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S. Pathak1, N. Sebire4, F. Jessop2, G. Hackett1, E. Murdoch3, C. Lees1 1Fetal Medicine, Obs & Gynae, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom; 2Pathology, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom; 3Neonataology, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom; 4Paediatric Pathology, Great Ormond Street Hospital, London, United Kingdom

Chromosomal translocations involving the Mixed-Lineage-Leukemia (MLL) gene on chromosome 11q23 are frequent in infant acute leukemia and give rise to the formation of MLL-fusion genes. Several studies have addressed the importance of MLL-fusion activity for the initiation and maintenance of hematopoietic transformation. However, the dependence of established leukemias on MLL-fusion activity has not been previously addressed. We have developed a model for conditional expression of MLL-ENL in hematopoietic progenitor cells, in which expression of the fusion oncogene is turned off by doxycycline. In this study, immortalized myeloid cells conditionally or constitutively expressing the MLL-ENL fusion gene were used to induce acute myeloid leukemia (AML) in vivo. Primary recipients developed AML with a mean latency of 81.4 (±4.8) days. Secondary recipients developed AML with much shorter latencies than primary recipients regardless of whether the leukemic cells were freshly transplanted (26.8 (±6.8) days) or cultured in vitro for one month prior to transplantation (18 (±3.9) days). Genetic analysis revealed that some leukemic cells had acquired gross chromosomal abnormalities such as trisomy 6 or gains and losses of chromosome regions, which were not detected in the immortalised cells from which they were derived. Despite the acquisition of additional genetic abnormalities, the leukemic cells remained dependent upon MLL-ENL expression in vitro and in vivo. The leukemic cells terminally differentiated into neutrophils upon doxycycline treatment in vitro and established leukemias regressed following administration of doxycycline to recipient mice in their drinking water. Leukemic regression was accompanied by the complete loss of leukemic cells from the peripheral blood and differentiation of leukemic cells in the spleen. In 7 out of 34 doxycycline treated mice, remission was not sustained and the leukemias relapsed. However, most of these were shown to have acquired constitutive expression of MLL-ENL. This study demonstrates that leukemic cells are addicted to MLL-ENL expression and suggests that targeting the transcriptional/signalling networks established by MLL-fusion oncogenes in patients with 11q23 rearrangements would be a major therapeutic advance.

Reversible acetylation of lysine residues on histone tails is associated with changes to chromatin structure and plays a key role in regulation of gene expression. In this process, histone hypoacetylation is generally associated with gene silencing and pharmacological inhibition of histone deacetylases (HDACs) leads usually to activation of gene expression. Decreased histone acetylation is a hallmark of cancer cells and increased HDAC expression or their mistargetting to specific gene promoters has been associated with a variety of tumors. In the past we have identified and cloned class IIa HDAC9. The HDAC9 gene is located in chromosome 7p21, which is frequently amplified in B-cell tumours such as mantle cell lymphoma (MCL) and in B-cell non-Hodgkin’s lymphoma cell lines. Consistently, initial analysis of patient samples and/or publicly available microarray data highlighted high levels of HDAC9 expression in chronic lymphocytic leukemia, folicullar lymphoma and MCL. Within the normal lymphoid system, HDAC9 is co-expressed with BCL-6 in germinal center B-cells (∼60% of cells). HDAC9 is also expressed in marginal zone B cells and a fraction of CD38 or CD27 positive subepithelial tonsilar cells. In order to examine the role of HDAC9 in the lymphoid development and pathogenesis of lymphoid malignancies we used Ig heavy chain enhancer (Eμ), which drives gene expression from early stages of B-cell development, to ectopically express HDAC9 in transgenic mice. Hemizygous and homozygous mice expressing Flag epitope tagged human HDAC9 (fHDAC9) transgene display throughout their lifespan altered B-cell development. Immunophenotypic analysis of B-cells isolated from bone marrow (BM) revealed an absence of cells expressing the pre-B/immature-B cell markers normally associated with C-E Hardy’s fractions. In vitro functional clonogenic assays for IL-7 responsive BM-derived B-cell progenitors demonstrated an increase (∼50%) in colony numbers in the transgenic BM. Moreover, morphologic and flow cytometric analyses of the transgenic colonies, but not those derived from normal BM, revealed the presence of granulocyte/macrophage colony forming units expressing the HDAC9 transgene, suggesting a lympho-myeloid lineage switch. This correlates with the finding that extramedullary myelopoiesis occurs in a fraction of mice presenting splenomegaly (44%). Furthermore, a subgroup of homozygous Eμ-fHDAC9 mice (n=16) developed tumours (81%) at middle age, and present with enlarged lymph nodes (6%) and abnormal hematopoietic elements in peripheral blood and BM. Taken together these data suggest that HDAC9 plays a role in B-cell maturation and its ectopic expression in early B-cells leads to perturbation of normal B-cell development, possibly predisposing transgenic mice to tumorigenesis.

