We present the first study that investigates the effect of maternal body mass index (BMI) on the quantity of circulating fetal cells available to use in cell-based noninvasive prenatal test (cbNIPT). ...cbNIPT has been proposed as a superior alternative to noninvasive prenatal test from cell-free fetal DNA. Kølvraa et al. Prenat Diagn. 2016 Dec; 36(12): 1127–34 established that cbNIPT can be performed on as few as one fetal cell, and Vestergaard et al. Prenat Diagn. 2017 Nov; 37(11): 1120–4 demonstrated that these fetal trophoblast cells could be used successfully in cbNIPT to detect chromosomal and sub-chromosomal abnormalities. This study on 91 pregnant women with high-risk pregnancies suggests that cbNIPT should not be hampered by an increased BMI because every pregnancy, irrespective of the BMI, has rendered fetal cells for downstream genetic analysis. The mean number of fetal cells per sample was 12.6, with a range of 1–43 cells in one sample. ANOVA showed that increasing maternal BMI tends to decrease the number of fetal cells, but not significantly.
Introduction
In Denmark, first trimester screening has a very high uptake (>90%). If Down syndrome is diagnosed, termination rates are high (>95%). The aim of this study was to investigate the timing ...of the decision to terminate pregnancy following a diagnosis of Down syndrome and the factors influencing this decision.
Material and methods
Semi‐structured, qualitative interview study with 21 couples who had received a prenatal diagnosis of Down syndrome and decided to terminate the pregnancy. Participants were recruited from obstetric departments between February 2016 and July 2017. Data were analyzed using thematic analysis.
Results
Five themes were identified: “initial decision‐making”, “consolidating the decision”, “reasons and concerns shaping the termination of pregnancy decision”, “the right decision is also burdensome”, and “perceived influences in decision‐making”. For most couples, the initial decision to terminate pregnancy was made before or during the diagnostic process, but it was re‐addressed and consolidated following the actual diagnosis. Imagining a family future with a severely affected Down syndrome child was the main factor influencing the termination of pregnancy decision. The decision was articulated as “right” but also as existentially burdensome for some, due to fear of regret and concern about ending a potential life. The decision to terminate pregnancy was considered a private matter between the couple, but was refined through interactions with clinicians and social networks.
Conclusion
All couples made an initial decision prior to receiving the Down syndrome diagnosis. Knowledge of the couple's initial decision may facilitate patient‐centered communication during and after the diagnostic process. Couples may benefit from counseling to deal with grief and existential concerns.
Introduction
Applying whole‐exome sequencing (WES) for the diagnosis of diseases in children has shown significant diagnostic strength compared with chromosomal microarray. WES may also have the ...potential of adding clinically relevant prenatal information in cases where a fetus is found to have structural anomalies. We present results from the first fetal exomes performed in a tertiary center in Denmark.
Material and methods
Couples/expectant parents were included in Central Denmark Region from July 2016 to March 2019. Inclusion was not systematic, but where one or more fetal malformations or severe fetal hydrops were detected, and a specific diagnosis had not been obtained by chromosomal microarray. WES was performed in ongoing pregnancies (N = 11), after intrauterine demise (N = 5), or after termination of pregnancy based on ultrasound findings (N = 19). In most cases, a trio format was applied comprising fetal and parental DNA.
Results
WES was performed in 35 highly selected fetal cases. Pathogenic variants, or variants likely to explain the phenotype, were detected in 9/35 (26%). Variants of uncertain significance were detected in 7/35 (20%) and there was one secondary finding (3%). Out of the 11 ongoing pregnancies, four reached a genetic diagnosis (36%). Detection rate was highest in cases of multisystem anomalies (7/13, 54%). WES was completed in all three trimesters and both autosomal dominant, autosomal recessive and X‐linked inheritance were revealed.
Conclusions
We present data from 35 cases of exome sequencing applied in a setting of fetal malformations. Importantly, though, we wish to share our personal experiences with implementing WES into a prenatal setting. As a medical society, we must continue to share what we do not understand, what went wrong, what is difficult, and what we do not agree upon. A common understanding and language are warranted. We also advocate that more research is needed concerning the clinical value, as well as costs and patient perspectives, of using WES in pregnancy. We believe that WES will lead to improved prenatal and perinatal care.
To examine the performance of the combined First Trimester Screening (cFTS) algorithm when outliers of 4 risk parameters (maternal age, nuchal translucency (NT) thickness, PAPP-A and β-hCG) were ...included in the classification of "high-risk".
