Pregnancy · Fetal Medicine
Abstract
Introduction
Analysis of data from cases of trisomy mosaicism can provide insight for genetic counselling after prenatal diagnosis and for the elucidation of the pathogenesis of trisomy during pregnancy.
Methods
Statistical analysis was carried out on data from 162 cases of pregnancies with prenatal diagnosis of trisomy 16 mosaicism.
Results
The majority of cases resulted in live birth (66%) with an average gestational age of 35.7 weeks and average birth weight of -1.93 standard deviations from the population mean. Among the live births 45% had at least one malformation, the most common being VSD, ASD, and hypospadias. The level of trisomy on direct CVS (cytotrophoblast) was associated with more severe intrauterine growth restriction (IUGR) and higher risk of malformation, while the level of trisomy on cultured CVS (chorionic villous stroma) was associated only with more severe IUGR. Similarly, the presence of trisomy on amniocentesis (amniotic fluid) was associated with both IUGR and malformation, while the presence of trisomy in the amniotic mesenchyme was associated only with IUGR. Surprisingly, the degree of trisomy in placental tissues appeared to be independent of the degree of trisomy in amniotic fluid and amniotic mesenchyme. The sex of the fetus was not associated with any outcome variables, although there was an excess of females (sex ratio = 0.45) that may be explained by selection against male mosaic trisomy 16 embryos before the time of CVS (approximately 9-12 weeks).
Conclusion
The levels of trisomy in different fetal-placental tissues are significant predictors of some measures of outcome in mosaic trisomy 16 pregnancies.
Topics
By this author
Reproductive Genetics · Chromosomal Abnormalities
Placental weight in pregnancies with trisomy confined to the placenta
Yong PJ et al., 2009 · Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC
Mosaicism with trisomy confined to the placenta is present in ~1% of ongoing pregnancies at the time of chorionic villus sampling. Some studies have found reduced fetal growth in confined placental trisomy. The objective of this study was to assess placental weight and feto-placental weight ratio in pregnancies with trisomy confined to the placenta, and to correlate them with the level of trisomy in the three major placental lineages. We conducted a retrospective study of 69 pregnancies with prenatally diagnosed mosaic trisomy in which the trisomic cells were confined to the placenta. Placental weight and feto-placental weight ratio were compared to those of matched controls, and placental weight was also analyzed for associations with the type and level of trisomy. Placental pathology was also reviewed. The pregnancies with mosaic trisomy were found to have lower placental weights than matched controls, but normal feto-placental weight ratios. Placental weight was not associated with the type or level of trisomic cells in the three placental lineages at term (chorionic plate, chorionic villus mesenchyme, and trophoblast). There were no pathognomonic findings on routine placental pathology of the trisomic placentas. Although placental weight was reduced (with normal feto-placental weight ratio) in pregnancies with trisomy confined to the placenta, the level of placental trisomy was not correlated with placental weight. Thus, trisomy may alter placental function rather than have a direct hypoplastic effect on placental growth. More in-depth studies beyond routine pathology are required to identify how trisomy affects placental function.
Birth Outcomes · Maternal Morbidity
Expectant management of severe preeclampsia remote from term: a structured systematic review
Magee LA et al., 2009 · Hypertension in pregnancy
To compare outcomes associated with expectant vs. interventionist care of severe preeclampsia in observational studies. Medline (01/1980-07/2007), bibliographies of retrieved papers, personal files, Cochrane Database of Systematic Reviews. Expectant or interventionist care of preeclampsia at <34 wk. TABULATION, INTEGRATION, Data abstraction independently by two reviewers. Median [IQR] of clinical maternal/perinatal outcomes presented. 72 publications, primarily from tertiary care centres in Dutch and developed world sites. Expectant care of severe preeclampsia <34 wk (39 cohorts, 4,650 women), for which 40% of women are eligible, is associated with pregnancy prolongation of 7-14 d, and few serious maternal complications (median <5%), similar to interventionist care (2 studies, 42 women). Complication rates are higher with HELLP <34wk (12 cohorts, 438 women) and severe preeclampsia <28wk (6 cohorts, 305 women), similar to interventionist care (6 cohorts, 467 women and 2 cohorts, 70 women, respectively). Expectant care of HELLP <34 wk (12 cohorts, 438 women) is associated with fewer days gained (median 5), but more serious maternal morbidity (e.g., eclampsia, median 15%). More than half of women have at least temporary improvement of HELLP. In the developed world, expectant (vs. interventionist) care of severe preeclampsia or HELLP <34 wk is associated with reduced neonatal death and complications. Stillbirth is higher in Dutch and developing world sites where viability thresholds are higher. For preeclampsia <24wk (4 cohorts), perinatal mortality is >80%. No predictors of adverse maternal/perinatal outcomes were identified (13 studies). Future research should establish the best maternal/fetal monito regimen and indications for delivery with expectant care. A definitive RCT is needed.
