Paul Chamberlain

Analysis of limb reduction defects in babies exposed to chorionic villus sampling

In 1991 we reported a cluster of babies with limb abnormalities and suggested that chorionic villus sampling (CVS) was aetiologically associated with these defects. To address the issue more objectively, we have assessed reported limb reduction defects in 75 babies exposed to CVS in utero. 13 babies had an absent limb or a defect through the humerus or femur; 9 had defects through the radius or tibia; 22 defects of the carpus, tarsus, metacarpus, or metatarsus; 25 defects of the digits; and 6 defects of the terminal phalanx or nail only. There was a strong correlation between the severity of the defects and the duration of gestation when CVS was done. The median gestational age at CVS ranged from 56 (range 49-65) postmenstrual days for the most severe category to 72 (51-98) days for the least severe. The relation was seen for both isolated limb defects and for cases with oromandibular-limb hypogenesis syndromes. This relation is further evidence that CVS has an aetiological role in some limb reduction anomalies.

6-year experience of prenatal diagnosis in an unselected population in Oxford, UK

BACKGROUND The benefits and harm associated with prenatal diagnosis are open to debate. We give a 6-year overview of the experience of one prenatal-diagnosis unit using a defined, unselected population. METHODS All congenital malformations suspected prenatally and all congenital malformations, including chromosome anomalies, confirmed at birth were identified from the local Congenital Malformation Register. All fetuses or infants of women booked for delivery at the Oxford Womens Centre who had an OX postcode and date of delivery between 1991 and 1996 were eligible for the study. FINDINGS 725 (2%) of 33,376 babies, were judged abnormal at delivery. 396 (55%) malformed fetuses and infants had been correctly identified prenatally. 174 fetuses had a suspected abnormality identified on scan and subsequently proved to be normal. 160 (92%) of these false-positive results were attributable to the reporting of so called ultrasound soft markers. Accuracy of ultrasound diagnosis was good for structural malformations. Ultrasound soft markers were responsible for a 4% increase in detection of malformations (from 51% to 55%) and a 12-fold increase in false-positive rate (one in 2332 to one in 188). 171 pregnancies (43% of prenatally diagnosed malformed babies) were terminated because of suspected abnormality. Suspicion of abnormality in these cases was first aroused after ultrasound scan in 136 (79%); chromosome analysis because of advanced maternal age, family history, or higher risk in biochemical screening test in 25 (15%); and molecular analysis of single gene defect because of family history in ten (6%). There was a 20% reduction in prevalence of conditions compatible with survival beyond the neonatal period because of termination of such pregnancies. INTERPRETATION More than half of all malformed fetuses can be identified prenatally in routine practice, mostly following initial suspicion from ultrasound examination. Ultrasound soft markers lead to a small increase in detection of malformations but a large increase in false positives. Further research on the impact, including psychological, and value of markers is required to determine whether the benefits of reporting them exceeds the harm. Because methods and techniques continually change, ongoing surveillance of prenatal diagnostic services is vital.

Autopsy after termination of pregnancy for fetal anomaly: retrospective cohort study.

Objective To study trends in termination of pregnancy for fetal anomaly over 10 years and to assess the contribution of autopsy to the final diagnosis and counselling after termination. Design Retrospective study with cases from a congenital anomaly register and a defined unselected population. Data sources Pregnancies resulting in termination for fetal anomaly identified from the Oxford congenital anomaly register. Details about the prenatal diagnosis and autopsy findings were retrieved from case notes. Results Of the 57 258 deliveries, 309 (0.5%) were terminated because of prenatally diagnosed abnormality. There were 129/29 086 (0.4%) terminations for fetal anomaly carried out in 1991-5 and 180/28 172 (0.6%) in 1996-2000. The percentage of fetuses that underwent autopsy fell from 84% to 67%. Autopsy was performed in 132 cases identified by ultrasound scan, with no evidence for abnormal karyotype. In 95 (72%) the autopsy confirmed the suspected diagnosis and did not add important further information, two cases were not classified, and in 35 (27%) the autopsy added information that led to a refinement of the risk of recurrence (reduced in 17, increased in 18); in 11 of these 18 cases it was increased to a one in four risk. Conclusions Though there has been an increase in the rate of terminations of pregnancy for fetal anomaly, there has been a decline in the autopsy rate. When a prenatal diagnosis was based on the results of a scan only, the addition of information from an autopsy by a specialist paediatric pathologist provided important information that changed the estimated risk of recurrence in 27% of cases and in 8% this was to a higher (one in four) risk.

The usefulness of ultrasound assessment of amniotic fluid in predicting adverse outcome in prolonged pregnancy: a prospective blinded observational study.

Objective To determine whether a single ultrasound scan at or beyond 40 weeks of gestation to detect a single deepest pool of amniotic fluid <2 cm and amniotic fluid index (AFI) <5 cm is clinically useful in the prediction of subsequent adverse pregnancy outcome.

