.Design Prospective cross sectional observational study.Setting Antenatal wards and clinics, day assessment unit and centre for fetal care at a tertiary referral hospital, London, UK.Population or Sample Three hundred and four singleton and multiple pregnancies, 15–41 weeks of gestation.Methods Using electrodes sited on the maternal abdomen, a fetal electrocardiography (fECG) system was developed and tested on 304 pregnant women from 15 to 41 weeks of gestation, of whom 241 were uncomplicated singletons, 58 had twin and 5 had triplet pregnancies. The composite abdominal signals were stored on a laptop computer and the fECG derived off-line using a digital signal processing technique. For singletons, linear regression was used to analyse PR, QRS, QT and QTc intervals, and construct time-specific reference ranges.Main outcome measure Duration of fECG time intervals as a function of gestational age. Success of signal seperation in singleton, twin and triplet pregnancies.Results For singletons, a total of 250 recordings was obtained from 241 individuals with a signal separation success rate of 85% (213/250). Success rates were significantly poorer between 27 and 36 weeks of gestation (2 × k χ2, P 〈 0.0001), with 84% (31/37) of separation failures occurring during this period. P, Q, R and S waves were seen in all cases where fetal signals were separated and were used to generate fECG time interval reference ranges. In 22% (43/199) of analysed cases, no T waves were identified, 63% (27/43) of whom were ≤24 weeks of gestation. In twins and triplets, separate fetal signals were obtained in 78% (91/116) and 93% (14/15), respectively; P, Q, R and S waves were evident in all averaged fECGs, while T waves were identified in 59% (54/91) and 57% (8/14).Conclusions This study provides reference ranges with gestation for fECG intervals derived non-invasively from normal singleton pregnancies and demonstrates the feasibility of obtaining complete fECG recordings non-invasively across a wide gestational range in pregnancies of all pluralities. The fECG time intervals described will enable the identification of pathological fECG recordings from high risk pregnancies where fECG abnormalities are suspected.

Notes: We recently reported the existence of fetal mesenchymal stem cells in first trimester fetal blood. Here we demonstrate that fetal mesenchymal stem cells from as early as eight weeks of gestation can be retrovirally transduced with 99% efficiency without selection. Circulating fetal mesenchymal stem cells are known to readily expand and differentiate into multiple tissue types both in vitro and in vivo, and might be suitable vehicles for prenatal gene delivery. With advances in early fetal blood sampling techniques, we suggest that genetic disorders causing irreversible damage before birth could be treated in utero in the late first/early second trimester by genetically manipulated autologous fetal stem cells.

Notes: Objective To establish the current availability of meta-analytical overviews of effective care in perinatal medicine, in the form of Effective Care in Pregnancy and Childbirth and the Oxford Database of Perinatal Trials, in English obstetric units and to find out how obstetricians without either one keep up to date.Design Standardised telephone questionnaire.Subjects The consultant obstetrician deemed to be the Royal College of Obstetricians and Gynaecologists' administrative contact in each of the 24 teaching hospitals, and in 74 of 173 (43%) district general hospitals in England.Main outcome measures Knowledge and use of Effective Care and the Oxford Database in the obstetric unit.Results Thirty-seven percent of units did not have access to either Effective Care or the Oxford Database, with significant differences between district general hospitals and teaching hospitals in lack of availability (33/74 (45%) versus 3/24 (12%) respectively, P= 0.02). Effective Care was available in 51% of district general hospitals and 79% of teaching hospitals, compared with the availability of the Oxford Database which was only available in 16% and 62%, respectively. Reasons given for not obtaining either included non-awareness, expense, and perceived lack of need. The consultants with neither Effective Care nor the Oxford Database claimed to keep up to date by various methods, usually as information from colleagues.Conclusions These results reflect both inefficient dissemination of medical knowledge in obstetrics and the reluctance of obstetricians to consider adapting their practice as a result of evidence from meta-analyses of randomised controlled trials. Although Effective Care is more widely available than the Oxford Database, its datedness renders it inferior to the database as a means of facilitating effective care in obstetrics.

Notes: Objectives To demonstrate that fetal human platelet antigen (HPA1) type can be determined, without the need for fetal blood sampling, by amplification of fetal DNA from amniotic fluid cells using polymerase chain reaction and allele specific oligonucleotide hybridisation.Design Oligonucleotide DNA primers were designed to amplify a portion of the platelet glycoprotein GpIIIa gene which spans the site of the single base change which differentiates HPAla from HPAlb. Specific oligonucleotides were designed to hybridise either to the amplified HPAla allele or to the HPAlb allele. Amniotic cells were used as the DNA template both directly and following formal isolation of DNA. Fetal HPA1 type, determined by this method in fifteen pregnancies not at risk of perinatal alloimmune thrombocytopaenia, was compared to typing of fetal blood obtained following cordocentesis. The methodology was then used to HPA type the fetus in two pregnancies at risk of the disease.Setting Department of Molecular Biology and Centre for Fetal Care, Queen Charlotte's Hospital.Subject Fifteen women undergoing amniocentesis and fetal blood sampling for other indications and two women at risk of perinatal allo-immune thrombocytopaenia whose partners were heterozygotes.Results In the 15 control cases and the two clinical cases, determination of fetal HPA1 type from amniotic fluid cells agreed with typing of fetal blood. There was no difference in the efficiency of amplification from amniotic fluid cells directly or from isolated DNA.Conclusions Fetal HPA type may be reliably determined by amplification of DNA from amniotic fluid cells, eliminating the need for fetal blood sampling or immunoglobulin administration when the fetus is HPAla negative.

Notes: Objective To determine in vivo whether monochorionic pregnancies complicated by twin-to-twin transfusion syndrome are associated with absence of haemodynamically-compensatory arterioarterial anastomoses.Design Forty monochorionic pregnancies were prospectively recruited for an ultrasonographic survey of the chorionic plate using colour Doppler energy. Arterio-arterial anastomoses were identified by their characteristic bidirectional interference pattern on spectral Doppler. Angioarchitecture was confirmed by postnatal injection study.Setting Fetal medicine tertiary referral centre in London.Main Outcome measures Presence of arterio-arterial anastomoses, development of twin-to-twin transfusion syndrome, survival.Results Arterio-arterial anastomoses were detected by colour Doppler energy in 21 pregnancies (53%), and there were no false positives. An arterio-arterial anastomosis was more commonly found in unaffected (n= 28) compared to pregnancies affected by twin-to-twin transfusion syndrome (n= 12), both by colour Doppler energy [20/28 (71%) vs 1/12 (8%); Δ= 63%, 95% CI 40%-86%] and by postnatal injection study [25/28 (89%) vs 3/12 (25%); Δ= 64%, 95% CI 37%-91%]. In pregnancies in which no arterio-arterial anastomoses were detected, a diagnosis of twin-to-twin transfusion syndrome was made in 58%, and the perinatal loss rate was 40%, compared with one case of twin-to-twin transfusion syndrome (5%) (P 〈 0.001) and a loss rate of 12% (P = 0.005) in pregnancies in which an arterio-arterial anastomosis was detected.Conclusion Twin-to-twin transfusion syndrome is associated with an absence of functional arterio-arterial anastomoses in vivo in monochorionic twin pregnancies. This contributes to our understanding of the pathophysiology of twin-to-twin transfusion syndrome and confirms ex vivo studies demonstrating that twin-to-twin transfusion syndrome is associated with a paucity of superficial anastomoses. Prospective studies are indicated to determine the utility of colour Doppler energy for arterio-arterial anastomoses in predicting risk in monochorionic pregnancies.