Confined placental mosaicism in term placentae: Analysis of 125 cases

In order to determine the incidence of confined placental mosaicism (CPM) in term placentae and to show the presence of specific sites and the effect on fetal development, 125 placentae from uneventful pregnancies were analysed by cytogenetic methods. The incidence was at least 4.8 per cent and there were no specific sites on the placenta. Although the number of cases is still too small, we found CPM to be associated with intrauterine growth retardation in six cases.     

Confined placental mosaicism in CVS and pregnancy outcome

The perinatal outcome of 26 patients with confined placental mosaicism (CPM) detected in chorionic villus sampling (CVS) who wished to continue their pregnancies was compared with that of two controls per patient matched for age and parity (n=52). There were no significant differences in birth weight or gestational age at delivery between patients with CPM and controls. There were no cases of intrauterine growth retardation (IUGR) in the CPM patients as compared with two (2/52, 3·8 per cent) in the control group (P>0·05). There was no significant increase in fetal loss between the study group (1/26, 3·6 per cent) and the controls (1/52, 1·9 per cent) (P>0·05).     

The significance of trisomy 7 mosaicism in chorionic villus cultures

Two cases of mosaic trisomy 7 confined to the cultured cells and not found in direct preparation were detected from 200 consecutive first-trimester chorionic villus samples (CVS) analysed. The mosaicism was similar in the two cases, but the pregnancy outcome was different. In both cases, the direct metaphases from the CVS were 46, XY. Culture metaphases were mos46,XY/47,XY, + 7; the trisomy 7 was seen in 34 per cent of cells from case 1 and 53 per cent from case 2. A sonogram at 15¹/₂ weeks revealed fetal death in utero in case 1, and the patient declined amniocentesis. The fetal tissue failed to grow in culture, but the placental cultured cells were 47,XY, + 7 in 28 (100 per cent) cells analysed. In the second case, all the amniotic fluid cells were 46,XY and the pregnancy resulted in a normal male with a 46,XY karyotype in the cord blood and foreskin fibroblast cultures. The term placenta was mosaic with 13/163 (8 per cent) trisomy 7 cells. Extensive cytogenetic studies on the placenta for the first time confirmed trisomy 7 mosaicism confined to the villus cultures.     

Follow-up and pregnancy outcome after a diagnosis of mosaicism in CVS

In 2103 consecutive diagnostic chorionic villus samples, examined in a 4-year period in our clinical genetics unit, 26 samples (1.2 per cent) presented chromosomal mosaicism in the direct and/or long-term culture preparations. Only once (46,XX/47,XX,+9) was the mosaicism confirmed in the fetus. In the cytogenetic follow-up studies of the remaining 25 pregnancies, in no cases could the aberration be confirmed in amniotic fluid or fetal tissue. One patient requested a termination after the CVS result. Of the remaining 24 pregnancies, four (16.7 per cent) ended in a spontaneous abortion. These findings suggest an association between placental mosaicism and fetal loss.     

Prenatal diagnosis of trisomy 9 mosaicism: Two new cases

We present two prenatal cases of trisomy 9 mosaicism, both of which presented intrauterine growth retardation (IUGR) and other abnormal ultrasound findings. In case A, mosaicism was found in amniotic fluid cell cultures, of which 65 per cent were trisomic cells, on average. In case B, trisomic cells were present in amniotic fluid cell cultures (12 per cent) but none were found in fetal cord blood. After autopsy, cytogenetic findings were confirmed in different tissue cultures. It is concluded that echographic indicators are a very useful tool for a correct prenatal diagnostic interpretation of trisomy 9. Suspected trisomy 9 mosaicism always requires further investigation and fetal cord blood cytogenetic analysis may not be considered as providing an accurate diagnosis of fetal trisomy 9.     

