Total uterine artery blood volume flow rate in nulliparous women is associated with birth weight and gestational age at delivery.

OBJECTIVES: To investigate the relationship between total uterine artery blood volume flow rate (TVFR) and birth weight and gestational age at delivery, and to establish normal ranges of TVFR throughout pregnancy. METHODS: This was a prospective cohort study of 334 nulliparous women booking antenatal care at University College London Hospital between August 2008 and September 2009. Women underwent a transabdominal ultrasound examination of uterine arteries for measurement of TVFR at 12, 20 and 24 weeks' gestation. Pregnancy outcomes were recorded and linear regression was used to study the relationship between TVFR and gestational age at delivery and birth weight. RESULTS: A total of 551 ultrasound scans were performed. There was a significant, positive correlation between TVFR at 11-13 weeks (TVFR1) and at 22-26 weeks (TVFR3) and birth weight. For every 100-mL/min increase in TVFR1 and TVFR3, there was an increase in birth weight of 45 g and 27 g, respectively. There was also a positive association between TVFR1 and gestational age at delivery, with a 1.4-day increase in gestational age for every 100-mL/min increase of TVFR1. CONCLUSION: Ultrasound measurement of TVFR in the first trimester is significantly associated with both birth weight and gestational age at delivery. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

The relationship between body mass index and mid-arm circumference in a pregnant population.

Our objective was to correlate body mass index (BMI) with mid-arm circumference (MAC) and also to ascertain whether maternal BMI could be calculated from MAC at booking. We approached all Caucasian women who met the inclusion criteria attending the University College Hospital, London between 1 April 1996 and 30 June 1997 and the Rotunda Hospital, Dublin, Ireland between 15 April 2003 and 19 May 2004. A total of 2,912 women agreed to participate in the research. The participants' maternal height and weight were measured. Their BMI was calculated using the formula: BMI = weight (kg) ÷ height (m(2)). The MAC was measured in cm. Statistical analysis was performed using SPSS for Windows version 11 with p < 0.05 as significant. We found that BMI is directly correlated with MAC (r = 0.836) and estimates of BMI may be calculated from the simple equation BMI = MAC ± 2. Alternatively, a MAC of ≥ 27 cm allowed for a detection rate for overweight patients of 75%, with a false positive rate of 15%.

Antenatal screening for Down's syndrome using the Integrated test at two London hospitals.

We carried out an audit of antenatal screening for Down's syndrome using the Integrated test (which provides a single screening result from information collected in the late first and early second trimesters of pregnancy) which was introduced into routine antenatal care at two London hospitals, University College Hospital (UCH) and St Mary's Hospital, in 2003-4. The audit was based on 15,888 women who accepted screening and booked in the first trimester. The Down's syndrome detection rate was 87% (95% confidence interval [CI], 74-95) consistent with an expected detection rate of 89% based on applying the estimates of screening performance of the Serum, Urine and Ultrasound Screening Study (SURUSS) to the maternal age distribution of women who were screened at UCH and St Mary's. The observed false-positive rate was 2.1% (95% CI, 1.9-2.3), compared with an expected of 2.5% for women of the same age. An audit trail (conducted at UCH) indicated that 98% (10,746/10,961) of women accepted integrated screening (2% having a first trimester test) and of these, 94% (10,116) completed both stages of the test. The audit demonstrated that it is feasible to conduct integrated screening within the NHS with a high acceptance rate and a screening performance consistent with that determined from previous research studies.

Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep.

