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.
Objective
To explore the relationship between small fetal second‐trimester head circumference (HC) and pregnancy outcome and identify a cutoff point for offering genetic testing.
Method
Data from ...second‐trimester scans in Denmark were linked to national registers. Fetuses with anomalies diagnosed before this scan were excluded. Fetuses were grouped according to HC z‐score.
Results
We included 352 515 singleton fetuses. The mean HC was significantly larger among males than among females with z‐scores averaging 0.52 more in males. Small HC was associated with chromosomal anomaly, malformations of the CNS and heart, miscarriage/perinatal death, termination, preterm delivery, and intrauterine growth restriction (test for trend: P < .001 for all outcomes). Fetuses in the group with z‐score less than –3 had the highest incidence of adverse outcome, irrespective of fetal sex. In the groups with z‐scores between –3 and –2.5, and between –2.5 and –2, risk of adverse outcome was lower for females than males for all outcome categories.
Conclusion
Small HC in second trimester is a prognostic marker for adverse outcome. The smaller the HC, the higher the risk of adverse outcome. We suggest an HC cutoff point of –2 SD for males and –2.5 SD for females for offering genetic testing.
What's already known about this topic?
Small fetal head size in second trimester is associated with adverse pregnancy outcome.
Boys are on average bigger than girls at birth and in late pregnancy.
What does this study add?
Absolute risks for adverse outcome at a given HC, applicable for counselling
HC z‐score is on average 0.52 larger in males than females at the second trimester scan
If small HC, the prediction of outcome is improved by sex‐specific cutoffs
To determine the stiffness of the pregnant uterine cervix in vivo.
Five women in early pregnancy and six women in late pregnancy were included. The EndoFlip is a 1-m-long probe with a 12-cm-long bag ...mounted on the tip. The tip of the probe was inserted into the cervical canal. Sensors spaced at 0.5-cm intervals along the probe were used to determine 16 serial cross-sectional areas of the bag. The diameter of the cervical canal could thereby be determined during inflation with up to 50 ml saline solution. Tissue stiffness was calculated from the geometric profiles and the pressure-strain elastic modulus (EP) at each sensor site. Three parts of the cervix were defined: the uterus-near part, the middle and the vaginal part. The EPmax was defined as the highest EP detected along the cervical canal.
The EPmax was always found in the middle part of the cervix. The median EPmax was 243 kPa (IQR, 67-422 kPa) for the early pregnant women and 5 kPa (IQR, 4-15 kPa) for those at term. In the early pregnant women the stiffness differed along the cervical length (p<0.05) whereas difference along the cervix was not found for late pregnant women. A positive correlation coefficient (Spearman's rho) was established between the EPs of the uterus-near and the middle part (0.84), between the vaginal and the middle part (0.81), and between the uterus-near and the vaginal part (0.85).
This new method can estimate the stiffness along the cervical canal in vivo. This method may be useful in the clinical examination of the biomechanical properties of the uterine cervix.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
We aimed to compare cell‐based NIPT (cbNIPT) to chorionic villus sampling (CVS) and to examine the test characteristics of cbNIPT in the first clinical validation study of cbNIPT compared ...to cell‐free NIPT (cfNIPT).
Material and Methods
Study 1: Women (N = 92) who accepted CVS were recruited for cbNIPT (53 normal and 39 abnormal). Samples were analyzed with chromosomal microarray (CMA). Study 2: Women (N = 282) who accepted cfNIPT were recruited for cbNIPT. cfNIPT was analyzed using sequencing and cbNIPT by CMA.
Results
Study 1: cbNIPT detected all aberrations (32/32) found in CVS: trisomies 13, 18 and 21 (23/23), pathogenic copy number variations (CNVs) (6/6) and sex chromosome aberrations (3/3). cbNIPT detected 3/8 cases of mosaicism in the placenta. Study 2: cbNIPT detected all trisomies found with cfNIPT (6/6) and had no false positive (0/246). One of the three CNVs called by cbNIPT was confirmed by CVS but was undetected by cfNIPT, two were false positives. cbNIPT detected mosaicism in five samples, of which two were not detected by cfNIPT. cbNIPT failed in 7.8% compared to 2.8% in cfNIPT.
Conclusion
Circulating trophoblasts in the maternal circulation provide the potential of screening for aneuploidies and pathogenic CNVs covering the entire fetal genome.
Key points
What is already known about this topic?
Circulating fetal trophoblasts can be isolated from maternal circulation and whole genome amplified DNA can be obtained.
Case studies have demonstrated its use in detecting aneuploidies, copy number variations (CNVs) and monogenic disorders.
What does this study add?
This is the first clinical validation study reporting high sensitivity and specificity for aneuploidies and likely also for CNVs over the entire genome.
Known microdeletion/duplication syndromes as well as unique disease causing CNVs >1 MB can be reliably detected.
Background:
Preeclampsia is a serious medical disorder affecting pregnancy. Screening in early pregnancy can identify women at risk and enable effective prophylactic treatment. Accurate blood ...pressure (BP) measurement is an important element of the screening algorithm. Automated self-screening, while attending the first trimester ultra sound scan, using a BP self-measurement (BPSM) station, could be a low-cost alternative to office BP measurements (OBPM) on both arms performed by clinical staff, if the measurement quality can be ensured.
Objectives:
The aim of this study was to compare automated BPSM using a self-measurement station on one arm, with OBPM performed by clinical staff on both arms. Primary outcome was the difference in mean arterial pressure (MAP) between the two methods and secondary outcomes were safety and practicality issues.
