Noninvasive prenatal testing (NIPT) using cell-free DNA (cfDNA) is typically carried out to screen for common fetal chromosomal anomalies, with the option to screen for a wider range of chromosomal ...changes (expanded NIPT) becoming increasingly available. However, little is known about pregnant patients' attitudes and preferences regarding expanded NIPT.
To address this gap, we surveyed general-risk patients having first-tier cfDNA screening at a private prenatal clinic on their expectations for expanded NIPT. Patients were asked questions regarding their current pregnancy and previous pregnancy history, their opinions on fetal DNA screenings during pregnancy and incidental findings, information and opinions on financial resources for NIPT, as well as socio-cultural questions to determine patient demographics.
Of the 200 survey participants, the majority were educated, self-reported as white, had a higher than average income, and reported no aneuploidy risk factors. When asked what information they would like to receive from cfDNA screening, the vast majority of participants wanted all information available that could have an immediate impact on fetal health (88%) or an immediate impact on infant health from birth (82%). Many participants also wanted information that could have a future impact on the child's health or an immediate or future impact on the pregnant woman's own health. Most participants wanted information about the sex of fetus (86%) and common trisomies (71%), with almost half of participants desiring information about rare autosomal aneuploidies and/or all genetic information that may affect the baby. In addition, participants were found to be comfortable screening for conditions that are well-known, influence care during pregnancy, and are treatable. Finally, while most respondents either had insurance coverage for NIPT or were able to afford NIPT out of pocket, the majority of our participants felt that expanded NIPT should be either free for everyone or for those considered high risk.
Our findings suggest that with appropriate pre-test counseling, pregnant patients may choose NIPT for an expanding list of conditions.
Cell-free (cf) DNA screening is a noninvasive prenatal screening approach that is typically used to screen for common fetal trisomies, with optional screening for sex chromosomal aneuploidies and ...fetal sex. Genome-wide cfDNA screening can screen for a wide variety of additional anomalies, including rare autosomal aneuploidies (RAAs) and copy number variants. Here, we describe a multi-cohort, global retrospective study that looked at the clinical outcomes of cases with a high-risk cfDNA screening result for a RAA. Our study cohort included a total of 109 cases from five different sites, with diagnostic outcome information available for 68% (74/109) of patients. Based on confirmatory diagnostic testing, we found a concordance rate of 20.3% for presence of a RAA (15/74) in our study population. Pregnancy outcome was also available for 77% (84/109) of cases in our cohort. Many of the patients experienced adverse pregnancy outcomes, including intrauterine fetal demise, fetal growth restriction, and preterm birth. These adverse outcomes were observed both in patients with fetal or placental confirmation of the presence of a RAA, as well as patients that did not undergo fetal and/or placental diagnostic testing. In addition, we have proposed some suggestions for pregnancy management and counseling considerations for situations where a RAA is noted on a cfDNA screen. In conclusion, our study has shown that genome-wide cfDNA screening for the presence of rare autosomal aneuploidies can be beneficial for both patients and their healthcare practitioners. This can provide a possible explanation for an adverse pregnancy outcome or result in a change in pregnancy management, such as increased monitoring for adverse outcomes.
Trisomy 20 has been shown to be one of the most frequent rare autosomal trisomies in patients that undergo genome-wide noninvasive prenatal testing. Here, we describe the clinical outcomes of cases ...that screened positive for trisomy 20 following prenatal genome-wide cell-free (cf.) DNA screening. These cases are part of a larger cohort of previously published cases. Members of the Global Expanded NIPT Consortium were invited to submit details on their cases with a single rare autosomal aneuploidy following genome-wide cfDNA screening for retrospective analysis. Clinical details including patient demographics, test indications, diagnostic testing, and obstetric pregnancy outcomes were collected. Genome-wide cfDNA screening was conducted following site-specific laboratory procedures. Cases which screened positive for trisomy 20 (n = 10) were reviewed. Clinical outcome information was available for 90% (9/10) of our screen-positive trisomy 20 cases; the case without diagnostic testing ended in a fetal demise. Of the nine cases with outcome information, one was found to have a mosaic partial duplication (duplication at 20p13), rather than a full trisomy 20. Only one case in the study cohort had placental testing; therefore, confined placental mosaicism could not be ruled out in most cases. Adverse pregnancy outcomes were seen in half of the cases, which could suggest the presence of underlying confined placental mosaicism or mosaic/full fetal trisomy 20. Based on our limited series, the likelihood of true fetal aneuploidy is low but pregnancies may be at increased risk for adverse obstetric outcomes and may benefit from additional surveillance.
Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity worldwide. However, current methods of screening are complicated and require special skill sets. In this observational study ...of prospectively collected samples, we wanted to evaluate if cell-free (
) DNA could be an efficient biomarker for identification of at-risk patients.