In singleton pregnancies at 10 to 14 weeks of gestation the prevalence of missed abortion is about 2%. In an ultrasound screening study at 10 to 14 weeks of gestation involving 492 twin pregnancies the prevalence of missed abortion was about twice as high as in singletons. The risk of subsequent miscarriage in twin pregnancies with one missed abortion was about ten times higher than in normal twin pregnancies. These findings may have important implications both in terms of counselling and for future research into the causes of miscarriage.

E DITOR—Gardosi et al say that any classification system that results in a high proportion of cases being defined as unexplained is not fulfilling its purpose.1 If it is true, however, that the mechanism or cause leading to death in an individual case cannot be determined with more than speculative certainty, it is entirely correct to classify the …

BACKGROUND: Defective trophoblastic invasion in early pregnancy is involved in the pathogenesis of preeclampsia. This study investigates the relationship between Doppler assessment of uterine artery resistance and endovascular trophoblastic invasion in the first trimester of pregnancy. METHODS: Patients undergoing termination of pregnancy for non-medical reasons were categorized as having a low- or high-resistance uterine artery blood flow pattern by transabdominal Doppler ultrasound. Products of conception were examined histologically with regard to the extent of decidual endovascular trophoblast invasion. RESULTS: There were 14 low-resistance and 17 high-resistance uterine artery blood flow pregnancies identified at 10‐14 weeks of gestation. Normal intradecidual endovascular trophoblast invasion was identified with a similar frequency in both groups (P = 0.79). However, the proportion of decidual vessels with endovascular trophoblast invasion was significantly higher in the low-resistance pregnancies (49%) compared with the high-resistance ones (34%, P = 0.02). CONCLUSIONS: The findings of this study support the use of uterine artery Doppler investigation for the non-invasive assessment of trophoblast invasion in early pregnancy. Further studies are necessary to clarify the biological significance of these observations and their potential clinical applications.

Background Congenital high airway obstruction syndrome (CHAOS) is a rare life-threatening condition characterised by complete or near-complete developmental obstruction of the foetal airway. Although antenatal imaging findings have been described, the postmortem MRI findings have not been reported. Objective To present postmortem MRI features of CHAOS. Materials and methods We retrospectively reviewed our hospital pathology and imaging databases for cases of CHAOS over a 2-year period. Results We identified two cases of CHAOS. In both cases, postmortem plain radiographs demonstrated gross abdominal distension with distortion and splaying of the rib cage. Both foetuses had characteristic postmortem MRI findings including large-volume fluid-filled lungs on T2-weighted imaging, diaphragmatic eversion, fluid-filled airway dilatation below the level of obstruction, centrally positioned and compressed heart, and massive ascites. One foetus had an associated limb abnormality. Conclusion Postmortem MRI in foetuses suspected of having CHAOS allows confirmation of the diagnosis, determination of the anatomical level of the atresia or stenosis, and identification of associated abnormalities without the need for invasive autopsy.