Methods:
Pregnant women attending ultrasound-examination at 12 weeks gestational age were recruited and randomized to start with having two OBPMs taken on both arms by staff, using two standard validated automatic upper arm BP devices, or self-measuring using an automated BPSM station following a crossover study design. The BPSM station consists of a validated blood pressure device, and an add-on sensor system capable of registering blood pressure values, rest-time, back-supported, legs-crossed, and ambient noise-levels respectively, and providing interactive guidance during the measurement process, for supporting the self-measurement process.
Results:
A total of 80 complete BP measurement sets were obtained, for a total of 240 BPSM measurements and 320 OBPM measurements. We found no significant difference between the OBPM and BPSM methods (p=0.86) for mean arterial pressure (MAP). However, erroneous measurements were observed frequently during the experiment, mainly during the first of the 3 BPSM measurements (6%), secondary during the second BPSM measurement (3%). Only one data set (1%) was excluded due to OBPM errors.
Conclusion:
No significant difference in MAP between the two methods was found. Means for detecting and repeating erroneous BP measurements should be implemented. Measurement errors was found in 9 % of the measurement sets which is not acceptable for clinical use. Thus, several measures have been identified in order to properly identify and recover from such measurement errors in the future.
Hypertensive disease and preeclampsia are serious medical disorders affecting pregnancy. Screening in early pregnancy may identify women at risk of developing hypertensive disease and enable ...prophylactic treatment. Accurate blood pressure measurement is an important part of this screening. The aim of this study was to investigate whether patients, with the aid of a context-aware sensor-based blood pressure self-measurement system, were able to correctly self-measure their blood pressure adhering to internationally established recommendations. Furthermore, to evaluate patient acceptance levels of performing self-measurements using context-aware adherence aids for guidance. A total of 100 pregnant women attending a routine ultrasound, at gestational week 12, at the outpatient clinic of the Department of Obstetrics and Gynecology, Aarhus University Hospital, were recruited in the waiting room before the scheduled scan. Blood pressure self-measurement was performed using a blood pressure self-measurement system called ValidAid consisting of a clinically approved blood pressure device, a sensor chair registering rest-time, back-supported, legs-crossed, and ambient noise levels respectively recording participant compliance, as well as a touch screen–based computer application with an interactive user interface for patient guidance and feedback, as well as a built-in decision support system. Acceptance of the automated self-measurement was evaluated by a questionnaire. In all, 99 percent followed the instructions with regard to both rest time and not talking. For both of these, ValidAid offered interactive and context-aware guidance. The recommendation of keeping legs uncrossed was only adhered to in 69 percent of measurements and back supported in 35 percent of measurements. For both of these, no interactive guidance was provided. The majority of the participants, 93 percent, felt comfortable using self-measurement equipment, while a minority of 8 percent would have preferred personnel-assisted measurements. The majority of participants were able to take reliable blood pressure self-measurements. Results indicate that recommendations that were not actively enforced were not followed to the same extent as those that were enforced. Thus, providing interactive context-aware guidance for all recommendations should be considered in the future. Furthermore, we found patient acceptance levels of performing self-measurements to be overall positive.
The C1QBP protein (complement component 1 Q subcomponent‐binding protein), encoded by the C1QBP gene, is a multifunctional protein predominantly localized in the mitochondrial matrix. Biallelic ...variants have previously been shown to give rise to combined respiratory‐chain deficiencies with variable phenotypic presentation, severity, and age at onset, from intrauterine with a mostly lethal course, to a late‐onset mild myopathy. We present two fetuses, one male and one female, of first‐cousin parents, with severe intrauterine growth retardation, oligo/anhydramnios, edema, and cardiomyopathy as the most prominent prenatal symptoms. Both fetuses showed no copy number variants by chromosome microarray analysis. Analysis of a fibroblast culture from one of the fetuses showed deficiency of respiratory chain complex IV, and using exome sequencing, we identified homozygosity for a novel variant in C1QBP in both fetuses. To our knowledge, only six patients with pathogenic variants in C1QBP have been reported previously and with this report, we add a novel pathogenic variant in C1QBP found in two related fetuses.
Several parameters are important when choosing the most appropriate animal to model human obstetrics, including gestation period, number of fetuses per gestation and placental structure. The ...domesticated long-tailed chinchilla (Chinchilla lanigera) is a well-suited and appropriate animal model of pregnancy that often will carry only one offspring and has a long gestation period of 105–115 days. Furthermore, the chinchilla placenta is of the haemomonochorial labyrinthine type and is therefore comparable to the human villous haemomonochorial placenta. This proof-of-concept study demonstrated the feasibility in laboratory settings, and demonstrated the potential of the pregnant chinchilla as an animal model for obstetric research and its potential usefulness for non-invasive measurements in the placenta. We demonstrate measurements of the placental and fetal metabolism (demonstrated in vivo by hyperpolarized MRI and in vitro by qPCR analyses), placental vessels (demonstrated ex vivo by contrast-enhanced CT angiography) and overall anatomy (demonstrated in vivo by whole-body CT).
We describe two cases where autologous amnion grafts were used to cover the neurosurgical repair of myelomeningocele (MMC) and the reconstructive flaps used for the skin defects. MMC is a severe ...fetal defect that evolves during embryonic development as a result of the neural tubes failure to close. In postnatal MMC closure, early timing of surgical repair is essential. We found that a free amnion graft is a viable choice in reconstructive surgery for myelomeningocele and that a multidisciplinary surgical team involving obstetrician, neurosurgeon and plastic surgeon is essential.
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