Introduction: Pseudoxanthoma elasticum (PXE) is an inherited multisystem disorder of the elastic tissue and the objective of this case report is to correlate ultrasonographic and histological appearances of placental calcification in PXE. Clinical Picture: We report a case of a 37-year-old white woman with PXE, whose antenatal imaging showed a markedly echogenic placenta due to extensive calcification confirmed on postpartum placental histology. Outcome: There were no maternal or fetal complications in the antenatal period. A healthy baby of appropriate maturity and weight was delivered via Caesarean section and remained well at 6 months. Conclusion: The majority of cases of PXE is caused by mutations in the ABCC6 gene. Serious complications in pregnancy can include gastrointestinal haemorrhage, congestive heart failure and cardiac arrhythmia but has not been shown to be associated with markedly increased fetal loss or adverse reproductive outcomes as reported in previous literature. Apart from the cosmetic deterioration of the abdominal skin, there were few serious complications and most have normal pregnancies. Obstetric prognosis is dependent on the vascular damage caused by the illness. There is no basis for advising women with PXE to avoid becoming pregnant, and most pregnancies in PXE are uncomplicated.

The Integrated test combines results from first-trimester nuchal translucency (NT) measurement with first- and second-trimester serum hormone levels to screen for Down syndrome (DS) and the test has been offered routinely to women booking for antenatal care at our institution since January 2003. Our current policy is to offer immediate invasive testing to women with an NT ≥ 3.5 mm and we evaluated this policy for the first 3 years of Integrated test screening. This was a retrospective study of 8311 women booked for antenatal care at University College London Hospital who were screened for DS by the Integrated test. First-trimester sonogram reports and pregnancy outcomes were analyzed using an NT measurement cut-off of ≥ 3.5 mm. The NT measured ≥ 3.5 mm in 151 (1.8%) of the women screened; 131 women (87%) whose fetus had an NT ≥ 3.5 mm opted for immediate invasive testing by chorionic villus sampling (n = 130) or amniocentesis (n = 1). The remainder continued with screening by the combined test (n = 5) or the Integrated test (n = 3). There were 46 cases of DS in the screened population of which 30 had an NT ≥ 3.5 mm (detection rate 65%). There were 23 other aneuploidies with an NT ≥ 3.5 mm, including trisomy 13 (n = 12), trisomy 18 (n = 5) and Turner's syndrome (n = 6). The detection rate of the Integrated test at UCLH for DS was 90% with a false-positive rate of 2.3%. In women undergoing Integrated screening we detected a high proportion of DS fetuses and other aneuploidies in the first trimester, using a policy of offering an immediate invasive test when the NT measurement was ≥ 3.5 mm. The majority of women in this high-risk group had invasive testing, but the DR for the Integrated test remained high.

We have evaluated a cohort of women booked for antenatal care at University College London Hospitals. The uptake of screening was 64.4% and was significantly higher (73 versus 46%) in women who booked before 14 weeks. Of the women who booked before 14 weeks, 96.8% opted for the integrated test (IT). Overall, 5.3% failed to attend for the second blood test. The false‐positive rate in the women who had the IT was 2.9%. All 11 cases of Down syndrome were detected prenatally. Our study is the first to evaluate implementation of the IT into routine clinical practice.

To evaluate the Integrated test (IT) for Down syndrome (DS) screening in routine clinical practice. Recent studies have suggested that the IT provides a highly effective method of screening for DS (SURUSS, FASTER). Criticism for this method of screening includes the fact that this is a two-stage screening test requiring women to have a scan to measure fetal nuchal translucency (NT) and a blood test to measure PAPP-A at 10 to 13 + 6 weeks and to subsequently return for a further blood test (AFP, βhCG, Ue3 and Inhibin A) at 15–22 weeks. Risk assessment is available after completing the second blood test. Fetuses with an NT ≥ 3.5 mm were referred to the fetal medicine unit. We have evaluated a cohort of women booked for antenatal care from 1st January 2003 to 28th February 2006. 11 919 women booked for antenatal care during this time, of which 8155 (68%) had a screening test for DS using either IT (75%), Combined test (2%) or quadruple test (23%). 98% of women booking in time and accepting screening chose to have the IT (n = 6.157). The median maternal age of women having the IT was 33 years. 5678 women (92%) successfully completed both stages of the IT. The median gestational age for the second blood test was 16 weeks + 1 day. In the women who completed the IT the detection rate (DR) for DS was 89% (16/18, 95% CI 74–100%). The false positive rate (FPR) was 2.5% (142/5660, 95% CI 2.1–2.9%). The odds of being affected given a positive result (OAPR) were 1 : 9. Based on the maternal age distribution of the screened population the expected DR was 91%, FPR 2.3% and OAPR 1 : 7. The results show that the IT is a highly effective screening test and can be successfully implemented in a routine antenatal clinic setting. At UCLH 92% of women completed both stages of the IT. In a population with a high median maternal age, the observed screening performance was close to that expected given the age distribution of the population screened.

Summary Objectives The aims of this study were to investigate if (i) urinary concentrations of activin A and inhibin A are altered in pre‐eclampsia (PE) and (ii) to study the relationship between uterine vein and peripheral vein concentrations of these hormones in PE patients. Design and method In a retrospective study, maternal peripheral vein and uterine vein serum and maternal urine samples collected at the time of delivery were analysed. There were three groups of patients; (i) group 1: term normal pregnancies ( n = 19) (ii) group 2: patients who developed PE ≤ 37 weeks ( n = 17) and (iii) group 3: patients who developed PE 37–40 weeks ( n = 8). Serum and urinary activin A, follistatin, inhibin A and pro alpha C and urinary creatinine levels were measured using enzyme immunoassays in the laboratory. Results Normal pregnant urine samples had very low levels of activin A and inhibin A. Both groups 2 and 3 PE patients had significantly higher levels of inhibin A ( P < 0·001) and activin A ( P < 0·001) compared to the controls. Pro‐alpha C was not altered and follistatin was below the detection limit of the assay in the urine. Maternal peripheral serum activin A and inhibin A were significantly higher in groups 2 ( P < 0·001) and 3 ( P < 0·05) patients compared to the controls. Pro‐alpha C‐containing inhibins were higher in group 2 patients ( P < 0·05) compared to the controls in the peripheral circulation. Uterine vein serum activin A and inhibin A levels were also significantly higher in groups 2 ( P < 0·001) and 3 ( P < 0·05) patients compared to the controls. There was a highly significant positive correlation between peripheral and uterine vein serum concentrations of activin A, follistatin, inhibin A and pro alpha C, suggesting the same source for these proteins in PE. Conclusion Urinary activin A and inhibin A are raised in groups 2 and 3 PE patients. The magnitude of rise (> 25‐fold) suggests these proteins may rise in patients before the onset of the clinical symptoms of PE. Uterine vein levels of these proteins are also raised in PE.