Impaired materno-placental perfusion causes two important obstetric complications, fetal growth restriction and preeclampsia. This study investigated whether adenoviral vector-mediated overexpression of vascular endothelial growth factor (VEGF) in the uterine arteries (UtAs) increases uterine artery blood flow (UBF). First-generation adenovirus vectors (5 x 10(11) particles) containing the VEGF gene (Ad.VEGF-A or -D) or the beta-galactosidase reporter gene (Ad.lacZ) were injected into the UtAs of pregnant sheep (n=6) at 88-102 days of gestation (term=145 days). UBF was measured using Doppler sonography before, and 4-7 days after injection. Mean UBF increased significantly from 233+/-156 (s.d.) ml min(-1) to 753+/-415 ml min(-1) following Ad.VEGF-A injection (P=0.005, n=5); Ad.lacZ infection had no significant effect. Organ bath experiments on uterine arterial sections 4-7 days after injection showed that, compared with Ad.lacZ vessels, Ad.VEGF-A-transduced vessels had a reduced contractile response to phenylephrine (E max 148+/-10.9 vs E max 228.2+/-27.5, P<0.05) but increased relaxation with bradykinin (pD2 (-log EC50) values 9.11+/-0.01 vs 8.65+/-0.11, P<0.05). Injection of Ad.VEGF-A into the UtAs increases UBF by enhancing vasodilatation. This may provide the basis for therapy in pregnancies complicated by uteroplacental insufficiency.

Association of isolated short femur in the mid-trimester fetus with perinatal outcome.

OBJECTIVES: To evaluate the prevalence of fetal isolated short femur in a cohort of women screened for Down syndrome by the integrated test, and to compare the outcome of fetuses with isolated short femur in the mid-trimester with that of fetuses with normal femur length (controls). METHODS: This was a retrospective cohort study of 1262 women booked for antenatal care and delivery at University College London Hospital. All women had integrated testing in the late first and early second trimesters and a detailed anomaly scan in the mid-trimester. All scan reports, screening results and neonatal data were analyzed statistically. RESULTS: The fetal femur was short (< 5(th) percentile) in 5.1% of patients and 4.7% had isolated short femur. In pregnancies with isolated short femur, the birth weight was significantly lower and there were higher rates of small-for-gestational age (SGA) and low birth weight (LBW) infants, compared with controls (P < 0.01). The odds ratios for SGA and LBW in pregnancies with isolated short femur were 3.0 (95% CI, 1.5-5.9) and 2.60 (95% CI, 1.1-6.2), respectively. Isolated short femur was associated significantly with low levels of pregnancy-associated plasma protein-A (P = 0.001). CONCLUSIONS: Isolated short femur in the mid-trimester fetus is associated with fetal growth restriction and SGA. In the context of normal Down syndrome screening and a normal anomaly scan, this marker should be regarded as a predictor for SGA, and fetal growth should be monitored during these pregnancies.

Urinary excretion of inositol phosphoglycan P-type in gestational diabetes mellitus.

OBJECTIVE: The mechanisms underlying insulin resistance during normal pregnancy, and its further exacerbation in pregnancies complicated by gestational diabetes mellitus (GDM), are generally unknown. Inositolphosphoglycan P-type (P-IPG), a putative second messenger of insulin, correlates with the degree of insulin resistance in diabetic subjects. An increase during normal pregnancy, in maternal and fetal compartments, has recently been reported. METHODS: A cross-sectional study was carried out in 48 women with GDM and 23 healthy pregnant women. Urinary levels of P-IPG were assessed spectrophotometrically by the activation of pyruvate dehydrogenase phosphatase in urinary specimens and correlated with clinical parameters. RESULTS: Urinary excretion of P-IPG was higher in GDM than in control women (312.1 +/- 151.0 vs. 210.6 +/- 82.7 nmol NADH/min/mg creatinine, P < 0.01) with values increasing throughout pregnancy in control subjects (r2 = 0.34, P < 0.01). P-IPG correlated with blood glucose levels (r(2) = 0.39, P < 0.01 for postprandial glycaemia and r2 = 0.18 P < 0.01 for mean glycaemia) and birthweight in the diabetic group (r2 = 0.14, P < 0.01). CONCLUSIONS: Increased P-IPG urinary excretion occurs in GDM and positively correlates with blood glucose levels. P-IPG may play a role in maternal glycaemic control and, possibly, fetal growth in GDM.