Follow-up of pregnancies complicated by placental mosaicism diagnosed by chorionic villus sampling

Thirty-nine (2.3 per cent) of 1724 chromosome studies from diagnostic chorionic villus samplings (CVS) done between 1983 and 1990 showed either level III (true) mosaicism (1.2 per cent) or level II (pseudo-) mosaicism (1.1 per cent) for chromosomal aneuploidy. Follow-up information on these 39 pregnancies was collected from questionnaires to families, paediatricians, and obstetricians. For all cases in which the pregnancy was continued and further testing was accomplished, the mosaicism was felt to be confined to the placenta. As compared with a control group of pregnancies evaluated by CVS with normal karyotypes, there was no increased incidence of pregnancy loss, congenital malformations, or developmental delay in the infants. Although intrauterine growth retardation occurred in several of the level III mosaic cases, adequate catch-up growth has been demonstrated.     

Confined placental mosaicism,IUGR, and adverse pregnancy outcome: A controlled retrospective U.K. collaborative survey

In a retrospective collaborative study involving 21 U.K. laboratories and 11775 CVS prenatal diagnostic procedures, a total of 73 cases of confined placental mosaicism (CPM) were identified among the 8004 first-trimester referrals because of advanced maternal age, a previous child with a numerical chromosome abnormality, or a family history of the same. Data were collected on subsequent cytogenetic follow-up and pregnancy outcome for each case and a referral matched control. Comparison with the control population failed to demonstrate a marked increase in adverse pregnancy outcome in the CPM group, but a significant increase in both low and high birth weight infants was recorded. In a parallel study, 7 out of 108 cases, referred for prenatal diagnosis because of ultrasound detection of isolated intrauterine growth retardation (IUGR) in the second or third trimester, were shown to have a chromosome abnormality restricted to the extraembryonic tissues. These included cases of CPM involving trisomy 9 and del(13)(q13), neither of which has previously been reported in association with IUGR.     

Identification of a case of maternal uniparental disomy of chromosome 10 associated with confined placental mosaicism

We report a case of maternal uniparental disomy of chromosome 10 discovered after chorionic villus sampling (CVS). Direct preparations revealed mosaic trisomy 10, while cultured CVS cells, as well as amniotic fluid cells, showed only a normal 46,XY complement. DNA analysis using microsatellite markers showed both chromosomes 10 to have been inherited from the mother. The pregnancy was complicated by polyhydramnios. A phenotypically normal male infant of appropriate size was delivered by Caesarean section at 41 weeks' gestation. Since only the direct preparations showed trisomy 10, this case illustrates the importance of CVS direct preparations in the detection of pregnancies at risk of uniparental disomy (UPD). Although the increased frequency of confined placental mosaicism (CPM) diagnosed when direct preparations are performed has been viewed negatively, identification of both CPM and UPD may have biological and clinical significance for a pregnancy. Even though only a single case of maternal disomy 10 is reported here, the apparently normal phenotype provides evidence that there are no major imprinted loci on chromosome 10 that affect in utero growth and development. However, other potential effects such as mental retardation will require long-term follow-up of this as well as additional cases.     

The dilemma of chromosomal mosaicism in chorionic villus sampling—‘direct’ versus long-term cultures

Chromosomal mosaicism is one of several unanswered dilemmas in first-trimester prenatal diagnosis. We report the course of a pregnancy in which a normal karyotype was detected on direct CVS preparation and fetal blood, 100 per cent trisomy 21 in one long-term CVS culture, and low-rate trisomy 21 mosaicism in a second long-term CVS culture and amniocentesis. The phenotypically normal infant had a 6 per cent mosaicism of trisomy 21. It appears that a persistent low-rate mosaicism in different tissues may be indicative of the true status of the fetus.     

Confined placental mosaicism for trisomy 14 and maternal uniparental disomy in association with elevated second trimester maternal serum human chorionic gonadotrophin and third trimester fetal growth restriction

A case of confined placental mosaicism (CPM) and maternal uniparental isodisomy 14 identified after placental karyotype revealed trisomy 14 in a newborn with intrauterine growth restriction (IUGR) and minor dysmorphic features is reported. During the second trimester of the pregnancy, multiple marker screening revealed an increased risk for Down syndrome of >1 in 10. The maternal serum human chorionic gonadotrophin (MShCG) was markedly elevated at 4.19 MoM. Amniocentesis revealed a normal 46,XX karyotype. Fetal growth restriction has been associated with elevated MShCG and placental aneuploidy with CPM for chromosomes 2, 7, 9 and 16. The present case of CPM for chromosome 14 was also associated with fetal growth restriction and elevated second trimester MShCG, suggesting a common link. Further studies need to be done to determine if indeed elevation of second trimester MShCG is associated with increased risk of CPM. The present case again demonstrates the need to perform placental karyotype in unexplained fetal growth restriction. Copyright © 2001 John Wiley & Sons, Ltd.     