Outcome of prenatally diagnosed anterior abdominal wall defects

One hundred consecutive cases of confirmed anterior abdominal wall defect, identified prenatally in the Oxford Prenatal Diagnosis Unit over 11 years, were studied. Fifty nine per cent of cases were suspected omphaloceles and 41% suspected gastroschisis. Fifty four per cent of omphaloceles were accompanied by other defects compared with 5% of those with gastroschisis. Overall, 29% of fetuses with omphalocele had an abnormal karyotype, and of those with another abnormality identified on scan (excluding four cases with no karyotype performed), 54% had an abnormal karyotype. Of the 27 cases with suspected isolated omphalocele, 14 were live born, all of whom have survived. If the 11 whose parents opted for termination of pregnancy are excluded, survival to birth was 88%. Six of the suspected isolated omphaloceles have Beckwith Wiedemann syndrome (BWS). Eight (57%) of the live born babies with omphaloceles had major problems up to the age of 2, but only one (7%) has long term major problems. This child has BWS and is deaf.  Of the 39 cases of suspected isolated gastroschisis, 33 (85%) pregnancies resulted in live birth and one in neonatal death after surgery. Survival rate (excluding terminated pregnancies) was 97%. Gastroschisis was associated with a younger maternal age than omphalocele (p<0.001) and lower birthweight centile (p<0.01).  Fifteen per cent of the gastroschisis babies had major problems up to the age of 2 years and 12% long term developmental problems. Ninety three per cent of the omphalocele babies and 88% of those who had gastroschisis have no long term problems. Over the study period there have been major changes in scanning equipment and expertise. Since 1991 no woman with a suspected isolated lesion has opted for termination of pregnancy.

Prenatal sex determination from maternal peripheral blood using the polymerase chain reaction

We have investigated the use of a nested polymerase chain reaction assay for the detection of a fetal-specific Y-chromosomal sequence (DYS14) from DNA extracted from unsorted maternal peripheral blood. Serial dilutions of male DNA into female cord blood DNA indicated that the assay could detect an equivalent of a single male cell in 300000 female cells. The assay exhibited absolute specificity for male DNA with no amplification from a DNA panel obtained from 10 female cord blood samples. When used on DNA extracted from unsorted peripheral blood from a series of pregnant women, the predictive values of a positive test for a male fetus were 86%, 67% and 87% in the first, second and third trimesters, respectively. We have also demonstrated that retesting the samples allows the detection of a proportion of male-bearing pregnancies with a high degree of accuracy, in that all 15 women who gave positive signals in two consecutive amplifications had male fetuses. We have also applied the test at 8 weeks post-partum to eight women who had previously delivered male babies; no Y-specific signal could be detected in any of them, suggesting that most women have cleared their circulation of fetal cells by 8 weeks after parturition.

Prenatal Determination of Fetal Rhesus D Status by DNA Amplification of Peripheral Blood of Rhesus‐Negative Mothers

We have developed a sensitive PCR-based assay for the RhD gene and used it to detect circulating fetal cells from RhD-positive fetuses from peripheral blood of RhD-negative mothers. With further improvement in diagnostic accuracy, this assay may have implications in the management of RhD-sensitized pregnancies in women whose partners are heterozygous for the RhD gene. Further studies are required to determine the relationship between maternal anti-D levels and circulating fetal cell numbers.

Congenital diaphragmatic hernia: prenatal diagnosis, outcome and continuing morbidity in survivors

Objective To improve counselling by investigating the prenatal diagnosis, outcome and morbidity in survivors of congenital diaphragmatic hernia.

Investigation into the Fusion of Multiple 4-D Fetal Echocardiography Images to Improve Image Quality

Recent advances in four-dimensional (4-D) ultrasound enable the acquisition and visualisation of the entire fetal heart. However, getting consistent, shadow free, data remains problematic due to the uncontrollable nature of fetal orientation. This article presents the first investigation into the utility of image fusion to improve the quality of volumetric fetal cardiac imaging. Multiple volume scans are registered using a semiautomatic approach and five fusion methods are assessed for their ability to remove artefacts and improve image quality. Image quality is assessed in terms of signal-to-noise ratio, contrast and contrast-to-noise ratio. Qualitative results are presented for the ability to remove artefacts. The fusion methods assessed were found to be divided into those that reduce noise and those that increase contrast. The effect of fusion on left ventricle segmentation using commercial state-of-the-art software is also considered. The use of image fusion is shown to reduce the variability of volume estimates by about 50% relative to measurement on a single scan.

Antenatal diagnosis of complete facial duplication—a case report of a rare craniofacial defect

We report a case of the prenatal sonographic detection of facial duplication, the diprosopus abnormality, in a twin pregnancy. The characteristic sonographic features of the condition include duplication of eyes, mouth, nose and both mid‐ and anterior intracranial structures. A heart‐shaped abnormality of the cranial vault should prompt more detailed examination for other supportive features of this rare condition.