Views of BRCA gene mutation carriers on preimplantation genetic diagnosis as a reproductive option for hereditary breast and ovarian cancer.

BACKGROUND: In May 2006, the UK Human Fertilization and Embryology Authority (HFEA) approved use of preimplantation genetic diagnosis (PGD) for lower penetrance, late onset cancer susceptibility syndromes such as hereditary breast and ovarian cancer (HBOC). This is the first report on views of BRCA gene mutation carriers on use of PGD for HBOC. METHODS: Between December 2005 and February 2006, a postal survey of BRCA mutation carriers attending a Familial Cancer Clinic was undertaken. RESULTS: Of 102 women sent questionnaires, 52 (51%) responded. Thirty-nine (75%) felt it was acceptable to offer PGD for HBOC. Fifteen (37.5%) of 40 who had completed their families would personally have considered PGD if it had been available. Only one of seven (14%) contemplating a future pregnancy would consider PGD. Eighteen (35%) wrote extensively about their concerns including increasing availability of effective treatment and good quality of life. CONCLUSIONS: The majority of BRCA gene mutation carriers are supportive of offering PGD to others, thus endorsing the HFEA decision. However, most women would not consider it personally. Concerns raised highlight the need for regular HFEA reviews of the licensing criteria, as HBOC may cease to be a "serious life threatening illness" in the future.

Practical issues drawn from the implementation of the integrated test for Down syndrome screening into routine clinical practice.

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.

Polymorphisms in the angiotensin converting enzyme gene and growth in the first year of life.

Abnormal patterns of fetal and infant growth have been associated with an increased risk of cardiovascular disease in adulthood. Catch-up growth during the first year of life has been associated with a higher prevalence of type 2 diabetes mellitus, whereas a lack of catch-up growth tracks with a risk of hypertension. The role of genetic factors influencing both growth and blood pressure have not been explored. We genotyped cord blood samples from 530 singleton, Caucasian, uncomplicated pregnancies, drawn from a larger cohort of 1650 pregnancies, and related polymorphism in the angiotensin converting enzyme (ACE) gene (alleles insertion (I) or deletion (D)) with measures of size at birth and at age of 1 year. ACE genotype did not significantly influence size at birth, although there was a greater proportion of individuals with the D/D genotype born with a birth weight less than the 10th centile (P=0.004). The ACE I/I genotype was significantly associated with higher weight (p=0.001), body mass index (p=0.001) and mid arm circumference (p=0.001) at 1 year of age compared to the ACE D/D and I/D genotypes. Individuals with the I/I genotype displayed catch-up (gain from birth size of >or=0.6 Standard Deviation Score) in weight (p=0.04), body mass index (p=0.03) and mid arm circumference (p=0.03) compared to the D/D group, the majority of which showed no change or catch-down. The I/D genotype was distributed equally across the catch up/catch down/no change categories. The effect was more marked in males, but ACE genotype and sex of the infant contributed independently to mid arm circumference measurements and there was no interaction between the two. There was no effect of maternal or paternal ACE genotype on birth size. In a multiple linear regression model ACE genotype, socioeconomic status and sex of the infant explained 10.9% of the variance in body mass index SDS at 1 year of age. We conclude that the ACE I/I genotype is associated with a higher weight and body mass index SDS at 1 year of age, along with catch-up in terms of these measures from birth to 1 year. The D/D genotype is associated with a greater proportion of babies, born at term, that at small for gestational age. These results suggest that due consideration should be given to the underlying genotype of an individual when evaluating the association of early human growth with the development of risk factors for cardiovascular disease. The observation of independent effects of genotype, sex of the individual and socioeconomic status on postnatal growth suggests the need to develop methodologies for the integration of genetic and environmental factors in causality modelling.

Clinically applicable procedure for gene delivery to fetal gut by ultrasound-guided gastric injection: toward prenatal prevention of early-onset intestinal diseases.