One hundred patients attending a private prenatal clinic in Canada were enrolled in their first trimester of pregnancy and a blood draw was carried out at 11 + 0 to 14 + 2 weeks' (timepoint A) and 17 + 6 to 25 + 5 weeks of gestation (timepoint B). CfDNA signals, namely concentration, fetal fraction, and fragment size distribution, were correlated with clinical outcomes in the test population to develop the logistic regression model.
Twelve patients developed PE-four early-stage and eight late-stage PE. Significant differences were observed between PE patients and control cases for all three cfDNA signals at timepoint A, while both fetal fraction and concentration were significantly different between PE patients and control cases at timepoint B. Overall, the model had a sensitivity of up to 100% and specificity of up to 87.5% at Timepoint A.
This proof-of-principle study showed that use of this logistic regression model could identify patients at risk of preeclampsia in the first trimester of pregnancy.
Partial monosomy of the long arm of chromosome 7 has been characterized by wide phenotypic manifestations, but holoprosencephaly (HPE) and sacral agenesis have frequently been associated with this ...chromosomal deletion. A clear relationship between genotype and phenotype remains to be defined in the 7q deletion syndrome. Three patients (1, 2, and 3) were investigated with 7q terminal deletion and compared with similar deletion cases in the literature in order to stratify the phenotypes associated with 7q35 and 7q36 terminal deletion patients. Patients 1, 2, and 3 were carrying a de novo terminal deletion at bands 7q36.2, 7q35, and 7q36.1, respectively. In patient 3, a small Xq28 duplication was also identified by array-CGH. Our patients presented with heterogeneous phenotypic manifestations, which could imply the possible role of environmental factors (multifactorial inheritance), structural variations in the non-coding regions, penetrance, and/or polymorphism. The varying length of deletion was also taken into account. Growth retardation was the most frequent symptom found in both 7q35 and 7q36 patients we reviewed. The occurrence of HPE and sacral malformation together was seen in less than 10% of the reviewed cases in both kinds of deletion. HPE was associated mainly in cases with an unbalanced translocation.
Objective We analyzed the cost-effectiveness (CE) and performances of commonly used prenatal Down syndrome (DS) screening strategies. Study Design We performed computer simulations to compare 8 ...screening options by applying empirical data from Serum, Urine, and Ultrasound Screening Study trials on the population of 110,948 pregnancies. Screening strategies outcomes, CE ratios, and incremental CE ratios were measured. Results The most CE DS screening strategy was the contingent screening method (CE ratio of Can$26,833 per DS case). Its incremental CE ratio compared to the second-most CE strategy (serum integrated screening) was Can$3815 per DS birth detected. Among the procedures respecting guidelines, our results identified the combined test as the screening strategy with the highest CE ratio (Can$47,358) and the highest number of procedure-related euploid miscarriages (n = 71). Conclusion In regard to CE, contingent screening is the best choice. The combined test, which is the most popular screening strategy, shows many limitations.
The purpose of this study was to determine the most cost-effective option to prevent alloimmunization against the Rh factor.
A virtual population of Rh-negative pregnant women in Quebec was built to ...simulate the cost-effectiveness of preventing alloimmunization. The model considered four options: (1) systematic use of anti-D immunoglobulin; (2) fetal Rh(D) genotyping; (3) immunological determination of the father's Rh type; (4) mixed screening: immunological determination of the father's Rh type, followed if positive by fetal Rh(D) genotyping. Two outcomes were considered, in addition to the estimated costs: (1) the number of babies without hemolytic disease, and (2) the number of surviving infants.
In a first pregnancy, two options emerged as the most cost-effective options: systematic prophylaxis and immunological Rh typing of the father, with overlapping confidence intervals between them. In a second pregnancy, the results were similar. In all cases (first or second pregnancy or a combination of the two) fetal genotyping was not found to be a cost-effective option.
Routine prophylaxis and immunological Rh typing of the father are the most cost-effective options for the prevention of Rh alloimmunization. Considering that immunological typing of the father would probably not be carried out by the majority of clinicians, routine prophylaxis remains the preferred option. However, this could change if the cost of Rh(D) fetal genotyping fell below $140 per sample.
Human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) have an endless self-renewal capacity and can theoretically differentiate into all types of lineages. They thus ...represent an unlimited source of cells for therapies of regenerative diseases, such as Duchenne muscular dystrophy (DMD), and for tissue repair in specific medical fields. However, at the moment, the low number of efficient specific lineage differentiation protocols compromises their use in regenerative medicine. We developed a two-step procedure to differentiate hESCs and dystrophic hiPSCs in myogenic cells. The first step was a culture in a myogenic medium and the second step an infection with an adenovirus expressing the myogenic master gene MyoD. Following infection, the cells expressed several myogenic markers and formed abundant multinucleated myotubes in vitro. When transplanted in the muscle of Rag/mdx mice, these cells participated in muscle regeneration by fusing very well with existing muscle fibers. Our findings provide an effective method that will permit to use hESCs or hiPSCs for preclinical studies in muscle repair.
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