Fetal Medicine · Fetal Growth
Postnatal follow-up of prenatally diagnosed trisomy 16 mosaicism
Langlois S et al., 2006 · Prenatal diagnosis
To determine the long-term outcome of pregnancies prenatally diagnosed with trisomy 16 and identify variables associated with the outcome. We reviewed all published and our unpublished data from trisomy 16 pregnancies for which outcomes were available for children of greater than 1 year of age. Nineteen cases were diagnosed with trisomy 16 on chorionic villus sampling (CVS) and 17 cases at amniocentesis. Age at last follow-up ranges from 1 to 13 years. Among the CVS group, four out of five patients, with a birth weight and/or length below -2 SD and postnatal growth information, showed catch-up growth (80%). Among the amniotic fluid (AF) group, the birth weight was available in 13 cases. Eleven of the 13 cases had a birth weight less than -2 SD. In eight cases, the length was also below -2 SD (length data unavailable in one case). Nine out of ten cases (90%) and seven out of eight (87.5%) showed catch-up growth for weight and length, respectively. In terms of development, no cases of CVS mosaicism had global developmental delay. One child had a history of delay in speech development. Among the AF-detected cases, 4/17 cases had global developmental delay. All four children with global developmental delay had more than one major malformation compared to 6 out of 32 children in the group with normal development (p = 0.004). The finding of uniparental disomy (UPD) was not associated with developmental delay. The majority of prenatally diagnosed trisomy 16 mosaic cases have a good postnatal outcome. However, the finding of mosaicism on AF and the presence of major congenital anomalies are associated with an increased risk of developmental delay.
Reproductive Genetics · Epigenetics
Evidence for imprinting on chromosome 16: the effect of uniparental disomy on the outcome of mosaic trisomy 16 pregnancies
Yong PJ et al., 2002 · American journal of medical genetics
Although a number of infants with maternal uniparental disomy of chromosome 16 (upd(16)mat) have been reported, the evidence for imprinting on chromosome 16 is not yet conclusive. To test the hypothesis that upd(16)mat has a distinct phenotype, which would support the existence of imprinted gene(s) on chromosome 16, statistical analysis was performed on a large series (n = 83) of mosaic trisomy 16 cases with molecular determination of uniparental disomy status. The incidence of upd(16)mat was 40%, which is consistent with the expected one third from random chromosome loss during trisomy rescue (P = 0.262). In pairwise comparisons, upd(16)mat was found to be associated with fetal growth restriction (P = 0.029) and with increased risk of major malformation (RR = 1.43; P = 0.053). Regression modeling showed that the effect of upd(16)mat on fetal/neonatal weight and malformation is independent of the degree of trisomy detected in the fetus. Regression modeling to control for the degree of trisomy detected in the placenta was not possible due to limited sample size. We conclude that upd(16)mat is associated with more severe growth restriction, and possibly, with higher risk of malformation. Our hypothesis is that imprinted gene(s) exist on chromosome 16 and that abnormal expression of these gene(s) in upd(16)mat cells during development results in decreased cell proliferation. Although we do not advocate prenatal testing for upd(16), studies on the long-term outcome of upd(16)mat neonates is necessary for counseling purposes.