SummaryBackgroundPost-mortem MRI is a potential diagnostic alternative to conventional autopsy, but few large prospective studies have compared its accuracy with that of conventional autopsy. We assessed the accuracy of whole-body, post-mortem MRI for detection of major pathological lesions associated with death in a prospective cohort of fetuses and children.MethodsIn this prospective validation study, we did pre-autopsy, post-mortem, whole-body MRI at 1·5 T in an unselected population of fetuses (≤24 weeks' or >24 weeks' gestation) and children (aged

Neurocutaneous melanosis (NCM) is the association of congenital melanocytic naevi (CMN) and melanotic lesions in the central nervous system. The original post-mortem description in 1861 was of progressive proliferative leptomeningeal melanocytosis [17], and until the advent of magnetic resonance imaging (MRI), NCM was thought of as universally fatal. With the recognition of a characteristic MR signal for melanin [1], it is now recognised that a significant proportion of individuals with CMN have CNS involvement in some form [9, 14]. Most commonly, the melanosis appears radiologically as foci of melanin within the brain parenchyma, favouring the amygdala, thalamus, cerebellum and pons [10, 14]. Leptomeningeal melanosis is much less frequent. Although intra-parenchymal melanosis on MRI is associated with an increased risk of neurological complications [9, 12, 14, 18], a significant proportion of children with CMN have abnormal clinical neurology with normal scans [4, 14, 18]. We report novel neuropathological findings in a case of NCM that support the hypothesis that there may be a wider abnormality of the brain in individuals with CMN, which are undetectable on MRI. A 17-year-old male with multiple CMN had generalised tonic–clonic seizures from the age of 1 year and frequent, highly refractory partial seizures typical of temporal lobe epilepsy from the age of 8 years. Neurodevelopmental assessments revealed a normal IQ but below average verbal skills. Investigations including MRI (Fig. 1a), SPECT scanning and EEG localised the epileptogenic focus to the left amygdala, which in addition was smaller than the right. No other lesions were detected on MRI. In particular, the left temporal neocortex was unremarkable. He underwent an uncomplicated anterior temporal lobectomy at the age of 14 years, and has been seizure free for 36 months and off all antiepileptic medication for 24 months. Fig. 1 Pre-operative MR images a showing T1 shortening, indicating melanin, in the left amygdala. The adjacent neocortex is radiologically normal. Brown melanin pigment was present within the cytoplasm of neurones and astrocytes as well as free in the neuropil ... Surgical specimens from the left amygdala and left temporal lobe were examined. In neither was pigment apparent macroscopically. In the temporal lobe neocortex, there was a well-circumscribed area of abundant brown melanin pigment in layers I–IV of the cortex. The pigment was both within cells and free in the neuropil (Fig. 1b–d). The overlying leptomeninges were slightly thickened due to fibrosis but contained neither pigment nor melanocytes. The cortical pigment stained black on a Masson Fontana (MF) preparation (Fig. 1e), was bleached by potassium permanganate and did not fluoresce when exposed to ultraviolet light. Immunohistochemical staining for pre-melanosomes (HMB45) was positive in many of the pigment-bearing cells, including pyramidal neurones and cells that morphologically resembled astrocytes. Staining for tyrosinase was equivocal. The neurones were not dysmorphic and binucleate forms were not evident. Melanocytes were not apparent morphologically by light or electron microscopy and there was no immunostaining for the melanocyte marker microphthalmia transcription factor. Staining for calbindin, calretinin, NeuN and parvalbumin demonstrated subtle irregularities of cortical lamination with mild neuronal loss, most marked in layers II and III (Fig. 1f). There was astrocytic gliosis following the pattern of neuronal loss, demonstrated by staining for GFAP (Fig. 1g). In addition, there was subpial (Chaslin’s) gliosis. CD68 stained a minority of the pigment-bearing cells. The Ki67 proliferation index was very low and there was no cytological atypia, mitotic activity or other evidence of tumour. The appearances of the tissue from the left amygdala were very similar with large amounts of pigment both in the neuropil and in cells, including neurones. In this specimen the architecture was less organised, in keeping with the site. Many of the pigmented cells were in the parenchyma adjacent to vessels. Of note, in both specimens, there were occasional clusters of small brown–red granules that were often associated with aggregates of extracellular pigment but were not stained on the MF preparation (Fig. 1h). To explore the nature of the melanin deposited in neurones, electron microscopy was undertaken. This showed melanin within neurones (Fig. 1i, j), melanophages (Fig. 1k) and blood vessels, including the endothelium and the lumina (Fig. 1l). A range of morphological patterns of melanin was noted. In some neurones, there were individual rounded membrane-bound melanosomes (Fig. 1i). However, in others, the neuronal melanin consisted of membrane-bound vesicles of differing electron density with distinct internal structure and often associated with small lipid droplets (Fig. 1j). The melanin containing organelles measured 0.4–1.2 µm in the neurones. Vesicles containing multiple granules of melanin were prevalent in the melanophages (Fig. 1k) but were not seen in neurones. Melanin granules in the melanophages measured

