Patricia A. Boyd

Survey of prenatal screening policies in Europe for structural malformations and chromosome anomalies, and their impact on detection and termination rates for neural tube defects and Down's syndrome

Objective  To ‘map’ the current (2004) state of prenatal screening in Europe.

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.

Autism, language and communication in children with sex chromosome trisomies

Purpose Sex chromosome trisomies (SCTs) are found on amniocentesis in 2.3–3.7 per 1000 same-sex births, yet there is a limited database on which to base a prognosis. Autism has been described in postnatally diagnosed cases of Klinefelter syndrome (XXY karyotype), but the prevalence in non-referred samples, and in other trisomies, is unclear. The authors recruited the largest sample including all three SCTs to be reported to date, including children identified on prenatal screening, to clarify this issue. Design Parents of children with a SCT were recruited either via prenatal screening or via a parental support group, to give a sample of 58 XXX, 19 XXY and 58 XYY cases. Parents were interviewed using the Vineland Adaptive Behavior Scales and completed questionnaires about the communicative development of children with SCTs and their siblings (42 brothers and 26 sisters). Results Rates of language and communication problems were high in all three trisomies. Diagnoses of autism spectrum disorder (ASD) were found in 2/19 cases of XXY (11%) and 11/58 XYY (19%). After excluding those with an ASD diagnosis, communicative profiles indicative of mild autistic features were common, although there was wide individual variation. Conclusions Autistic features have not previously been remarked upon in studies of non-referred samples with SCTs, yet the rate is substantially above population levels in this sample, even when attention is restricted to early-identified cases. The authors hypothesise that X-linked and Y-linked neuroligins may play a significant role in the aetiology of communication impairments and ASD.

Quantitative structural studies on human placentas associated with pre‐eclampsia, essential hypertension and intrauterine growth retardation

Summary. Placentas from pregnancies complicated by pre‐eclampsia, essential hypertension, hypertension complicated by pre‐eclampsia and from normotensive pregnancies resulting in the birth of a singleton small‐for‐dates (SFD) infant have been studied by quantitative mor‐phometry. The findings have been compared with those from placentas of uncomplicated pregnancies. The placentas from pregnancies compli‐cated by pre‐eclampsia and those resulting in a SFD baby had a signifi‐cantly lower total volume, volume of parenchyma and villous surface area when compared with normal pregnancies of comparable gestation. They also had an increase in areas of multiple infarction and in the volume proportions occupied by fetal capillaries. The placentas from women with essential hypertension uncomplicated by pre‐eclampsia were as large as those from normal pregnancies and the villous surface areas were as high. Villous surface arca measurements in the different groups were related to gestation and to fetal weight.

Prevalence of congenital anomalies in five British regions, 1991–99

Aims: To describe trends in total and live birth prevalence, regional differences in prevalence, and outcome of pregnancy of selected congenital anomalies. Methods: Population based registry study of 839 521 births to mothers resident in five geographical areas of Britain during 1991–99. Main outcome measures were: total and live birth prevalence; pregnancy outcome; proportion of stillbirths due to congenital anomalies; and secular trends. Results: The sample consisted of 10 844 congenital anomalies, giving a total prevalence of 129 per 10 000 registered births (95% CI 127 to 132). Live birth prevalence was 82.2 per 10 000 births (95% CI 80.3 to 84.2) and declined significantly with time. The proportion of all stillbirths with a congenital anomaly was 10.5% (453 stillbirths). The proportion of pregnancies resulting in a termination increased from 27% (289 cases) in 1991 to 34.7% (384 cases) in 1999, whereas the proportion of live births declined from 68.2% (730 cases) to 58.5% (648 cases). Although similar rates of congenital anomaly groups were notified to the registers, variation in rates by register was present. There was a secular decline in the total prevalence of non-chromosomal and an increase in chromosomal anomalies. Conclusions: Regional variation exists in the prevalence of specific congenital anomalies. For some anomalies this can be partially explained by ascertainment variation. For others (neural tube defects, diaphragmatic hernia, gastroschisis), higher prevalence rates in the northern regions (Glasgow and Northern) were true differences. Live birth prevalence declined over the study due to an increase in terminations of pregnancy.

Paper 6: EUROCAT member registries: organization and activities

BACKGROUND EUROCAT is a network of population-based congenital anomaly registries providing standardized epidemiologic information on congenital anomalies in Europe. There are three types of EUROCAT membership: full, associate, or affiliate. Full member registries send individual records of all congenital anomalies covered by their region. Associate members transmit aggregate case counts for each EUROCAT anomaly subgroup by year and by type of birth. This article describes the organization and activities of each of the current 29 full member and 6 associate member registries of EUROCAT. METHODS Each registry description provides information on the history and funding of the registry, population coverage including any changes in coverage over time, sources for ascertaining cases of congenital anomalies, and upper age limit for registering cases of congenital anomalies. It also details the legal requirements relating to termination of pregnancy for fetal anomalies, the definition of stillbirths and fetal deaths, and the prenatal screening policy within the registry. Information on availability of exposure information and denominators is provided. The registry description describes how each registry conforms to the laws and guidelines regarding ethics, consent, and confidentiality issues within their own jurisdiction. Finally, information on electronic and web-based data capture, recent registry activities, and publications relating to congenital anomalies, along with the contact details of the registry leader, are provided. CONCLUSIONS The registry description gives a detailed account of the organizational and operational aspects of each registry and is an invaluable resource that aids interpretation and evaluation of registry prevalence data.

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.

Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe

The aim of this study is to quantify the prevalence and types of rare chromosome abnormalities (RCAs) in Europe for 2000–2006 inclusive, and to describe prenatal diagnosis rates and pregnancy outcome. Data held by the European Surveillance of Congenital Anomalies database were analysed on all the cases from 16 population-based registries in 11 European countries diagnosed prenatally or before 1 year of age, and delivered between 2000 and 2006. Cases were all unbalanced chromosome abnormalities and included live births, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. There were 10 323 cases with a chromosome abnormality, giving a total birth prevalence rate of 43.8/10 000 births. Of these, 7335 cases had trisomy 21,18 or 13, giving individual prevalence rates of 23.0, 5.9 and 2.3/10 000 births, respectively (53, 13 and 5% of all reported chromosome errors, respectively). In all, 473 cases (5%) had a sex chromosome trisomy, and 778 (8%) had 45,X, giving prevalence rates of 2.0 and 3.3/10 000 births, respectively. There were 1 737 RCA cases (17%), giving a prevalence of 7.4/10 000 births. These included triploidy, other trisomies, marker chromosomes, unbalanced translocations, deletions and duplications. There was a wide variation between the registers in both the overall prenatal diagnosis rate of RCA, an average of 65% (range 5–92%) and the prevalence of RCA (range 2.4–12.9/10 000 births). In all, 49% were liveborn. The data provide the prevalence of families currently requiring specialised genetic counselling services in the perinatal period for these conditions and, for some, long-term care.