Related research
Reproductive Genetics · Chromosomal Abnormalities
The association between preeclampsia and placental trisomy 16 mosaicism
Yong PJ et al., 2006 · Prenatal diagnosis
Prenatally diagnosed trisomy 16 mosaicism is associated with the increased risk of poor pregnancy outcome including intrauterine growth restriction, intrauterine death and fetal malformation. While maternal preeclampsia has also been reported in some cases, this has not been systematically evaluated. To better define the risk of preeclampsia and the clinical course of preeclampsia in these pregnancies and to identify associated clinical variables, we reviewed 25 cases of prenatally diagnosed trisomy 16 mosaicism for which molecular studies were undertaken and sufficient obstetrical data were present to include/exclude the diagnosis of preeclampsia. Six of 25 (24%) mosaic trisomy 16 cases exhibited preeclampsia as compared to 3 of 44 (7%) matched controls. There were no differences between those mosaic trisomy 16 cases presenting with preeclampsia and those that did not, in terms of the presence/absence of UPD, IUGR, malformation, or trisomy on amniocentesis. Four of the 6 (67%) preeclampsia-associated fetuses were male, compared with only 4 of 19 (21%) (p = 0.06) nonpreeclampsia case fetuses, and three of these also had hypospadias. The levels of trisomy tended to be high in placentas associated with preeclampsia; however very high levels of placental trisomy were also often seen in the absence of preeclampsia. As it is impossible to predict which subset of cases is at highest risk, all women receiving a prenatal diagnosis of trisomy 16 mosaicism should be closely monitored for signs of preeclampsia.
Outcomes and Effectiveness · Live Birth Rates
Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use
Viotti M et al., 2021 · Fertil Steril
To study how the attributes of mosaicism identified during preimplantation genetic testing for aneuploidy relate to clinical outcomes, in order to formulate a ranking system of mosaic embryos for intrauterine transfer. Compiled analysis. Multi-center. PATIENT(S): A total of 5,561 euploid blastocysts and 1,000 mosaic blastocysts used in clinical transfers in patients undergoing fertility treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation (gestational sac), ongoing pregnancy, birth, and spontaneous abortion (miscarriage before 20 weeks of gestation). RESULT(S): The euploid group had significantly more favorable rates of implantation and ongoing pregnancy/birth (OP/B) compared with the combined mosaic group or the mosaic group affecting only whole chromosomes (implantation: 57.2% vs. 46.5% vs. 41.8%; 52.3% vs. 37.0% vs. 31.3%), as well as lower likelihood of spontaneous abortion (8.6% vs. 20.4% vs. 25%). Whole-chromosome mosaic embryos with level (percent aneuploid cells) <50% had significantly more favorable outcomes than the ≥50% group (implantation: 44.5% vs. 30.4%; 36.1% vs. 19.3%). Mosaic type (nature of the aneuploidy implicated in mosaicism) affected outcomes, with a significant correlation between number of affected chromosomes and unfavorable outcomes. This ranged from mosaicism involving segmental abnormalities to complex aneuploidies affecting three or more chromosomes (implantation: 51.6% vs. 30.4%; 43.1% vs. 20.8%). Combining mosaic level, type, and embryo morphology revealed the order of subcategories regarding likelihood of positive outcome. CONCLUSION(S): This compiled analysis revealed traits of mosaicism identified with preimplantation genetic testing for aneuploidy that affected outcomes in a statistically significant manner, enabling the formulation of an evidence-based prioritization scheme for mosaic embryos in the clinic.
Outcomes and Effectiveness · Live Birth Rates
Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial
Capalbo A et al., 2021 · Am J Hum Genet · Free full text on PubMed Central
Chromosome imbalance (aneuploidy) is the major cause of pregnancy loss and congenital disorders in humans. Analyses of small biopsies from human embryos suggest that aneuploidy commonly originates during early divisions, resulting in mosaicism. However, the developmental potential of mosaic embryos remains unclear. We followed the distribution of aneuploid chromosomes across 73 unselected preimplantation embryos and 365 biopsies, sampled from four multifocal trophectoderm (TE) samples and the inner cell mass (ICM). When mosaicism impacted fewer than 50% of cells in one TE biopsy (low-medium mosaicism), only 1% of aneuploidies affected other portions of the embryo. A double-blinded prospective non-selection trial (NCT03673592) showed equivalent live-birth rates and miscarriage rates across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos. No instances of mosaicism or uniparental disomy were detected in the ensuing pregnancies or newborns, and obstetrical and neonatal outcomes were similar between the study groups. Thus, low-medium mosaicism in the trophectoderm mostly arises after TE and ICM differentiation, and such embryos have equivalent developmental potential as fully euploid ones.
Pregnancy › Fetal Medicine › Fetal Growth
PMID 12624135 12624135 DOI 10.1136/jmg.40.3.175 10.1136/jmg.40.3.175 Yong et al. 2003, Yong 2003