A rapid method to determine quality for placental proteomic studies is required due to varying lengths of time between delivery and sampling in routine protocols. We developed a rapid 10 min LC-MS based scanning method to profile free peptides liberated from natural proteolytic degradation. The assay was applied to placenta samples obtained following refrigeration for varying time periods post-delivery (12 h, +24 h, +48 h and +72 h). Analysis reveals time dependant overlapping profiles for groups

This extended series of 303 monochorionic twin pregnancies examined at 10-14 weeks gestation explores the possible association of increased fetal nuchal translucency thickness (NT) in the early prediction of severe twin-to-twin transfusion syndrome (TTS), Of 303 pregnancies, there were 16 in which at least one fetus was structurally or chromosomally abnormal and in the remaining 287 ongoing pregnancies there were 43 (15%) which developed severe TTS, The median fetal NT was 1.0 multiples of the median (MOM) and NT was >95th centile in 47 (8.2%) fetuses and in at least one fetus in 37 (12.9%) pregnancies. The prevalence of increased NT in the pregnancies that developed TTS [17.4% (n = 15) of fetuses and 28% (n = 12) of pregnancies] was significantly higher than in the non-TTS group [6.6% (n = 32) and 10.2% (n = 25) respectively; Z = -3.4, P < 0.001 and Z = 3.2, P < 0.001 respectively],, likelihood ratio of increased fetal NT for prediction of TTS = 3.5 [95% confidence interval (CI) 1.9-6.2], In 153 of the pregnancies, an ultrasound examination was also performed at 15-17 weeks gestation and intertwin membrane folding was seen in 49 (32%) cases; 21 of these (43%) subsequently developed TTS compared to two (1.9%) of the 104 pregnancies without membrane folding (Z = 6.6, P < 0.001), likelihood ratio of membrane folding for prediction of TTS = 4.2 (95% CI 3.0-6.0).

Objective To examine options of management and outcome of twin pregnancies affected by fetal trisomies. Design Retrospective study. Setting Research Centre for Fetal Medicine. Population Twenty-seven twin pregnancies affected by fetal trisomy. Methods A computer search was made of our database for twin pregnancies concordant or discordant for trisomies. The data were reviewed for gestation at diagnosis of the chromosomal abnormality, management and pregnancy outcome. Main outcome measures Pregnancy management and outcome in relation to type and gestation at diagnosis of the trisomies. Results There were seven cases where both fetuses were trisomies and in these the parents opted for termination of pregnancy; termination was also performed in another pregnancy where one fetus had trisomy 18 and the chromosomally normal co-twin had a major facial cleft. In 19 cases one fetus had either trisomy 21 (n= 14) or trisomy 18 (n= 5) and the other was normal. Selective fetocide was carried out in 13 of 14 pregnancies discordant for trisomy 21 and in one of the five with trisomy 18. In the four cases discordant for trisomy 18 that were managed expectantly, the trisomic baby died in utero or in the neonatal period, whereas the normal co-twin was liveborn at 33 to 40 weeks (median 37). In the 14 cases of selective fetocide, the chromosomally normal co-twin was live born at 24 to 41 weeks of gestation (median 38), and there was a nonsignificant inverse correlation between the gestation at fetocide and gestation at delivery. Conclusions In twin pregnancies discordant for fetal trisomies the main determinant in deciding whether to perform selective fetocide or adopt expectant management is the degree of lethality of the chromosomal defect.