Labor induction in second- and third-trimester therapeutic termination of pregnancy (TOP) is associated with an increased risk of maternal hemorrhage in cases with placenta previa1. Recently, it was demonstrated that second- and third-trimester therapeutic TOP in cases with complete placenta previa is feasible and that the incidence of maternal hemorrhage decreases when feticide is performed a few days before delivery2. However, despite the authors suggesting that feticide might decrease uteroplacental blood flow, thus reducing maternal blood loss, they could not demonstrate this. We followed a 31-year-old woman, gravida 2 para 1, with one previous Cesarean section, who was referred at 29 weeks' gestation because of prenatal diagnosis of multiple fetal malformations (anencephaly and large defect of the anterior abdominal wall) associated with a complete placenta previa. Feticide was performed by injecting 5–15 mL potassium chloride (1.34 mmol/mL) into the fetal circulation under ultrasound guidance. The uteroplacental blood supply was then followed sonographically by three-dimensional (3D) power Doppler and pulsed color Doppler of the uterine arteries using a Voluson 730-expert (GE Medical System, Waukesh, WI, USA) ultrasound machine equipped with a 5–9-MHz transvaginal probe. The placental vascularization index (VI) and volume were calculated using pre-established power Doppler settings (quality, high; wall motion filter, low1; smooth, 5/5; frequency, mid; dynamic set, 3; density, 8; balance, G > 150; pulse repetition frequency, 0.9), the rotational technique (VOCAL™ software) and the 3D power Doppler histogram. The VI (color voxels/total voxels) was used to evaluate the placental blood supply: it describes the percentage of color within the volume of interest and therefore provides an indication of how many vessels can be detected within the tissue block, i.e. its vascularity3-6. Delivery occurred 4 days after feticide. Arterial resistance increased in both uterine arteries mainly on the second day after feticide. Estimated placental volume and placental blood supply (VI) decreased progressively from 549.85 cm3 and 12.05% before feticide to 413.51 cm3 and 4.14% on the third day after the procedure (Figures 1 and 2). Despite maternal bleeding, the placenta detached spontaneously during delivery and the difference between hemoglobin levels before and after delivery was 0.9 g/dL (10.5 g/dL before and 9.6 g/dL after). Multiplanar imaging of placental volumes before feticide (Pre), and 1 day (D1), 2 days (D2) and 3 days (D3) after feticide. Placental volume (a), placental vascularization index (b) and pulsatility indices of right (dashed line) and left (solid line) uterine arteries (c) before fetal demise (Pre), 24 h after fetal demise (D1), and on the second (D2) and third (D3) days after fetal demise. To our knowledge, there have been only three studies on TOP in cases with placenta previa. In the first two studies, TOP was performed up to 24 weeks, allowing suction evacuation and curettage procedures to be performed1, 7. In the third report, the authors analyzed TOP with complete placenta previa in which vaginal delivery occurred between 18 and 31 weeks of gestation2. They demonstrated that the difference between pre- and post-delivery maternal hemoglobin levels was significantly lower in cases in which feticide was performed prior to delivery compared with cases in which feticide was not performed. In our case, delivery took place 4 days after feticide and the hemoglobin difference was 0.9 g/dL, very similar to rates published previously2. Our case demonstrates that feticide performed a few days before induction of labor and delivery in cases with complete placenta previa reduces uteroplacental flow. While reduction in placental blood supply can be observed indirectly by an increase in resistance of the uterine arteries, it can be quantified directly using 3D power Doppler ultrasound. We used the VI to follow the decrease in placental vascularity, because it quantifies directly the number of vessels detected within the tissue block, making it possible to determine the placental vascular blood supply. Analysis of the variation in VI after feticide indicated that a considerable reduction in placental blood supply may occur 2 days after feticide. However, further studies to confirm this are necessary. Meanwhile, we suggest the use of 3D power Doppler for monitoring the placental blood supply after feticide in order to better organize delivery and to reduce the risk of maternal hemorrhage in TOPs with complete placenta previa. R. Ruano*, M. M. Kondo*, V. Bunduki*, C. Rodeck , M. Zugaib*, * Fetal Medicine Unit, Obstetrics Department, Hospital das Clinicas, Faculdade de Medicina da Universidade de São Paulo, R. Valentim Magalhães, 100 ap 62, 031184-090 São Paulo, SP, Brazil, Department of Obstetrics and Gynaecology, Royal Free and University College Medical School, London, UK

OBJECTIVE:This prospective observational pilot study was undertaken to assess the efficacy of mifepristone and misoprostol, both administered vaginally. The ultimate goal is to investigate alternative means of reducing the time interval between the two treatments involved. The efficacy of the early medical abortion regimen utilizing mifepristone and misoprostol is beyond doubt. The regimen usually involves administering misoprostol 36 h following oral administration of mifepristone. The interval between the two treatment components might affect a woman's choice of the medical method.METHODS:Eighteen women undergoing abortion for nonmedical reasons were recruited.RESULTS:Seven women required further intervention to achieve complete abortion. Median induction-to-abortion interval was 7.66 h in the 11 women with complete abortion.CONCLUSION:The complete abortion rate of 61% in this study was lower than that with the standard medical regimen.

Somatic gene delivery in utero is a novel approach to gene therapy for genetic disease based on the hypothesis that prenatal intervention may avoid the development of severe manifestations of early-onset disease, allow targeting of otherwise inaccessible tissues including expanding stem cell populations, induce tolerance against the therapeutic transgenic protein and thereby provide permanent somatic gene correction. This approach is particularly relevant in relation to prenatal screening programmes for severe genetic diseases as it could offer prevention as a third option to families faced with the prenatal diagnosis of a genetically affected child. Most investigations towards in utero gene therapy have been performed on mice and sheep fetuses as model animals for human disease and for the application of clinically relevant intervention techniques such as vector delivery by minimally invasive ultrasound guidance. Other animals such as dogs may serve as particular disease models and primates have to be considered in immediate preparation for clinical trials. Proof of principle for the hypothesis of fetal gene therapy has been provided during the last 2 years in mouse models for Crigler Najjar Disease, Leber's congenital amaurosis, Pompe's disease and haemophilia B showing long-term postnatal therapeutic effects and tolerance of the transgenic protein after in utero gene delivery. However, recently we have also observed a high incidence of liver tumours after in utero application of an early form of third-generation equine infectious anaemia virus vectors with SIN configuration. These findings highlight the need for more investigations into the safety and the ethical aspects of in utero gene therapy as well as for science-based public information on risks and benefits of this preventive gene therapy approach before application in humans can be contemplated.

To evaluate the incidence and significance of fetal anomalies and soft markers following risk stratification for Down syndrome using the integrated screening test. A retrospective study of 2332 women booked for antenatal care at University College London Hospital who were screened for Down syndrome by the integrated test and who received a detailed anomaly scan. Scan reports and integrated test results were analyzed statistically by SPSS v11.0 software. The integrated test stratified 68 women (1 : 34) at high risk for Down syndrome (> 1 : 150). There were 12 cases affected by Down syndrome, 10 (1 : 7) in the high risk group and 2 (1 : 1132) in the low risk group. The findings of the detailed anomaly scan are presented in Table 1. In the high risk group, the risk of Down syndrome was reduced by 33% by the absence of soft markers or structural anomalies on ultrasound scan and by 76% by the additional presence of normal BPD/OFD and BPD/FL ratios. However, up to 50% of affected cases would have been missed if karyotyping had not been performed in high risk women with normal sonography. In the low risk population, the presence of an intracardiac echogenic focus was the most predictive of Down syndrome compared to other soft markers and increased the risk by 11.5 fold. However, karyotyping based on the presence of this soft marker would have increased the amniocentesis rate by 2.5 fold with a high false positive rate (7.4%). In women stratified at low risk of Down syndrome by the integrated screening test, the presence of isolated soft markers should not be considered as an indication for amniocentesis due to a substantial increase in the false positive rate. Using sonographic markers to adjust the risk of Down syndrome in the high risk group would decrease the rate of amniocentesis by 40–70% but would reduce the detection rate by 10–50%.