Targeting gene therapy vectors to the fetal intestinal tract could provide a novel means toward prevention of the early postnatal intestinal pathology of cystic fibrosis and other conditions, such as congenital enteropathy, that cause intestinal failure. Among these conditions, cystic fibrosis is by far the most common lethal genetic disease. It is caused by a functional absence or deficiency of the cystic fibrosis transmembrane conductance regulator and manifests in the gut as meconium ileus. Prenatal treatment of genetic disease may avoid early-onset tissue damage and immune sensitization, and may target cells that are less accessible in the adult. We investigated gene transfer to the fetal gut, using a minimally invasive injection technique. First-generation replication-deficient adenoviral vectors encoding the beta-galactosidase gene and transduction-enhancing agents were injected into the stomach of early-gestation fetal sheep (n = 8, 60 days of gestation; term, 145 days) under ultrasound guidance. Reporter gene expression was observed 2 days after injection in the villi of the gastrointestinal epithelia after 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining and beta-galactosidase immunohistochemistry of fetal tissues. Expression of beta-galactosidase, as measured by enzyme-linked immunosorbent assay, was enhanced after pretreatment of the fetal gut with sodium caprate, which opens tight junctions, and after adenovirus complexation with DEAE-dextran, which confers a positive charge to the virus. Instillation of the fluorocarbon perflubron after virus delivery resulted in tissue transduction from the fetal stomach to the colon. Using a clinically relevant technique, we have demonstrated widespread gene transfer to the fetal gastrointestinal epithelia.

Ultrasound-guided injection and occlusion of the trachea in fetal sheep.

OBJECTIVES: To access the fetal sheep trachea by ultrasound-guided transthoracic injection in order to deliver gene therapy vectors or occlude the trachea with a detachable balloon. METHODS: Fetal sheep were operated on at a mean gestational age of 102 (range, 81-116) days (term = 145 days). Under ultrasound guidance, either a 20-G spinal (for vector delivery) or a 16-G Kellett (for placement of an occlusive balloon) needle was inserted via the fetal thorax into the fetal trachea. RESULTS: Using the 20-G spinal needle the trachea was accessed successfully in 33/36 fetuses, with 97% survival. Failure to inject was related to fetal position and gestational age. Blood vessel damage causing significant morbidity occurred in two fetuses (6%). Tracheal occlusion was achieved by puncturing the trachea with the 16-G needle and advancing an endoluminal balloon in three out of five attempts in a mean time of 17 (range, 16-19) min, with 100% survival. In one case, the balloon became sited within the accessory lobe bronchus and was not inflated. At postmortem examination 21 days later, all balloons remained inflated and occluded the trachea, and the lung-to-body weight ratio and airways morphometric indices were consistent with relative pulmonary hyperplasia in the obstructed lungs. CONCLUSIONS: Ultrasound-guided transthoracic tracheal puncture is a reliable technique in fetal sheep, with low morbidity and mortality. Using this technique, a detachable endotracheal balloon can be placed to provoke pulmonary growth. Advances in needle design and balloon size may improve the success rate.

Uterine vein and maternal urinary levels of activin A and inhibin A in pre-eclampsia patients.

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 < or = 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.

Prenatal diagnosis for severe inherited skin disorders: 25 years' experience.

BACKGROUND: Over the last 25 years there have been major advances in methods for prenatal testing of inherited skin disorders. Since 1979, our group at the St John's Institute of Dermatology has performed 269 prenatal diagnoses, using a variety of approaches, including fetal skin biopsy (FSB), chorionic villus sampling (CVS) and preimplantation genetic diagnosis (PGD). OBJECTIVES: This study was designed to review the clinical indications, testing procedures and laboratory analyses for all prenatal tests conducted at St John's over this period. METHODS: FSBs were examined for morphological and, when relevant or feasible, immunohistochemical abnormalities. The DNA-based tests involved screening by nucleotide sequencing, restriction enzyme digests or, in a few cases, by linkage analysis. Results Of the 269 tests, 191 were FSB, 76 were CVS and two were PGD. The major indications for FSB were epidermolysis bullosa (EB) (138 cases, including 88 junctional and 48 dystrophic), ichthyoses (37 cases, including 22 tests for harlequin ichthyosis) and oculocutaneous albinism (12 cases). Of the CVS procedures, 75 were for EB (40 junctional, 35 dystrophic) and one was for the EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome. Both of the PGD procedures were for the skin fragility-ectodermal dysplasia syndrome. All tests provided accurate diagnoses and the fetal loss rate was approximately 1% for both FSB and CVS. CONCLUSIONS: The development of prenatal testing has proved to be of great benefit for individuals or couples at risk of having children with severe inherited skin disorders and, in the absence of a cure, prenatal testing along with appropriate counselling has become an important translational benefit of basic research and an integral part of clinical management.