In an ultrasound screening study at 10 to 14 weeks of gestation for measurement of fetal nuchal translucency thickness there were 102 monochorionic and 365 dichorionic twin pregnancies. In the monochorionic compared with the dichorionic pregnancies there was a higher rate of fetal loss before 24 weeks of gestation (12.2% versus 1.8%), perinatal mortality (2.8% versus 1.6%), prevalence of delivery before 32 weeks (9.2% versus 5.5%), and prevalence of birthweight below the 5th centile in both twins (7.5% versus 1.7%). However, the proportion of pregnancies with a birthweight discordancy of more than 25% was similar in the two groups (11.3% versus 12.1%).

The obstetric risks of adverse outcome during pregnancy in women agedor =35 years were quantified using a retrospective analysis of data from 385 120 singleton pregnancies in the North West Thames Region, UK, between 1988 and 1997. A comparison of pregnancy outcome was made on the basis of maternal age at delivery: 18-34 years (n = 336 462), 35-40 years (n = 41 327) and women aged40 years (n = 7331). Women aged18 years (n = 5246) were excluded from the study. Data are presented as percentages of 18-34 year old women, 35-40 year old and40 year old women, with adjusted odds ratios (OR) according to age group. Pregnant women aged 35-40 years were at increased risk of: gestational diabetes, OR = 2.63 [99% confidence interval (CI) 2.40-2.89]; placenta praevia = 1.93 (1.58-2.35); breech presentation = 1.37 (1.28-1.47); operative vaginal delivery = 1.5 (1.43-1.57); elective Caesarean section = 1.77 (1.68-1.87); emergency Caesarean section = 1.59 (1.52-1.67); postpartum haemorrhage = 1.14 (1.09-1.19); delivery before 32 weeks gestation = 1.41 (1.24-1.61); birthweight below the 5th centile = 1.28 (1.20-1. 36); and stillbirth = 1.41 (1.17-1.70). Women aged40 years had higher OR for the same risks. Pregnant women aged/=35 years are at increased risk of complications in pregnancy compared with younger women.

A policy of expectant management until 32 weeks of gestation in 29 dichorionic preg- nancies discordant for growth retardation resulted in an overall mortality of 24% (95% CI 13.9-37.2%) and a handicap of 2.2% (95% CI 0-12.0%). None of the normally grown co-twins died or was handicapped as a result of iatrogenic pre- maturity. (Arch Dis Child 1997;77:F235-F236) In singleton pregnancies with fetal growth retardation due to presumed utero-placental insuYciency the aim of antenatal care is to select the appropriate time for delivery. This is achieved by balancing the relative risks of intrauterine death with expectant management and neonatal death or handicap from iatro- genic preterm delivery. In dichorionic twin pregnancies discordant for intrauterine growth retardation the condition of both fetuses needs to be considered. This study reports the results of our policy of managing such pregnancies expectantly by avoiding iatrogenic preterm delivery, irrespective of the condition of the smaller twin, unless the minimum gestation was 32 weeks and /or the estimated fetal weight of the larger twin was more than 1500 g in 29 dichorionic pregnancies discordant for intrau- terine growth retardation.