To examine the implementation of the integrated screening for Down syndrome in a government maternity unit providing routine antenatal care. Recent studies have suggested that integrated screening for Down syndrome may provide the most effective method of screening for Down syndrome. However the data available are from modeling of previous studies or observational studies. We have evaluated prospectively a cohort of women booked for antenatal care in UCLH during a period of 18 months. During this period we have evaluated the uptake of screening for Down's syndrome, type of screening test performed, the rate of invasive prenatal diagnosis and diagnosis of Down syndrome. The uptake of screening during the study period was 62.3% and was significantly higher in women who booked before 14 weeks of gestation (79.9% vs. 46.3%, p < 0.001). The screen-positive rate for each test is presented in Table 1. The overall screen positive rate was significantly lower than previously achieved by the Double test. Two thirds of the screen positive patients opted for an invasive test. 12/26 fetuses with abnormal karyotype (4 trisomy 21) were diagnosed among women that had chosen to have an invasive test due to abnormal findings at 11–14 weeks. In the screen positive groups there were 9 cases of trisomy 21 and two cases of other chromosomal abnormalities. Two fetuses with trisomy 21 were born to patients who did not have any screening. This is the first study to evaluate the introduction of this new method of screening into routine clinical practice for all women booking for antenatal care in a government hospital. In our population the uptake of screening was comparable to other implementation studies and was significantly higher for patients booked in the first trimester. The implementation of our screening policy resulted in a decrease in the screen positive rate and a high detection rate.

The fetal trachea is increasingly seen as a target organ for therapeutic interventions and it can be accessed by ultrasound guided transthoracic injection. Fetoscopic occlusion of the fetal trachea with a detachable balloon in congenital diaphragmatic hernia has a high rate of membrane rupture and preterm delivery.We aimed to occlude the fetal sheep trachea by ultrasound guided insertion and inflation of a detachable balloon. A detachable balloon (GVB 16, Cathnet Science) was inflated in the fetal sheep trachea (n = 4, 1 singleton, 3 twins, 102 days of gestation, term = 145 days) after placement via ultrasound guided transthoracic injection of a 16G Kellett needle (Rocket Medical). Regular ultrasound examination confirmed that tracheal occlusion was maintained after balloon inflation. At post mortem examination 3 weeks after surgery, the lungs and trachea were removed en bloc and weighed. The left lung was inflated with 6% formalin, fixed at 25 cm H2O for 72 hours and processed to determine vascular and airways morphometric indices. Ultrasound guided tracheal occlusion was successful in 3 out of 5 attempts (60%) in a mean time of 17 minutes (16-19) with 100% survival. In one twin pregnancy, the balloon became sited within the accessory lobe bronchus and was not inflated. Attempts to inject its co-twin failed due to fetal position and it died from intrathoracic haemorrhage. All balloons remained inflated and occluded the trachea until post mortem examination. Post mortem and histological examination showed no injection site, haemorrhage or inflammation. The lung to bodyweight ratio increased from a mean of 0.034 (0.02-0.04) in control fetuses to 0.129 (0.10-0.14) in obstructed fetuses. The mean linear intercept (Lm) was larger, and the Lm-wall mean transection length per airspace and mean terminal bronchial density were smaller in obstructed as compared with control lungs. A detachable occlusive balloon can be placed in the fetal sheep trachea using ultrasound guided transthoracic injection with a success rate of 60%.

OBJECTIVE:To investigate the procedure-related complications of rapid amniodrainage in the treatment of polyhydramnios. METHODS:We followed prospectively all patients with polyhydramnios treated with rapid amniodrainage under continuous ultrasound guidance using a vacuum wound-drainage system from 1995 to 2002 in the fetal medicine unit of a university teaching hospital. We recorded: maternal age, type of pregnancy (singleton/twin), cause of polyhydramnios, gestational age at amniocentesis, volume of amniotic fluid drained, duration of the procedure, other intrauterine procedures in addition to the amniodrainage, and procedure-related complications including placental abruption, premature rupture of membranes (PROM), chorioamnionitis, fetal bradycardia and preterm delivery within 48 h of amniodrainage. RESULTS:Seventy-four consecutive women had 134 rapid amniodrainage procedures during the study period. Four procedures were excluded because the women were already in labor at the time of amniodrainage and they delivered within 48 h of the procedure. The final database therefore consisted of 70 patients with 130 procedures. Sixty-two percent (80/130) of the procedures were performed for the treatment of twin-twin transfusion syndrome (TTTS). There were altogether four procedure-related complications (3.1%; 95% CI, 1.0-8.0%). Three of them occurred in the TTTS group (3/80 procedures, 3.8%; 95% CI, 1.0-11.0%): one case each of placental abruption, PROM and fetal bradycardia. One PROM occurred in the non-TTTS group (1/50 procedures, 2.0%; 95% CI, 0-11.0%). In both cases of PROM the women presented in labor. CONCLUSIONS:Rapid amniodrainage using a vacuum wound-drainage system is safe and efficient to treat severe polyhydramnios, with a 3.1% complication rate.