A retrospective analysis of singleton pregnancies undergoing cFTS between 2008 and 2011 in Denmark. Abnormal karyotypes were classified as trisomy 21 (T21), trisomy 13 (T13) and trisomy 18 (T18), sex chromosome aberrations and atypical abnormal karyotypes.
cFTS was completed in 193,638 pregnancies. In 10,205 (5.3%) cases, cytogenetic or molecular analysis was performed pre- or postnatally. An abnormal karyotype was seen in 1,122 (11.0%). The algorithm identified 87% of T21, 80% of T13, 75% of T18, 79% of sex chromosome aberrations and 35% of atypical abnormal karyotypes. Additional classification of a single risk parameter outlier (low PAPP-A or free β-hCG (< 0.2 MoMs), high β-hCG (≥5.0 MoMs), maternal age ≥45 years or NT ≥3.5 mm) as being at high-risk would have improved detection rates to 88, 80, 81, 81 and 37% respectively. The screen positive rate increased from 4.4 to 4.8%.
Addition of outliers of the 4 parameters used in cFTS algorithm will lead to a statistically significant increase in detection rates for chromosomal abnormality.
Introduction
Home management in general is considered to improve patient well‐being, patient involvement and cost‐effectiveness, for obstetric patients as well. But concerns regarding inclusion of ...intermediate‐ and high‐risk pregnant women are an issue and a limitation for clinical implementation. This retrospective study evaluated the outcome and safety of extended remote self‐monitoring of maternal and fetal health in intermediate‐ and high‐risk pregnancies.
Material and methods
The study reports on 400 singleton pregnancies complicated by preterm premature rupture of membranes (PPROM), fetal growth restriction, preeclampsia, gestational diabetes mellitus, high‐risk of preeclampsia, or a history of previous fetal or neonatal loss. Remote self‐monitoring was performed by pregnant women and included C‐reactive protein, non‐stress test by cardiotocography, temperature, blood pressure, heart rate, and a questionnaire concerning maternal and fetal wellbeing. Data were transferred to the hospital using a mobile device platform and evaluated by healthcare professionals. In case of non‐reassuring registrations, the pregnant women were invited for assessment at the hospital. Primary outcome was perinatal death. Secondary outcomes were other maternal and perinatal complications.
Results
No severe maternal complications were observed. Nine fetal or neonatal deaths occurred, all secondary to malformations, severe fetal growth restriction, extreme prematurity or lung hypoplasia in cases of PPROM before 24 weeks. Even in the latter group, fetal and neonatal survival was 78% (18/23) and rose to 97% (60/62) when PPROM occurred after a gestational age 23+6 weeks. None of the fetal or neonatal deaths were attributable to the home‐management setting.
Conclusions
Home‐monitoring including remote self‐monitoring of fetal and maternal well‐being in intermediate‐ and high‐risk pregnancies seems to be a safe alternative to inpatient or frequent outpatient care, which sets the stage for a new way of thinking of hospital care. The implementation process included staff training workshops and development of patient enrollment practice with clarification of expectations and responsibilities, which can be crucial to the results.
The objective of this study was to evaluate the fetal cardiac function in human pregnancies exposed to sertraline (a selective serotonin reuptake inhibitor) compared to unexposed pregnancies.
We ...included 44 women in gestational week 25 + 0 days to week 26 + 6 days. Fifteen women used sertraline (50-150 mg per day), and 29 women used no daily medication. We assessed fetal cardiac function by Myocardial Performance Index (MPI), E/A ratios and by tricuspid and mitral annular plane systolic excursion (TAPSE and MAPSE) measured by 2D M-mode and by 4D eSTIC M-mode.
There were no differences between the sertraline exposed and the unexposed. The mean difference of MPI was 0.03 (95% CI −0.08-0.03), of tricuspid and mitral E/A ratios 0.00 (95% CI −0.03-0.05) and 0.03 (95% CI −0.07-0.01), respectively. The mean difference of TAPSE, by 2D and eSTIC, was 0.07 mm (95% CI −0.56-0.41) and 0.10 mm (95% CI −0.55-0.34). Mean difference of MAPSE, by 2D and eSTIC was 0.16 mm (95% CI −0.22-0.53) and 0.24 mm (95% CI −0.16-0.65), respectively. Serum levels of sertraline in exposed participants ranged from 33-266, median 92 nmol/L.