Objective To examine the usefulness of selecting the appropriate techque for fetal karyotyping in twin pregnancies by using maternal age and fetal nuchal translucency thickness to determine risk for chromosomal defects in each fetus. Setting Fetal Medicine Centre, London, United Kingdom. Subjects Sixty-seven twin pregnancies identified at the time of an ultrasound scan for determination of fetal nuchal translucency thickness, where the parents requested karyotyping. Intervention The risk for chromosomal defects in each fetus was calculated from the maternal age and fetal nuchal translucency thickness at 10 to 14 weeks of gestation. If the estimated risk for either fetus was 1 in 50 or greater, chorion villus sampling was the method of choice, whereas if the risk was less than 1 in 50 second trimester amniocentesis was performed. Results The estimated risk for trisomies was more than 1 in 50 in 34 pregnancies and 23.5% of these fetuses were found to be chromosomally abnormal. In contrast, in the 33 low risk pregnancies chromosomal abnormalities were found in only 1.5% of the fetuses. Conclusions In twin pregnancies the technique for fetal karyotyping may be selected by calculating the risk for chromosomal abnormality based on maternal age and fetal nuchal translucency thickness.

Objective To examine options of management and outcome of twin pregnancies discordant for anencephaly. Design Retrospective study. Setting Research Centre for Fetal Medicine. Population Twenty-four twin pregnancies discordant for anencephaly. Methods A computer search was made of our database for twin pregnancies discordant for anencephaly. The data were reviewed for gestation at presentation, chorionicity, management and pregnancy outcome. Main outcome measures Pregnancy outcome in relation to chorionicity and management. Results There were 13 dichorionic and 11 monochorionic twin pregnancies discordant for anencephaly. In the dichorionic group five pregnancies had selective fetocide at 17 to 21 weeks; one pregnancy resulted in spontaneous abortion but in the others a healthy infant was born at a median gestation of 37 weeks. The other eight dichorionic pregnancies were managed expectantly, but three developed polyhydramios at 26 to 30 weeks; in one case amniodrainage was performed and in another selective fetocide was carried out. In this group the median gestation at delivery was 35 weeks. All 11 monochorionic pregnancies were managed expectantly and in three there was intrauterine death of both fetuses. In the other eight cases the normal twin was liveborn at a median gestation of 34 weeks; in four of these pregnancies polyhydramnios developed and two were managed by amniodrainage. Conclusions In monochorionic pregnancies, expectant management is associated with a high rate of intrauterine lethality of the normal twin. In dichorionic pregnancies selective fetocide in the second trimester prevents the development of polyhydramnios and is associated with a lower risk of preterm delivery but can cause miscarriage.

Maternal serum alpha-fetoprotein concentration was determined in nine pregnancies with fetal anencephaly, seven with exomphalos containing liver, two with spina bifida and 100 normal controls at 10 to 14 weeks of gestation. The median alpha-fetoprotein in the group with fetal anencephaly and exomphalos was significantly higher than in normal fetuses but the sensitivity of this test is likely to be only about 30% for a false positive rate of 5%.

Background Gastrointestinal food allergy (GIFA) occurs in 2 to 4 % of children, the majority of whom are infants (85 % (OR > 5.67) of having abnormal histological findings compared to those without. Those with isolated PR bleeding or diarrhoea were associated with 74 % and 68 % probability (OR: 2.85 and 2.13) of an abnormal biopsy, respectively. Conversely, children presenting with faltering growth or reflux/vomiting showed any abnormal mucosal histology in only 50.8 % and 45.3 % (OR: 1.04 and 0.82) respectively. Conclusions Food allergy may occur in very young children and is difficult to diagnose. Since endoscopy in infants has significant risks, stratification of decision-making may be aided by symptoms. At least one mucosal biopsy demonstrated an abnormal finding in around half of cases in this selected population. Infants presenting with diarrhoea, PR bleeding, urticaria and irritability are most likely to demonstrate abnormal histological findings.

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.