In 1975, I was a clinical lecturer at King’s College Hospital Medical School, trying to organize a major study on fetal monitoring without much success. The following year, Stuart Campbell moved to King’s as head of department and asked what were my interests. Here was an opportunity to drop the fetal monitoring project! I said I was interested in more direct access to the fetus, such as fetoscopy, and asked if he thought it had a future. His friend John Hobbins at Yale was doing some work in that area, and he suggested that I visit and look into it. I had a very enjoyable 2 weeks there in September 1976, observed two cases, and returned to England with a Dyonics Needlescope in my luggage.Dyonics was a small company in Woburn near New Haven, Connecticut, and the Needlescope was a 1.7-mm diameter modified arthroscope. It made fetoscopy a clinical possibility because it could be introduced percutaneously under local anesthesia and on an outpatient basis. Previous attempts at fetoscopy by Valenti, (1) Scrimgeour, (2) and others used larger diameter endoscopes and required a laparotomy—an approach that never entered clinical practice. The Needlescope was used by several groups in North America, including Hobbins at Yale, Benzie in Toronto, and Perry in Montreal. Hobbins and Mahoney (3) reported a technique for obtaining fetal blood in 1974, but it had some drawbacks. It could be used only if the placenta was posterior because the risks of perforating an anterior placenta (eg, fetal bleeding and placental separation) were deemed to be too high. Also, the samples obtained usually consisted of a mixture of fetal red cells, amniotic fluid, and sometimes maternal blood. They were taken by passing a 27-gauge needle down the side channel of the cannula, puncturing a fetal vessel on the chorionic plate of the posterior placenta under direct vision, and aspirating while pulling the tip back into the amniotic fluid. Such mixed samples usually were adequate for prenatal diagnosis of hemoglobinopathies because the diagnosis was based on globin chain production by the fetal reticulocytes.Placentacentesis was another method of obtaining fetal red cells for prenatal diagnosis of hemoglobinopathies that was being used by the San Francisco group (4) and a collaboration of teams from Boston and University College London. The aim was to introduce a needle into the placenta, usually “blindly” (ie, without ultrasonographic guidance), and to perforate fetal vessels on the chorionic plate. This procedure made the anterior placenta amenable to sampling, but the aspirates usually were less suitable for diagnosis than those obtained by the Hobbins and Mahoney technique. In approximately 15% of cases, the number of fetal red cells was inadequate and the procedure had to be repeated. Furthermore, there was a 10% fetal mortality rate due to exsanguination. As fetoscopy became more widespread, most centers abandoned placentacentesis.At King’s, we decided to focus on fetoscopy and to make it an ultrasonographically guided procedure, using the recent advances in real-time ultrasonography. One of our motivations was prenatal diagnosis of the hemoglobinopathies because the immigrant population in South London provided the highest concentration of the sickle cell gene in Europe. In addition, we had a hemophilia center and were interested in diagnosing severe hemophilia prenatally. To do this, we had to obtain uncontaminated fetal plasma in which coagulation had not been initiated. The samples obtained with the then current techniques would not suffice.Thus, we had two goals: 1) to use fetoscopy whether the placenta was anterior or posterior and 2) to obtain pure fetal blood every time. We began with patients who were having second-trimester termination of pregnancy; they received intra-amniotic prostaglandins after the fetoscopy, which initially was performed under general anesthesia. Every week I carried an ADR real-time scanner to nearby Dulwich Hospital, which was the location of our gynecology department. The anesthetist cynically observed that the fetoscope was another gadget doomed to be discarded on the surgical scrap-heap!To achieve our two goals we had to break two cardinal rules. The first was “Keep to the midline,” which was based on the possibility of the trocar in a lateral approach damaging bowel or major uterine vessels. However, to avoid perforating an extensive anterior placenta, an extremely lateral entry into the uterus frequently had to be used. In my experience of some 2,000 fetoscopies, there never were any maternal complications. The puncture site was selected with great care using ultrasonography. By 18 weeks’ gestation, the uterus had pushed bowel aside, and the major vessels were too deep in the pelvis. Readiness to adopt a lateral approach combined with careful ultrasonographic planning and selection of the entry point enabled the safe use of the fetoscope whatever the placental site.The second rule that we broke was “Don’t touch the cord.” It was believed that this was dangerous because of the likelihood of bleeding or umbilical vessel spasm. The first time I broke this taboo and punctured a vessel at the base of the cord, the choice was either to touch the cord or not to obtain a sample, thereby failing to make a diagnosis for the patient. The problem had been that puncturing chorionic plate vessels (the Hobbins/Mahoney technique) was difficult when the placenta was anterior and the fetoscope entry was lateral. The view was across the surface of the chorionic plate, and the vessels could not be seen readily; conversely, the cord insertion stood out like a beacon. The vessels had acquired a white covering, the Wharton’s jelly, so that they lost some of their color, but they were, of course, larger, and it still was possible to distinguish umbilical arteries from vein. It was with some trepidation that I plunged the tip of the 27-gauge needle into a vessel at the base of the cord. There was no hint of spasm! Furthermore, pure fetal blood was aspirated into the 1-mL syringe far more easily and quickly than from chorionic plate vessels, and after withdrawal of the needle, there was much less bleeding into the amniotic fluid. The Wharton’s jelly closed the puncture hole and acted as a hemostat.It rapidly became clear that this was a reliable and safe technique. (5)(6) The ease of aspiration of fetal blood meant that coagulation was not initiated during the process. Further, Reuben Mibashan, director of our Haemophilia Centre, could perform accurate coagulant assays for factors VIII and IX (7) as well as other factors on 100-mcL aliquots. It also was clear that 4 to 5 mL of blood could be taken from a fetus at 20 weeks’ gestation without causing any harm.It was not long before six to eight patients a week were coming for prenatal diagnosis of hemoglobinopathies and hemophilia A and B from all over Europe and further afield. Other diagnostic possibilities became possible using fetal red cells, white cells, platelets, and plasma. Normal physiologic ranges could be studied and differences between umbilical artery and vein blood documented. New diagnostic procedures, such as fetal skin and liver biopsy, were performed fetoscopically, as were the first successful percutaneous intravascular fetal transfusions. The latter transformed the prognosis for fetuses that had early severe hydropic hemolytic disease. We felt the age of fetal medicine had dawned! (8)(9)Change has been rapid, largely due to improvements in ultrasonographic technology. Fetoscopy was an ultrasonographically guided procedure, but the final placement of the needle was performed under direct endoscopic vision. In the early 1980s, ultrasonographic equipment enabled the needle to be guided solely by ultrasonography. (10)(11) By the mid-1980s, all centers were taking fetal blood by ultrasonographic guidance. It was easier to perform, less invasive than fetoscopy, and led to a further increase in the number of physicians capable of performing the procedure, the indications for the procedure, and the number of patients undergoing it.Since the heyday of fetal blood sampling in the 1990s, there has been a steep decline in its use. The reasons for this include better noninvasive assessment of fetal anemia and intrauterine growth restriction (by Doppler ultrasonography); molecular techniques for the prenatal diagnosis of genetic diseases (by chorionic villus sampling), fetal rhesus genotyping, and fetal infection; and above all, polymerase chain reaction for chromosome analysis on amniotic fluid. In most fetal medicine units, fetal blood sampling has become sufficiently infrequent to make it impossible to give all trainees a practical experience and even to maintain the skills of experts. It is vital not to lose this expertise entirely because therapeutic interventions such as fetal gene or stem cell therapy in the future may require access to the fetal vascular compartment. (12)[To read the original article describing fetal blood sampling by fetoscopy written by Rodeck and Campbell in 1978 and reprinted with permission from the British Medical Journal, click here.]

The aims of this study were to investigate the relationship between inhibins, activin A and follistatin in first trimester fetal fluids, maternal serum, placenta and decidua, and to investigate if these hormones are present in the circulation of the early second trimester human fetus. Amniotic and coelomic fluid, maternal serum, placental villi and decidual tissue were obtained from normal pregnancies at 8-12 weeks. Fetal blood by cardiocentesis and maternal blood were collected at 14-16 weeks gestation. Placental extracts had higher concentrations of inhibins, activin A and follistatin compared with decidual extracts. In the second trimester, inhibins and follistatin were detectable in fetal blood at 14-16 weeks gestation. Maternal serum concentrations of inhibin A (P < 0.001) and follistatin (P < 0.05) were significantly higher than fetal serum whereas inhibin B (P < 0.01) and pro-alpha C concentrations (P < 0.001) were higher in fetal serum. Inhibin B concentrations were also higher in male fetal serum samples that had higher concentrations of testosterone. The presence of all molecular forms of inhibins, activin A and follistatin in the first trimester fetal fluids, placental and decidual extracts in the first trimester confirms other reports. In the second trimester, high concentrations of inhibin B with testosterone in the fetal circulation indicate that these hormones may interact in the development of the male fetal gonads.