We found no significant differences in fetal cardiac function, assessed by TAPSE, MAPSE, MPI and E/A ratios, in pregnancies exposed to sertraline compared to the unexposed.
Paracetamol (N-acetyl-p-aminophenol (APAP), also known as acetaminophen) is used to relieve mild to moderate pain and reduce fever. APAP is widely used during pregnancy as it is considered safe when ...used as directed by regulatory authorities. However, a significant amount of epidemiological and experimental research suggests that prenatal exposure potentially alters fetal development. In this paper, we summarize the potentially harmful adverse effects of APAP and the limitations of the current evidence. It highlights the urgent need for a clinical trial, and the aim of the presented qualitative pilot study on APAP use during pregnancy is the feasibility of a large-scale randomized controlled trial (RCT). In the qualitative study, we included 232 Danish women from three hospitals in the spring of 2021. After recognizing the pregnancy, 48% had taken any APAP, and 6% had taken it weekly or more than weekly. A total of 27% who had taken APAP in the first trimester of pregnancy (even rarely) would potentially participate in an RCT. In a potential clinical trial, the women would need to be included early in the 1.sup.st trimester as the suspected harmful effects of APAP lies within this early reproductive developmental window. A possible recruitment strategy was explored. These data suggest that the target population appears positive towards an RCT. As a negative attitude among users has been considered the major hindrance for such a study, we cannot see hindrances for performing an RCT.
Objective
Trophoblastic fetal cells harvested from maternal blood have the capacity to be used for copy number analyses in a cell‐based non‐invasive prenatal test (cbNIPT). Potentially, this will ...result in increased resolution for detection of subchromosomal aberrations due to high quality DNA not intermixed with maternal DNA. We present 5 selected clinical cases from first trimester pregnancies where cbNIPT was used to demonstrate a wide range of clinically relevant aberrations.
Method
Blood samples were collected from high risk pregnancies in gestational week 12 + 1 to 12 + 5. Fetal trophoblast cells were enriched and stained using fetal cell specific antibodies. The enriched cell fraction was scanned, and fetal cells were picked using a capillary‐based cell picking instrument. Subsequently, whole genome amplification (WGA) was performed on fetal cells, and the DNA was analyzed blindly by array comparative genomic hybridization (aCGH).
Results
We present 5 cases where non‐invasive cell‐based prenatal test results are compared with aCGH results on chorionic villus samples (CVS), demonstrating aneuploidies including mosaicism, unbalanced translocations, subchromosomal deletions, or duplications.
Conclusion
Aneuploidy and subchromosomal aberrations can be detected using fetal cells harvested from maternal blood. The method has the future potential of being offered as a cell‐based NIPT with large high genomic resolution.
What's already known about this topic?
Enriched fetal cells from maternal blood can be used for performing whole genome amplification, followed by array CGH.
What does this study add?
cbNIPT can detect aneuploidy, microduplication, unbalanced structural rearrangements, and mosaic cases.
cbNIPT can identify subchromosomal aberrations >10 Mb
To examine the association of isolated single umbilical artery (iSUA) confirmed at the mid-trimester anomaly scan and adverse pregnancy outcome and congenital malformations with up to 10 years ...postnatal follow up.
This retrospective cohort study included 116,501 singleton pregnancies consecutively enrolled in first trimester screening for aneuploidies and mid-trimester anomaly scan at three University Hospitals in the Capital Region of Copenhagen, Denmark.
Data from the Danish Fetal Medicine Database (2008-2017) were verified by manually scrutinizing pre- and postnatal records. The main outcomes of interest were intrauterine fetal demise (IUFD), small for gestational age (SGA), preterm delivery, cesarean section and unrecognized pre- and postnatal congenital malformations.
In total, 775 pregnancies with iSUA were identified. Isolated SUA were associated with a significantly increased risk of IUFD (OR 4.16, 95% CI 2.06-8.44), SGA < 3
rd
centile (aOR 2.41, 95% 1.85-3.14) and SGA < 10
th
centile (aOR 1.84, 95% CI 1.53-2.21), but not with preterm delivery or cesarean section. The laterality of the missing artery was not associated with SGA. In total, 4.3% of pregnancies with iSUA had unrecognized congenital malformations. 1.5% with iSUA had congenital cardiovascular malformations, which were considered minor.
Isolated SUA is associated with IUFD and SGA, supporting surveillance during third trimester. If, during the mid-trimester scan, the sonographer achieves thorough, extended cardiac views and finds no additional malformation other than SUA, fetal echocardiography seems not to be needed.
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