Objective To determine the prevalence of increased fetal nuchal translucency thickness in twin pregnancies and to evaluate screening for trisomy 21 by a combination of translucency thickness and maternal age. Design Prospective screening study at 10 to 14 weeks of gestation. Setting Fetal Medicine Centre. Population 22,518 self-selected pregnant women at 10 to 14 weeks of gestation, including 21,477 singleton and 448 twin pregnancies with live fetuses. Methods Fetal nuchal translucency thickness was measured by ultrasound examination at 10–14 weeks. Sensitivity and false positive rates of screening for trisomy 21 by a combination of fetal nuchal translucency thickness and maternal age were calculated. Main outcome measures Prevalence of increased nuchal translucency thickness and detection of trisomy 21. Results In the 448 twin pregnancies the nuchal translucency thickness was above the 95th centile of the normal range (for crown-rump length in singletons) in 65/896 fetuses (7.3%), including 7/8 (88%) with trisomy 21. Increased translucency was also present in four fetuses with other chromosomal abnormalities. In the chromosomally normal twin prebmancies the prevalence of increased nuchal translucency was higher in fetuses from monochorionic (8.4%; 16/190) than in those with dichori-onic pregnancies (5.4%; 37/688). The minimum estimated risk for trisomy 21, based on maternal age and fetal nuchal translucency thickness, was 1 in 300 in 19.5% (175/896) of the twins including all eight of those with trisomy 21. Conclusions In twin pregnancies the sensitivity of fetal nuchal translucency thickness in screening for trisomy 21 is similar to that in singleton pregnancies, but the specificity is lower because translucency is also increased in chromosomally normal monochorionic twin pregnancies.

BACKGROUND: Primary antiphospholipid antibody syndrome (PAPS) is an established cause of recurrent pregnancy loss, traditionally presumed to be due to ‘intraplacental thromboses’. This study examines products of conception (POC) from early pregnancy failures to investigate the mechanism of pregnancy loss. METHODS: POC from patients attending a recurrent miscarriage clinic and from terminations of pregnancy for non-medical reasons were examined histologically with particular regard to the presence or absence of vascular or intervillous thromboses and decidual endovascular trophoblast invasion. RESULTS: There were 31 PAPS–positive, 50 PAPS–negative, 34 aneuploid and 20 control cases at 6–14 weeks gestation. Villous morphology and frequency of intervillous thrombosis were not different among groups. Normal intradecidual endovascular trophoblast invasion was identified significantly less frequently in PAPS cases (24%), compared with controls (75%), aneuploid (53%), or PAPS– cases (61%; Z –3.0, P < 0.01). In all cases there was apparently normal interstitial extravillous trophoblast invasion. CONCLUSIONS: Defective decidual endovascular trophoblast invasion, rather than excessive intervillous thrombosis, is the most frequent histological abnormality in PAPS associated early pregnancy loss. Furthermore, endovascular trophoblast invasion is not significantly reduced in the majority of fetal aneuploidy-associated pregnancy failures.

Placental function in multifetal pregnancies before and after embryo reduction was investigated by measuring maternal serum concentrations of pregnancy associated placental protein-A (PAPP-A) and pregnancy specific beta-1-glycoprotein (SP-1), Three groups of pregnant women were studied following assisted reproduction; groups 1 and 2, were 12 singleton and 12 twin pregnancies respectively, and group 3 comprised 12 women with multifetal pregnancies undergoing embryo reduction, PAPP-A and SP-l were measured serially at 8-21 weeks gestation, In all pregnancies, maternal serum PAPP-A and SP-1 increased with gestation, In twin pregnancies the mean concentrations of SP-1 were significantly higher than in singletons at all gestations, whereas for PAPP-A, concentrations were similar between these groups, In multifetal pregnancies before embryo reduction, the serum concentrations of both proteins were significantly higher than in twin pregnancies. Following reduction, the concentrations of PAPP-A remained significantly higher than for twins throughout, whereas the concentrations of SP-l gradually converged towards those of twins; by 19 weeks there was no difference between the means of the two groups, These findings suggest that circulating concentrations of SP-1 reflect total placental mass, which is proportional to the number of live fetuses, whereas the pattern of PAPP-A changes suggests that this protein is produced by the placenta, decidua and other tissues.