British Journal of HaematologyVolume 124, Issue 4 p. 433-453 Free Access Transfusion guidelines for neonates and older children First published: 23 January 2004 https://doi.org/10.1111/j.1365-2141.2004.04815.xCitations: 267 Dr F. Boulton, National Blood Service, Southampton Centre, Oxford Road, Southampton SO16 5AF, UK. E-mail: frank.boulton@nbs.nhs.uk AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat This document updates the ‘Guideline for the Administration of Blood Products: Transfusion of Infants and Neonates’, published in 1994. In doing so it acknowledges changes in transfusion practice during the past decade, particularly in respect of safety issues and further published transfusion-related guidelines. The transfusion requirements of the neonate are recognized as unique, but there are other groups of children who are regularly transfused and who have very specific transfusion needs. There remains a lack of evidence for many transfusion practices in the neonatal period and childhood, making recommendations difficult in a number of areas. The British Committee for Standards in Haematology published its last Guideline for the Administration of Blood Products regarding the Transfusion of Infants and Neonates in 1994 (British Committee for Standards in Haematology, 1994). This highlighted the lack of scientific evidence for many of the then widely accepted practices, which were often based on outdated information, particularly in neonatal transfusion. It sought to replace these with recommendations for which there was some scientific support or, at a minimum, defendable broad agreement. It influenced practice positively, but a number of transfusion guideline documents have been published in the last few years incorporating recommendations for transfusion practice in neonates and children. However, in the absence of controlled evaluation, many areas of uncertainty still remain. In addition, the National Health Service Executive (2002), entitled ‘Better blood transfusion: appropriate use of blood’ is as applicable to children as it is to adults. Transfusion practice has advanced since 1994, particularly with respect to safety issues regarding the risk of transfusion-transmitted variant Creutzfeldt-Jacob disease (vCJD). (See the Guidelines for the use of fresh frozen plasma (FFP), cryoprecipitate and cryosupernatant (http://www.bcshguidelines.com) and the vCJD position statement in the document library of the UK Blood Services; http://www.transfusionguidelines.org.uk.) Although there is no current alternative to red cells and platelets from UK donors if the UK demand for these products is to be satisfied, sourcing FFP from donors residing in areas where bovine spongiform encephalopathy (BSE) and vCJD have never been endemic is more feasible. However, this may introduce other risks (e.g. if the prevalence of transfusion-transmissible diseases caused by known organisms is relatively high in such areas), but most of these diseases can be effectively eliminated from plasma by virus inactivation procedures. Although these procedures do not inactivate prions, by applying them to imported plasma the overall risks of transmitting infection (including vCJD) from treated products will be reduced. Important changes in transfusion practice include: • Leucocyte depletion (LD) of blood components, operative throughout the UK from 1 November 1999. This Guideline assumes that all cellular blood components, except granulocyte concentrates, are leucocyte depleted at the point of manufacture to comply with recent specifications (The Stationary Office, 2002) (<5 × 106 white blood cells per component in at least 99% of components with 95% confidence). This is monitored by a statistical control process as the residual leucocyte content is not ascertained in all components issued (3·52 million in the UK in 2000/2001). • The manufacture of fractionated pooled products from non-UK sourced plasma from November 1999. • Although single donor plasma products (FFP, cryoprecipitate and cryosupernatant) are currently still prepared from UK-sourced plasma, FFP subjected to virus inactivating procedures (‘virus inactivated plasma’, VIP), such as photo-inactivation in the presence of methylene blue (MB FFP) or treatment with solvent detergent (SD FFP), has been available in limited quantities since 2002. However, virus inactivated cryoprecipitate is not yet available. Recipients of SD FFP have been infected with parvovirus B19 (a non-lipid enveloped virus which is less susceptible to inactivation) (Koenigbauer et al, 2000). • The SD FFP is sourced from the USA where neither BSE nor vCJD are endemic. MB FFP, sourced from the USA, will become available from 2004. These are suited to children born after January 1996 who have therefore not been exposed to BSE in the food chain. • Plasma treated with psoralen S-59 and UVA light has undergone clinical trials in the USA in patients with liver disease and those with rare single clotting factor deficiencies. No significant differences from other VIP have been noted. S-59-UVA-treated FFP is produced from single units of plasma and may become available in the UK soon. Clinical advances have proceeded at an even greater pace. Progress in neonatal intensive care, extra corporeal membrane oxygenation (ECMO), cardiac bypass surgery, bone marrow and solid organ transplantation, and the management of haemoglobinopathies and malignancy means that any neonate or child requiring transfusion will be among the most intensively transfused of all hospital patients. Furthermore, they are likely to need highly specified products; the intensity of their transfusion, their age and potential life expectancy makes safety paramount. This Guideline re-evaluates current transfusion practices, particularly evidence-based practices where they exist, and updates recommendations in existing guidelines in the light of developments in transfusion and clinical practice. Indications for transfusion, product selection, compatibility testing and administration of blood products, will be considered (see Appendix 1 for detailed recommendations). 1. Blood and blood component specification 1.1. General recommendations (fetuses, neonates, infants and children) More precise product specifications for cellular and plasma components, including cryoprecipitate, are given in the ‘Guidelines of the UK Blood Transfusion Services’ (The Stationary Office, 2002). More details on granulocyte preparations are given in Section 3.2.4 of this Guideline. 1.1.1. Donors Components for transfusion in utero or to children under 1 year of age must be prepared from blood donated by donors who have given at least one previous donation within the past 2 years, which was negative for all mandatory microbiological markers. 1.1.2. Leucocyte depletion All components other than granulocytes should be leucocyte depleted (not more than 5 × 106 leucocytes per unit) at the time of manufacture (level IV evidence, grade C recommendation). 1.1.3. Cytomegalovirus The ‘Guidelines of the UK Transfusion Services’ (The Stationary Office 2002) state that blood transfused in the first year of life should be cytomegalovirus (CMV) seronegative. The evidence for this is still under review, so this advice holds for the present. Other authorities state that components that have been leucodepleted to <5 × 106/unit have a significant reduction in risk of CMV transmission (American Association of Blood Banks, 2000; Council of Europe, 2002: level IIb evidence, grade A recommendation). Those at greatest risk of transfusion transmitted CMV are fetuses and infants weighing under 1·5 kg, immunodeficient patients and stem cell transplant recipients. Some clinicians may prefer CMV seronegative components for recipients of haematopoietic stem cell transplants and patients with cellular immunodeficiency who are considered to be particularly susceptible to severe CMV infection. Although the efficiency with which blood products in the UK are depleted of leucocytes is high, only a few products are directly tested for compliance with the specification. This means that there is no guarantee that an individual product has been sufficiently depleted, so that the use of products that are CMV seronegative is still recommended where CMV-free products are indicated. However, in an emergency and where seronegative blood components are not available, transfusion of leucodepleted components is an acceptable, although less desirable, alternative (American Association of Blood Banks, 2000; Ronghe et al, 2002; The Stationary Office, 2002). 1.1.4. Irradiation Blood components should be irradiated prior to transfusion in line with the Guidelines published by the British Committee for Standards in Haematology (1996a) (see also Appendix 2). It is essential to irradiate all red cell and platelet components (with the exception of frozen red cells) for: 1 Intrauterine transfusion (IUT) (level III evidence, grade B recommendation). 2 Exchange transfusion (ET) of red cells after IUT (level III evidence, grade B recommendation). 3 Top-up transfusion after IUT (level III evidence, grade B recommendation). 4 When the donation is from a first- or second-degree relative or a human leucocyte antigen (HLA)-selected donor (level III evidence, grade B recommendation). 5 When the child has proven or suspected immunodeficiency (level III evidence, grade B recommendation). 6 Other indications as listed in the above Guidelines. The component must be irradiated to a minimum dose of 25 Gy. For IUT and large volume transfusion (e.g. ET), the component should be used within 24 h of irradiation and within 5 d of donation (level IV evidence, grade C recommendation). Red cells for top-up transfusion may be irradiated at any time up to 14 d after collection, and thereafter stored for a further 14 d from irradiation (level IV evidence, grade C recommendation). Platelets transfused in utero to treat alloimmune thrombocytopenia and platelet transfusions given after birth to infants who have received either red cells or platelets in utero should be irradiated. However, there is no need to irradiate other platelet transfusions in preterm or term infants, unless they are from first- or second-degree relatives (level III evidence, grade B recommendation). All granulocytes should be irradiated for patients of any age and transfused as soon as possible after irradiation (level III evidence, grade B recommendation). 1.1.5. Plasma and platelet compatibility Platelets should be ABO and RhD identical with the recipient. If this cannot be ensured, then compatible components lacking high titre anti-A or anti-B should be transfused to group A or B recipients. Group AB FFP, specifically for transfusion in the first year of life, may be given. For platelet and FFP transfusions, plasma compatibility should be ensured whenever possible. Both products contain enough red cell stroma to stimulate Rh immunization (level IIb evidence, grade B recommendation and level IV evidence, grade B recommendation). Therefore, RhD-negative girls for whom only RhD positive products are available should receive anti-D immunoglobulin. The dose should be 50 IU anti-D per unit of FFP (200–300 ml) or per 500 ml of platelets transfused, or 250 IU per adult therapeutic dose of platelets (c. 250–350 ml, whether from a single aphaeresis donation or from a pack derived from a buffy coat pool from four donations). Components must not contain other clinically significant red cell antibodies. 1.1.6. Administration All components should be transfused through a standard blood giving set with a screen filter (170–200 μ) or an alternative system incorporating the same filtration. Where small volumes are drawn into a syringe an appropriate filter must be used. Microaggregate filters (40 μ) are not required for LD components. 1.2. Pretransfusion testing for neonates and infants within the first four postnatal months Wherever possible, samples from both mother and infant should be obtained for initial ABO and RhD group determination. Investigations on the maternal sample: • ABO and RhD group. • Screen for the presence of atypical red cell antibodies. Investigations on the infant sample: • ABO and RhD. ABO by cell group only, repeated on same sample if no historical result (a reverse group would detect passive maternal antibodies). • Direct antiglobulin test (DAT) performed on the neonate's red cells. • In the absence of maternal serum, screen infant's serum for atypical antibodies by an indirect antiglobulin technique (IAT). A positive DAT on the neonate's red cells or an atypical red cell antibody in maternal or neonatal serum suggests possible haemolytic disease of the newborn (HDN). In such cases, special serological procedures will be necessary to allow selection of appropriate blood (level IV evidence, grade C recommendation). 1.2.1. Selection of blood component Components should be • Of the neonate's own ABO and RhD group, or an alternative compatible ABO and RhD group. • Compatible with any ABO or atypical red cell antibody present in the maternal or neonatal plasma. • An electronic cross-match may not select blood that is compatible with maternally derived ABO antibodies in the neonate's plasma. Therefore, it may not be appropriate to include neonatal samples in electronic cross-match protocols unless an appropriate algorithm has been created. ABO identical adult blood transfused to an infant with maternal anti-A or anti-B may haemolyse even if the pretransfusion DAT is negative, due to stronger ABO antigen expression on adult cells (see Section 3.1.3; level IV evidence, grade C recommendation). • Small volume transfusions can be given repeatedly over the first 4 months of life without further serological testing, provided that there are no atypical maternal red cell antibodies in the maternal/infant serum, and the infant's DAT is negative when first tested. • If either the antibody screen and the DAT (or both) are positive, serological investigation or full compatibility testing will be necessary. Infants rarely produce atypical red cell antibodies other than following repeated large volume transfusion and (possibly) the use of blood from donations collected up to 5 d before transfusion. It is only under these circumstances that repeat antibody screening of the recipient is advised (level IIb evidence, grade B recommendation). After the postnatal age of 4 months, compatibility tests should be conducted in accordance with national guidelines for pretransfusion testing in adult practice (British Committee for Standards in Haematology, 1996b, 2003a) (see Table I). Table I. Choice of ABO group for blood products for administration to children. Patient's ABO group ABO group of blood product to be transfused Red cells Platelets FFP* O First choice O O O Second choice – A A or B or AB A First choice A A A or AB Second choice O† O† – B First choice B B‡ B or AB Second choice O† A or O† – AB First choice AB AB‡ AB Second choice A, B A A Third choice O† *Group O fresh frozen plasma (FFP) should only be given to patients of group O. Although group AB FFP can be given to people of any ABO blood group, supplies are usually limited. †Group O components which test negatively for ‘high titre’ anti-A and anti-B should be selected. ‡Platelet concentrates of group B or of group AB may not be available. 