P-type inositol phosphoglycans in serum and amniotic fluid in active pre-eclampsia.

OBJECTIVES: Abnormal secretion of P-type inositol phosphoglycans (IPG-P) has been described in maternal urine of pre-eclamptic women. The aim of this study was to determine the origin of production of IPG-P. We examined the IPG-P content of maternal and fetal serum, maternal urine and amniotic fluid in both normal pregnancy and pre-eclampsia. DESIGN: Established extraction and bioactivity assay techniques were used to compare total IPG-P levels in serum samples, and a polyclonal-antibody-based ELISA to assay the amniotic fluid and urine samples in matched pairs of women. SUBJECTS: Eleven women with pre-eclampsia requiring caesarean section (subjects), 11 pregnant women requiring elective caesarean section for reasons other than pre-eclampsia (controls). RESULTS: Our data confirm the abnormal level of IPG-P in maternal urine during pre-eclampsia. Moreover, IPG-P levels were higher in umbilical sera than in maternal sera samples. Amniotic fluid as well as urine ELISA results were significantly higher in the pre-eclamptic group compared with normal controls. Total IPG-P bioactivity in serum did not vary between serum compartments in normal pregnancy. Uterine vein IPG-P levels were lower in pre-eclampsia when compared with normal pregnancy. A possible correlation was observed between urine and amniotic fluid levels in normal women. No correlation was observed between measured blood levels and those in urine and amniotic fluid. CONCLUSIONS: It is hypothesized that steady state equilibrium of IPG-P in serum in normal pregnancy is disrupted in pre-eclampsia. Additionally, an abnormal IPG-P sub-fraction, detectable in urine and amniotic fluid, may be present and involved in the pathophysiology of the syndrome, although sites of production of this abnormal form remain unclear.

Gene therapy progress and prospects: fetal gene therapy--first proofs of concept--some adverse effects.

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.

SURUSS in perspective.

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.

Ethical and legal controversies in cloning for biomedical research--a South African perspective.

Therapeutic embryonic stem cell research raises a number of ethical and legal issues. The promised benefits are new and important knowledge of human embryological development, gene action, and the production of transplantable tissue and organs that could be effective in reversing or curing currently irreversible disease processes. However, this research involves the deliberate production, use, and ultimate destruction of cloned embryos, hence re-awakening the debate on the moral status of the embryo. Other moral anxieties include the possibility that women (as donors of ova) would be exploited, that this research would land on the slippery slope of reproductive cloning, and that promises made too early could lead to false hope among sick patients. It also raises the question of intellectual and actual property rights in human cell lines and the techniques by which they are produced. Review of legal systems internationally reveals that there is no global consensus on therapeutic embryonic stem cell research. Legal considerations are very much influenced by ethical deliberations on the moral status of the embryo. The South African parliament is promulgating legislation permitting therapeutic cloning, thereby demonstrating a commitment by the state to act in the best interests of patients and of regenerative medicine.

SURUSS in perspective.

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 [uE(3)], free beta or total human chorionic gondaotrophin (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, uE(3), 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, uE(3), and hCG) tests, or nuchal translucency alone (with or without maternal age) in antenatal screening for Down's Syndrome.