Postnatal placental confirmation of trisomy 2 and trisomy 16 detected at chorionic villus sampling: A possible association with intrauterine growth retardation and elevated maternal serum alpha-fetoprotein

Detection of trisomy 2 and trisomy 16 mosaicism through chorionic villus sampling (CVS) is not an infrequent finding. We describe here two cases, one of non-mosaic trisomy 2 and the other of high level mosaicism for trisorny 16. Amniocentesis in both cases demonstrated non-mosaic 46,XY karyotypes. Each pregnancy continued to delivery of liveborn, normal-appearing boys; both pregnancies were complicated by severe intrauterine growth retardation (IUGR). Postnatal studies of placental biopsies in both cases confirmed the original CVS findings, whereas cord blood karyotypes were normal in both boys. Both children have demonstrated adequate catch-up growth.     

The European collaborative study on mosaicism in chorionic villus sampling: Data from 1986 to 1987

Data on a total of 11 855 diagnostic chorionic villus samples obtained in the years 1986 and 1987 were compiled from a questionnaire filled in by 36 European cytogenetic centres. Mosaicism was reported in 141 cases. The cytogenetic findings were followed by induced abortion in 24 cases. Spontaneous abortion was observed in nine mosaic pregnancies, a rate not significantly different from that observed for CVS in total. Mosaicism was found in 1.2 per cent of analyses by direct analysis/short-term culture, in contrast to the 0.6 per cent found after long-term culture. Evidence for fetal non-mosaicism was found in 99 of the 141 cases. The finding of mosaicism in first-trimester CVS should always elicit further analyses, preferably after amniocentesis, to substantiate the suspected fetal chromosome aberration.     

Management of prenatally detected trisomy 8 mosaicism

We report on ten pregnancies with trisomy 8 mosaicism. Nine cases were prenatally detected in chorionic villi (n=6), amniotic fluid (AF) cells (n=2) or fetal blood (FB) lymphocytes (n=1). Follow-up laboratory investigations showed confined placental mosaicism (CPM) or pseudomosaicism in eight cases. In one case with ultrasound abnormalities, trisomy 8 mosaicism was detected in FB cells although cultured AF cells showed normal cells only. Another case of mosaic trisomy 8 was prenatally missed; cytogenetic analysis of short-term cultured villi revealed a normal male karyotype, while postnatally, trisomy 8 mosaicism was detected in peripheral blood lymphocytes and skin fibroblasts of the affected child. These findings indicate the difficulties in the prenatal diagnosis of trisomy 8 mosaicism. When found in chorionic villi, it mostly represented CPM, while in a case of true fetal trisomy 8 mosaicism, the cytotrophoblast cells showed a normal karyotype. So, the cytotrophoblast compartment of chorionic villi is a poor indicator of the presence or absence of fetal trisomy 8 mosaicism. Follow-up investigations including amniocentesis and especially fetal blood sampling are required to come to a definite prenatal diagnosis of trisomy 8 mosaicism. Copyright © 2001 John Wiley & Sons, Ltd.     