2. Intrauterine transfusion 2.1. Indications and aims Intrauterine transfusions are usually administered only on specialized units. Intrauterine red cell transfusion is indicated to correct fetal anaemia caused by red cell alloimmunization (most important antigen-RhD followed by Rhc and K) or, less commonly, for fetal parvovirus infection. Intrauterine platelet transfusions are indicated to correct fetal thrombocytopenia caused by platelet alloimmunization. The aims of IUT are (i) to prevent or treat fetal hydrops before the fetus can be delivered and (ii) to enable the pregnancy to advance to a gestational age that will ensure survival of the neonate (in practice, up to 36–37 weeks) with as few invasive procedures as possible (because of the risk of fetal loss). This is achieved by (i) starting the transfusion programme as late as safely possible but before hydrops develops and (ii) maximizing the intervals between transfusions, by transfusing as large a volume of red cells as is considered safe. Cell counting should be available close to fetal sampling or transfusion to provide an immediate haematocrit/haemoglobin or platelet count. 2.2. Component and procedure specification (see ) 2.2.1. Red cells preparations Red Table II cells preparations for IUT should Table II. Component volumes to be transfused to children and neonates. Component Volume Red cell concentrates A. Exchange transfusion For a term infant 80–160 ml/kg For a preterm infant 100–200 ml/kg B. Top-up transfusion Desired Hb (g/dl) − actual Hb × weight (kg) × 3 (usually 10–20 ml/kg) Platelet concentrates Children weighing <15 kg 10–20 ml/kg Children weighing >15 kg Single aphaeresis unit/standard pool Fresh frozen plasma 10–20 ml/kg Cryoprecipitate 5 ml/kg or 15–30 kg = 5 units, >30 kg = 10 units • be group O (low titre haemolysin) or ABO identical with the fetus (if known) and RhD negative. K-negative blood is recommended to reduce additional maternal alloimmunization risks. In exceptional cases, e.g. for haemolysis because of maternal anti-c, it may be necessary to give RhD positive, c-negative blood; • be IAT-cross-match compatible with maternal serum and negative for the relevant antigen(s) determined by maternal antibody status. • be <5 d old and in citrate phosphate dextrose (CPD) anticoagulant; • be CMV seronegative; • be irradiated as above (see Section 1.1.4); • be have a haematocrit (packed cell volume, PCV) of up to but not more than 0·75; • not be transfused straight from 4°C storage. As no specifically designed warming systems exist for the small volume of blood used for IUT, any active warming must be carried out with great care and the blood product not exposed to temperatures higher than 30°C. Active warming may not be necessary if the infusion is conducted carefully and at an appropriate rate (see below); • be in a volume calculated from the formula of Rodeck and Deans (1999): where BV is blood volume; • be transfused at a rate of 5–10 ml/min. 2.2.2. Platelet preparations Platelet preparations for IUT should • be group O RhD negative and test negatively for high-titre anti-A or anti-B (i.e. have a low titre haemolysin) or group specific/compatible with maternal antibody; • be human platelet-specific alloantigen (HPA) compatible with maternal antibody; • preferably be collected by aphaeresis. A platelet concentrate derived from whole blood donations is less preferred; • be irradiated as above (see Section 1.1.4); • be concentrated to a platelet count of at least 2000 × 109/l; • be warmed, if warmed at all, with extreme care. As the ambient temperature for storing platelet concentrates is 22°C, and as the recommended rate of infusion (see below) is slower than that for red cells, active warming may not be needed. If it is conducted, it should not be beyond 30°C; • be in a volume calculated from the formula • be transfused at a rate of 1–5 ml/min (transfused more slowly than red cells because of the increased risk of fetal circulatory stasis and asystole). Compatible platelets should be available at the time of diagnostic fetal sampling for alloimmune thrombocytopenia, even if the primary purpose is not that of transfusion, because in the presence of severe fetal thrombocytopenia, fetal haemorrhage can be prevented by platelet transfusion. Teflon-coated needles should be used because they are considered to allow samples of fetal blood which give more accurate cell counts (Welch et al, 1995: level IIb evidence, grade B recommendation). 3. Neonatal transfusion 3.1. Exchange transfusion 3.1.1. Indication and aims Exchange transfusion may be used to manage severe anaemia at birth, particularly in the presence of heart failure, and to treat severe hyperbilirubinaemia, usually caused by HDN. In the treatment of HDN, the aim is to remove both the antibody-coated red cells and the excess bilirubin. Controversial indications such as metabolic disease, septicaemia and disseminated intravascular coagulation (DIC) have not been subjected to adequate clinical evaluation. Exchange transfusion is a specialist procedure associated with a potential for serious adverse events. As such, it should be undertaken only by staff who are experienced in the procedure. 3.1.2. Principles While there is, as yet, no consensus amongst neonatologists, plasma-reduced red cells with a haematocrit of 0·50–0·60 should be suitable for ET for both hyper-bilirubinaemia and severe anaemia (level IV evidence, grade C recommendation). Whole blood, with a haematocrit of 0·35–0·45 may result in a postexchange Hb of <12 g/dl in a severely anaemic baby and thus increase subsequent donor exposure. Packed red cells may have a haematocrit of up to 0·75, leading to an unacceptably high postexchange haematocrit. Exchanging the estimated volume of the baby's blood in a ‘single-volume exchange’ will remove 75% of red cells, while a double-volume exchange (160–200 ml/kg, depending on gestation) removes 90% of the initial red cells. A double-volume exchange can remove 50% of available intravascular bilirubin. The pH of a unit of whole blood or plasma-reduced red cells is around 7·0. This does not contribute to acidosis in the infant. Acidosis is more likely to be a result of underlying hypovolaemia, sepsis or hypoxia. ‘Correction’ of pH to physiological levels by the addition of buffer solutions is not indicated. 3.1.2.1. Component and procedure specifications. Red cells for ET should • be group O or ABO compatible with maternal and neonatal plasma, RhD negative (or RhD identical with neonate); • be negative for any red cell antigens to which the mother has antibodies; • be IAT-cross-match compatible with maternal plasma; • be 5 d old or less (to ensure optimal red cell function and low supernatant potassium levels); • be collected into CPD anticoagulant; • be CMV seronegative; • be irradiated and transfused within 24 h of irradiation. Irradiation is essential if the infant has had a previous IUT and is recommended for all ETs (see Section 1.1.4 and Appendix 2). Irradiation for ET in absence of IUT is not essential if this would lead to clinically significant delay; • have a haematocrit of 0·50–0·60; • not be transfused straight from 4°C storage. If it is decided to warm the product prior to transfusion, extreme care must be taken to avoid over-heating. There is no easy way of achieving this for babies as the equipment designed to warm whole packs of blood warms it immediately prior to infusion; this arrangement is not suited to the intermittent bolus nature of ET procedures. Most clinical units allow the infusate to approximate the ambient temperature while the blood is flowing from the primary pack through the syringes and filters before finally entering the patient's blood circulation; • volume transfused is usually 80–160 ml/kg for a term infant and 100–200 ml/kg for a preterm infant (i.e. 1–2 × blood volume) depending on the clinical indication (see Table I; all level IV evidence, grade C recommendation). 3.1.3. ABO haemolytic disease of the newborn Haemolysis may develop in fetuses and neonates who are ABO incompatible with their mother. Clinically significant haemolysis generally occurs only if the mother is group O and the infant group A (occasionally in group B babies). The haemolysis is due to the IgG anti-A or anti-B crossing the placenta and binding to the fetal red cells. Group A babies of group O mothers have a lower mean Hb and a higher mean cord bilirubin than in ABO compatible pairs. Nevertheless, clinically significant haemolysis is uncommon. The expression of A and B antigens on neonatal red cells is much weaker than on adult red cells which reduces the number of molecules of IgG which can bind, thus reducing or preventing haemolysis. The diagnosis of HDN is complicated. Mothers with a high titre of IgG anti-A or anti-B are more likely to have affected babies but there is no direct relationship with the antibody titre. In addition, although severely affected babies will almost always have a positive DAT, this is not always the case. The preparation of eluates from DAT negative cells has been recommended but a positive DAT and positive eluate can be found in infants who have no evidence of haemolysis. Thus, at times the diagnosis of ABO HDN must be a diagnosis of exclusion: a relatively low cord blood Hb which continues to fall, a raised bilirubin level, ABO incompatibility with the mother and a positive DAT in the absence of any other alloantibodies. Spherocytes are a prominent feature on the blood smear. A high titre IgG anti-A or anti-B in the mother is supportive evidence but a low titre does not exclude the diagnosis. If transfused with blood of their own group, group A or B babies who have maternal anti-A or anti-B in their plasma may convert to DAT positivity and develop haemolysis. This is due to the increased expression of A and B antigens on adult cells of those groups. Group O blood, compatible with the maternal plasma, should be used for transfusion (level IV evidence, grade C recommendation). If an ET is required in ABO HDN, this should be with group O red cells with low titre plasma anti-A and anti-B, or with group O red cells suspended in AB plasma (level IV evidence, grade C recommendation). 3.2. Small volume transfusion Most neonatal transfusions are small volumes (10–20 ml/kg), given to replace phlebotomy losses (see Tables II and III). Most departments have local guidelines with a range of haemoglobin values, depending on clinical status, at which to initiate transfusion. Table III. Suggested transfusion thresholds for infants under 4 months of age. Transfusion of red blood cells Anaemia in the first 24 h Hb 12 g/dl (Hct c. 0.36) Cumulative blood loss in 1 week, neonate requiring intensive care 10% blood volume Neonate receiving intensive care Hb 12 g/dl Acute blood loss 10% Chronic oxygen dependency Hb 11 g/dl Late anaemia, stable patient Hb 7 g/dl Administration of platelets Preterm or term neonate, with bleeding 50 × 109/l Sick preterm or term infant, not bleeding 30 × 109/l Stable preterm or term infant, not bleeding 20 × 109/l Dedicating aliquots from a single donation of red cells (or aphaeresis platelets) to allow sequential transfusions from the same donor for neonates and small children who are likely to be repeatedly transfused is considered good practice. These must be transfused within the normal shelf-life (currently 35 d for red cells in additive solution, 5 d for platelets). 3.2.1. Guidelines for administration of red cells It is impossible to produce clear evidence-based criteria for the administration of red cells in the neonatal period. However, clinicians who transfuse according to agreed local guidelines give fewer transfusions and it is recommended that local transfusion protocols be established in all neonatal units (Ross et al, 1989: level Ib evidence, grade A recommendation). Furthermore, there is no difference in outcome as determined by mortality or duration of hospital stay by transfusion approach. Table II gives proposals for neonatal red cell audit criteria. These are not ‘transfusion triggers’per se, but represent standards against which individual nurseries can assess the appropriateness of their local transfusion policies (level IV evidence, grade C recommendation). Surrogate markers of anaemia include respiratory irregularity, tachycardia, poor weight gain, lethargy, poor suck and increased blood lactate levels. All of these are susceptible to influence from confounding factors. Patients with a higher oxygen extraction ratio (>40%), a measure of adequacy of oxygen delivery, seem more likely to benefit from transfusion (Ross et al, 1989). Although red cell transfusions may improve these parameters, there is no clear evidence of an associated improved outcome, such as reduced mortality or hospital stay. Furthermore, similar benefits may be obtained simply by volume expansion, implying that some of these surrogate markers may reflect a hypovolaemic state (Alverson et al, 1988). 3.2.1.1. Anaemia of prematurity. The aim of a top-up transfusion is to restore or maintain adequate tissue oxygen delivery without a marked increase in oxygen consumption (Alverson et al, 1988; Maier et al, 2000). 3.2.1.2. Oxygen dependency. Neonates with severe pulmonary disease are thought to benefit from a higher haemoglobin or haematocrit (0·40), which allows oxygen delivery to be optimized in the presence of underlying respiratory insufficiency. There is now some evidence that systemic oxygen delivery is improved and o

