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Session 4A BMFMS: Fetal Medicine

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4.1 LOCAL DELIVERY OF VASCULAR ENDOTHELIAL GROWTH FACTOR ADENOVIRUS TO THE UTERINE ARTERY INCREASES VASORELAXATION AND BLOOD FLOW TO THE PREGNANT SHEEP UTERUS LONG TERM

K. Abi Nader1, B. Torondel2, V. Wigley1, I. Zachary2, J. Martin2, M. Boyd3, T. Cook4, C. H. Rodeck1, D. M. Peebles1, A. L. David1. 1Institute for Women’s Health, University College London, London, UK, 2Department of Cardiovascular Medicine, University College London, London, UK, 3Biological Sciences Unit, Royal Veterinary College, London, UK, 4Department of Pathology, Imperial College, London, UK

Introduction: Impaired uteroplacental perfusion causes fetal growth restriction. Our work aims to treat fetal growth restriction by increasing uteroplacental perfusion. Using Doppler ultrasound we previously showed significantly increased uterine blood flow (UBF) 5 days after adenovirus vector-mediated overexpression of vascular endothelial growth factor (VEGF) in the uterine artery. This study investigated the long-term effect of this vector.

Methods: We implanted ultrasonic flow probes (Transonic Inc, USA) around both uterine arteries in mid-gestation pregnant sheep (n  =  6, 90 days of gestation, term 145 days) and measured UBF telemetrically to obtain baseline data. Five days later we injected adenovirus vectors (5 × 1010 particles) containing the VEGF (Ad.VEGF-A) gene into one uterine artery and β-galactosidase (Ad.lacZ) into the other. UBF was monitored daily until term when a postmortem examination was performed. Uterine artery sections were taken at four levels and studied in an organ bath. We assessed VEGF expression in the uterine artery by ELISA and immunohistochemistry 5 days (n  =  6) and 30 days (n  =  6) after vector injection.

Results: By term, (30 days post-injection) UBF increased by 33.3% from baseline in Ad.VEGF-A-injected vessels compared with 16.9% in Ad.LacZ-injected vessels. Ad.VEGF-A-transduced vessels contracted significantly less with phenylephrine (Emax 135 SE:12.1 versus Emax 156.1 SE:23.3, p<0.05) than Ad.LacZ-injected vessels. The bradykinin relaxation response was not significantly different. VEGF expression was detected by ELISA and was observed in the uterine artery perivascular adventitia by immunohistochemistry at 5 days but not at 30 days after injection.

Conclusions: Adenovirus-mediated overexpression of VEGF increases UBF and uterine artery relaxation long term.

4.2 AMNIOCENTESIS FOR SOFT MARKERS: A 6-YEAR REVIEW 2000–5

E. M. Knox1, A. M. Tonks2, M. P. Wyldes2. 1Birmingham Women’s Hospital, Birmingham, UK, 2Perinatal Institute, Birmingham, UK

The West Midlands regional policy for the incidental detection of soft markers at mid-trimester ultrasound was introduced in 2002. This comprised karyotyping for either an isolated nuchal pad, multiple other soft markers (echogenic bowel, echogenic cardiac foci, short femur, pyelectasis and choroid plexus cysts), or a single marker with high previous risk for Down’s syndrome. Within the region, all women are offered a dating scan, triple test and an 18–20-week anomaly scan. Routine screening for soft markers is not performed.

All amniocenteses following abnormal scan findings were reviewed, 3 years before and after the introduction of the policy. The indications for karyotyping were grouped into categories summarising the presence of single or multiple soft markers according to the policy. The rates of aneuploidy were generated for each group.

14 875 amniocenteses were performed in a birth population of 381 127 (39.0 per 1000 births); 357 were performed following the finding of one or more soft markers.

In categories in which karyotyping was indicated by the policy, the aneuploidy rate was 14% (7.5% trisomy 21). The highest aneuploidy rate (21%) was in cases of nuchal pad as an isolated ultrasound finding.

There was one Down’s syndrome pregnancy in the 6-year period with a single soft marker (excluding nuchal pad). This case had translocation trisomy 21 associated with echogenic bowel following a very low-risk result from private combined first trimester screening.

The policy has been successful in both limiting the number of amniocenteses and in identifying cases with abnormal karyotype.

4.3 FETAL TROPONIN-T AND PRO-BRAIN NATRIURETIC PEPTIDE IN FETUSES OF MOTHERS WITH TYPE 1 DIABETES

N. Russell1, M. Higgins1, M. Amaruso2, M. Foley1, R. G. Firth2, F. McAuliffe1. 1University College Dublin, Dublin, Ireland, 2National Maternity Hospital, Dublin, Ireland

Objective: To determine if fetal serum markers of cardiac function differ between normal and type 1 diabetic pregnancy.

Methods: This is a prospective observational study of 45 type 1 diabetic pregnancies and 39 normal pregnancies with ethics approval. Cord bloods were taken at the time of delivery, centrifuged immediately and stored at −20° until analysis by electrochemiluminescence immunoassay (ECLIA, Roche).

Results: The cord blood pro-brain natriuretic peptide (BNP) and troponin-T levels were higher in the diabetic cohort than in the normal cohort (p<0.005). Pro-BNP correlates positively with troponin-T (p<0.0001), birthweight (0.157, p<0.05) and birthweight centile (0.174, p<0.05). There was no correlation between either fetal troponin-T or fetal pro-BNP and booking or third trimester haemoglobin A1c (see table).