Cytogenetic analysis of 2928 CVS samples and 1075 amniocenteses from randomized studies

We report cytogenetic results from a randomized Danish chorionic villus sampling (CVS) and amniocentesis (AC) study including 2928 placental and 1075 amniotic fluid specimens processed in the same laboratory. The results are presented in groups comparing CVS with amniocentesis and transabdominal (TA) CVS with transcervical (TC) CVS as randomized. More abnormalities and more ambiguous diagnostic problems were found in placental tissues than in amniotic cells. There were no diagnostic errors and no incorrect sex predictions. Mosaicism was detected in 1 per cent of all cases of CVS (discordancies included). When confirmation studies were done, 90 per cent were found to be confined to the placenta. Eight cases (0.7 per cent) of mosaicism/pseudomosaicism were seen in amniotic fluid specimens, and two cases of five with confirmation studies were confirmed in the fetus. The rate of mosaicism/pseudomosaicism in CVS and AC specimens differed (P <0.05). The rate of pseudomosaicism in cultures of villi and amniotic fluid cells was 0.5 and 0.6 per cent, respectively. Single-cell aneuploidy was observed in 1.8 per cent of villi and 1.4 per cent of amniotic fluid cell specimens. Maternal cell contamination (MCC) was seen more often after TC sampling (4.5 per cent) compared with TA sampling (1.5 per cent), but posed no problems in interpretation. Compared with the processing of cultured specimens, the short-term method of preparation of villi in our laboratory doubled the technicians' workload. For practical and economic reasons we have ceased the routine use of short-term preparations.     

A canadian collaborative study of mosaicism in amniotic fluid cell cultures

Data on chromosomal mosaicism was collected retrospectively on 12 386 amniotic fluid samples cultured over a 10 year period in 14 Canadian centres. Level I mosaicism (a single abnormal cell—excluding single cell monosomy) was encountered in 863 cases (7.1 per cent). Level II mosaicism (multiple cells with the same abnormality in a single flask or colony) was encountered in 138 cases (1.1 per cent). Level III mosaicism (multiple cells distributed over multiple flasks or colonies) was encountered in 34 cases (0.3 per cent). Analysis of the details of these cases allowed five major conclusions to be drawn: (1) Single cell abnormalities should not be taken as an indication of true fetal mosaicism. Only rarely will this interpretation prove to be incorrect. (2) Mosaicism involving multiple cells confined to a single flask should not be regarded as an indication of true fetal mosaicism. Only occasionally will this interpretation prove to be incorrect. (3) Mosaicism involving multiple cells distributed over more than one flask should be regarded as a strong indication of true fetal mosaicism. Sixty per cent will be confirmed by karyotype analysis of the fetus or infant. (4) Mosaicism of the XX/XY type is usually due to maternal cell contamination. Occasionally it can be a female fetus with XY cells from an unknown source. (5) The in situ or colony method of chromosome analysis has no clear advantage over the flask method for either the detection of true fetal mosaicism or for the ability to distinguish true mosaics from false positives.     

A prospective cytogenetic study of third-trimester placentae in small-for-date but otherwise normal newborns

Data in the literature suggest that confined placental mosaicism might be associated with intrauterine growth retardation. However, this association may be coincidental and due to bias of ascertainment. We therefore started a prospective study based on the cytogenetic evaluation of placentae derived from growth-retarded newborns. We further minimized possible bias by excluding those small-for-date infants displaying findings which already could explain intrauterine growth retardation (mothers who are smokers, multiple pregnancies, gestosis, dysmorphic infants). In a collection of 71 small-for-gestational age newborns, we did not see a single case of true confined placental mosaicism.     

Mosaicism for trisomy 12: Four cases with varying outcomes

Trisomy 12 observed in chorionic villus sampling (CVS) may reflect generalized mosaicism or indicate mosaicism confined to only the placenta. In this report, four cases of trisomy 12 observed in CVS or cultured placental biopsies with varying outcomes are presented. Seven dinucleotide repeat polymorphisms for chromosome 12 were used to determine the chromosome 12 origins in the fetus or child and to delineate the mechanism(s) that gave rise to the trisomy. In two cases (cases A and C), the mosaicism was confined to the placenta, resulting in normal liveborns. Although, in one case, the molecular results suggested an apparent duplication of one paternal chromosome 12 in the placenta, normal biparental inheritance was found in the diploid fetal cell line in both cases. In two other cases (cases B and D), trisomy 12 was observed in both extraembryonic and fetal tissues. In one of these pregnancies, a child was born by Caesarean section at 37 weeks because of intrauterine growth retardation and oligohydramnios, and resulted in neonatal death. Molecular markers and fluorescence in situ hybridization (FISH) revealed low-level trisomy 12 mosaicism in the spleen. In the fourth case, fetal abnormalities were detected on ultrasound and low-level trisomy 12 mosaicism was observed in amniotic fluid cells using conventional cytogenetics and FISH. Molecular markers revealed a maternal meiosis I non-disjunction of chromosome 12 in DNA from a cultured placental biopsy. Although predicting the outcomes of pregnancies involving confined placental mosaicism remains difficult, molecular techniques are valuable tools for distinguishing uniparental from biparental disomy and mechanisms of mosaicism.     