The objective of this study was to document the awareness of risk and the nature of advice given by obstetricians to pregnant women who intend to travel by air and to compare the results with the advice given in an opinion paper of the Royal College of Obstetricians and Gynaecologists. The results were based on a self-completed questionnaire. All registered members of the Royal College of Obstetricians and Gynaecologists comprising 1349 individuals, obtained from a list provided by the RCOG, were invited to participate. An anonymous postal questionnaire was completed by the individuals before publication of the opinion paper of the RCOG. A total of 862 (62%) questionnaires returned, and 690 (51%) were available for analysis; 67% of obstetricians regard flying as being safe throughout pregnancy, 33% only in the 2nd and 3rd trimester. Nearly all obstetricians advised on simple prophylactic measures such as mobilisation, fluid intake and leg exercise. Fifty-three per cent would advise the use of prophylactic aspirin (75 mg), 49% the use of compression stockings; 4% recommended heparinisation; 44% believed this advice to be applicable only for the 2nd and 3rd trimester, while the RCOG emphasises that the risk of developing venous thromboembolism begins in the 1st trimester. Obstetricians as well as other health professionals need to be made aware that advice on air travel in pregnancy needs to start in the 1st trimester. Further research is needed to explore the relevance of the duration of flight when considering the application of thromboprophylactic measures as well as the value and choice of pharmacological treatment such as aspirin and heparin.