Conclusions: Cord blood pro-BNP and troponin-T are higher in fetuses of diabetic mothers than in the normal population. These data suggest that maternal type 1 diabetes is associated with significant effects on fetal cardiac function, consistent with findings of studies that show fetuses of type 1 diabetes demonstrate cardiomyopathy. Consistently higher values in fetal troponin and pro-BNP in type 1 diabetes suggest that the effects on cardiac function are significant and may contribute to the susceptibility to hypoxia seen in these pregnancies.

4.2 THREE-STAGE CONTINGENCY SCREENING FOR DOWN’S SYNDROME: THE STAFFORD PILOT

A. Tonks, S. Hodgkiss, J. Gardosi. Perinatal Institute, Birmingham, UK

Background: The National Screening Committee (NSC) recommends combined first trimester screening, which requires routine nuchal translucency (NT) scans. Our ultrasound services are, however. constrained by shortages of trained staff and/or funding. We piloted an alternative model that requires less ultrasound resources.

Methods: A contingent model was developed that includes three stages across the first and early second trimesters, using serum markers and NT measurement. NT is only offered if the first trimester serum test result is not reassuring.

Results: A total of 1561 women entered into the 12-month screening programme. There was a total 10 cases of Down’s syndrome in the screened population, and all (100%) were identified as high risk. The false positive rate was 26/1542 or 1.7% for normal karyotypes, with an additional four cases with other aneuploidies detected. Invasive procedures for maternal age were reduced from 34 per annum before the pilot to a total of five during the 12-month study period. The proportion of women in the screened population in each stage of the screening pathway were as predicted by modelling. Only 22% of women required an NT scan and 94% of women received their results in the first trimester.

Conclusions: The pilot suggests that three-stage contingency screening is effective, safe and acceptable for mothers and professionals and implementation is feasible. It performs at least as well as predicted by modelling and will be able to meet the NSC target, while staying within currently available ultrasound resources.

4.5 DNA MICROARRAYS IN THE INVESTIGATION OF ABNORMAL ANTENATAL ULTRASOUND: A PROSPECTIVE PILOT STUDY

K. E. Cohen1, E. Sheridan2, G. C. Mason1. 1Department of Fetal Medicine, Leeds General Infirmary, Leeds, UK, 2Yorkshire Regional Genetics Service, Leeds, UK

The presence of fetal abnormalities on antenatal ultrasound assessment increases the risk of poor outcome, with an underlying chromosomal abnormality detected in up to 15% of cases. When fetal karyotype is normal, the risk of poor outcome persists; with a nuchal translucency of greater than 4.5 mm the likelihood of having a healthy baby is only 50%.

We hypothesise that a proportion of fetal ultrasound abnormality is caused by an underlying chromosomal imbalance currently undetectable by conventional methods. The limitations of antenatal karyotype are well documented and array comparative genomic hybridisation combines the advantages of a genome-wide screen with the increased resolution of molecular testing.

We have recruited 24 women with abnormal fetal ultrasound. Inclusion criteria are increased nuchal translucency (greater than 3 mm), major structural abnormality or multiple (more than two) soft markers. Routine karyotyping is performed as standard; however, surplus fetal tissue from either chorionic villus sampling or amniocentesis is cultured further for DNA extraction. DNA is further analyzed using a 500 kb resolution BAC-clone DNA microarray (BlueGnome Cytochip). Parental DNA is banked for later confirmation of fetal chromosomal imbalances.

Results from eight microarray experiments have been obtained. Three of eight fetuses had an aneuploidy identified on routine karyotyping. Of the five normally karyotyped fetuses, three had submicroscopic areas of chromosomal gain or loss. Poor quality DNA from cultured placental and amniotic cells increases the background noise in DNA microarray experiments, affecting the interpretation of results. Enhanced DNA extraction techniques and the use of direct fetal tissue improves quality control metrics and aids interpretation.

4.6 GASTROSCHISIS IN THE UNITED KINGDOM: A PROSPECTIVE NATIONAL STUDY OF PREVALENCE, MANAGEMENT AND OUTCOMES USING OBSTETRIC, PAEDIATRIC SURGICAL AND CONGENITAL ANOMALY REPORTING SYSTEMS

M. Knight. National Perinatal Epidemiology Unit, Oxford, UK

Background: The birth prevalence of gastroschisis has increased worldwide; however, incomplete geographical coverage by regional congenital anomaly registers makes this difficult to study on a national basis in the United Kingdom. The aims of this study were to document the prevalence of gastroschisis nationally and to describe management and outcomes.

Methods: Parallel national descriptive studies were conducted using the UK Obstetric Surveillance System (UKOSS) and the British Association of Paediatric Surgeons Congenital Anomalies Surveillance System (BAPS–CASS), commencing in October 2006. Cases were compared with cases reported to the British Isles Network of Congenital Anomalies Registers (BINOCAR).

Results: There were 288 cases of gastroschisis identified through UKOSS and BAPS–CASS in an estimated 726 517 total births. Seven further cases were identified through BINOCAR, representing an estimated total prevalence of 4.1 cases/10 000 births (95% CI 3.6 to 4.6/10 000). 284 cases (99%) were diagnosed antenatally; 17 (6%) had additional non-bowel anomalies. The median age of mothers was 21 years (range 16–45). 5% admitted recreational drug use in early pregnancy. 35% had suspected intrauterine growth retardation antenatally, 20% had oligohydramnios and 3% had polyhydramnios. Outcomes are known for 260 pregnancies. Eight were terminated (five fetuses with additional anomalies); one miscarried; there were eight intrauterine deaths (32/1000 births) and seven infant deaths (28/1000 births).

Discussion: The national prevalence of gastroschisis estimated from this study is almost double the most recent figure from the National Congenital Anomaly System (NCAS), corroborating reports of under-ascertainment through NCAS. This study suggests the national prevalence of gastroschisis is increasing in line with estimates from BINOCAR.

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