Isochromosome 5p mosaicism at prenatal diagnosis: observations and outcomes in six cases at chorionic villus sampling and one at amniocentesis

We present six cases of 47,+i(5p)/46 mosaicism diagnosed at chorionic villus sampling (CVS), this being the first prospective series to be reported. The clinical indication in each was advanced maternal age. Further prenatal studies in four (amniocentesis, plus fetal blood sampling in one) did not show the isochromosome. In one case, subsequent amniocentesis showed 1/48 in situ colonies with the isochromosome, but fetal blood was karyotypically normal. These five pregnancies resulted in phenotypically normal livebirths; further normal follow-up reports (from age 4 months through 4 years) are noted in four of these. Analysis of placental tissue in one case confirmed the presence of the i(5p) mosaicism. In the remaining case, in which 100% of CVS cultured cells had the i(5p), the pregnancy was terminated. Fetal skin fibroblasts did not show the i(5p). Thus, in none of these six cases was true fetal mosaicism detected, nor an abnormal phenotype noted. We suggest that a 47,+i(5p)/46 karyotype, detected at CVS, may frequently reflect confined placental mosaicism. In addition, we report a case of the primary diagnosis of 47,+i(5p)/46 mosaicism at amniocentesis. The infant appeared normal at birth, but a brain malformation was subsequently identified. Copyright © 2002 John Wiley & Sons, Ltd.     

Molecular cytogenetic analysis of term placentae suspected of mosaicism using fluorescence in situ hybridization

In first-trimester chorionic villus sampling (CVS) for prenatal diagnosis, abnormal chromosomal findings, such as mosaicism, trisomies, or suspect abnormal karyotypes, are found more frequently than at amniocentesis. The fact that these chromosomal abnormalities do not always reflect the fetal karyotype but may be restricted to the placenta is a major problem in diagnosis and counselling. In this paper we present the results of fluorescence in situ hybridization (FISH) studies on interphase nuclei of three term placentae investigated because of false-positive findings at first-trimester CVS. The chorionic villi of the first case showed a mosaic chromosome pattern involving a trisomy 10 cell line and a normal cell line, those of the second case a total trisomy 8 cell line, while in the third case a complete monosomy X was found. Follow-up amniocentesis in each of these three cases revealed a normal karyotype. By using FISH, we were able to confirm the presence of the aberrant cell lines, which were all confined to one part of the placenta. FISH on interphase nuclei allows the investigation of large numbers of cells for the existence of numerical chromosome aberrations in a quick and reliable way.     

Chorionic mosaicism: Association with fetal loss but not with adverse perinatal outcome

Cytogenetic data from the United States NICHD collaborative study of chorionic villus sampling (CVS) were used to evaluate the clinical significance of chorionic mosaicism. The 10 754 patients with normal cytogenetic results were compared wtih 108 patients (1.0 per cent) with placental mosaicism and 181 patients (1.6 per cent) with pseudomosaicism. Of the pregnancies intended to continue, the pregnancy loss rate was significantly greater in patients with placental mosaicism than in the cytogenetically normal cohort (8.6 vs. 3.4 per cent, p <0.05). However, there was no difference in the frequencies of abruptio placenta, preterm labour or delivery, small-for-gestational-age newborns, pregnancy-induced hypertension, or neonates with Apgar scores less than 7.