BACKGROUND Until the publication of the Serum Urine and Ultrasound Screening Study (SURUSS) report, it was difficult to compare the different antenatal screening tests for Down's Syndrome because of variations in study designs. We here present the main results from SURUSS, updated to take account of recent information on nuchal translucency in Down's Syndrome pregnancies, and discuss their implications. METHODS SURUSS was a prospective study of 47,053 singleton pregnancies (including 101 pregnancies with Down's Syndrome) conducted in 25 maternity units. Nuchal translucency measurements were taken. Serum and urine samples collected between 9 and 13 weeks, and again between 14 and 20 weeks of pregnancy were stored. Samples from each affected pregnancy and five matched controls were tested for currently used or suggested biochemical Down's Syndrome screening markers. Pregnancies were followed up to determine the presence or absence of Down's Syndrome. For an 85% Down's Syndrome detection rate, the false-positive rate for the Integrated test (nuchal translucency and pregnancy associated plasma protein-A [PAPP-A] at 11 completed weeks of pregnancy, and alpha-fetoprotein, unconjugated oestriol [uE3], free beta or total human chorionic gonadotrophin (hCG) and inhibin-A in the early second trimester) was 0.9%, the Serum integrated test (without nuchal translucency) 2.7%, the Combined test (nuchal translucency with free beta-hCG and PAPP-A at 11 weeks) 4.3%, the Quadruple test (alpha-fetoprotein, uE3, free beta or total hCG and inhibin-A) 6.2%, and nuchal translucency at 11 weeks, 15.2%. All tests included maternal age. Using the Integrated test at an 85% detection rate, there would be six diagnostic procedure-related unaffected fetal losses following amniocentesis per 100,000 women screened compared with 35 using the Combined test or 45 with the Quadruple test. CONCLUSIONS The Integrated test offers the most effective and safe method of screening for women who attend in the first trimester. The next best test is the Serum integrated test. The Quadruple test is the best test for women who first attend in the second trimester. There is no justification for retaining the Double (alpha-fetoprotein and hCG) or Triple (alpha-fetoprotein, uE3, and hCG) tests, or nuchal translucency alone (with or without maternal age) in antenatal screening for Down's Syndrome.

Objective: Duchenne muscular dystrophy (DMD) is a lethal degenerative muscular disease. Fetal gene therapy may correct the primary genetic defect. Our aim was to achieve expression of a reporter gene in the respiratory muscles of early gestation fetal sheep.Study design: An adenovirus vector containing the beta-galactosidase reporter gene (AdRSV beta gal) was injected into the thoracic musculature (n = 3) and pleural cavity (n = 6) of fetal sheep (61-67 days' gestation), under ultrasound guidance. Tissues were harvested after 48 hours and site and intensity of beta-galactosidase expression were assessed.Results: Limited transgene expression observed after a single injection was improved by multiple injections, but remained localized. Ultrasound-guided creation of a hydrothorax led to an increase in the intensity of beta-galactosidase expression (ELISA). X-gal staining and immunohistochemistry showed that vector spread was confined to the innermost intercostal musculature.Conclusion: Ultrasound-guided injection can deliver gene therapy vectors to the fetal pleural cavity and achieve transduction of the respiratory muscles. (C) 2005 Mosby, Inc. All rights reserved.