ABSTRACT
BACKGROUND: A significant proportion of major fetal structural anomalies can be detected in the first trimester by ultrasound examination. However, the test performance of the first-trimester anomaly scan (FTAS) performed in a low-risk population as part of a nationwide prenatal screening program is unknown. Potential benefits of the FTAS include early detection of fetal anomalies, providing parents with more time for reproductive decision-making. OBJECTIVES: To investigate the uptake, test performance and time to a final prenatal diagnosis after referral. STUDY DESIGN: A nationwide implementation study was conducted in the Netherlands (November 2021-November 2022). The FTAS was performed between 12+3 and 14+3 weeks gestation by certified sonographers using a standard protocol. Women were referred to a tertiary care center if anomalies were suspected. Uptake, test performance and time to a final prenatal diagnosis (days between referral and date of final diagnosis/prognosis for reproductive decision-making) were determined. Test performance was calculated for first-trimester major congenital anomalies, such as anencephaly and holoprosencephaly and all diagnosed anomalies <24 weeks gestation. RESULTS: The FTAS uptake was 74.9% (129 704/173 129). In 1.0% (1 313/129 704), an anomaly was suspected, of which 54.9% (n=721) had abnormal findings on the detailed first-trimester diagnostic scan and 44.6% (n=586) showed normal results. In 0.5% (n=6), intra-uterine fetal death occurred. In the total group of 721 cases with abnormal findings, 332 structural anomalies, 117 genetic anomalies, 82 other findings (abnormal fetal biometry, sonomarkers, placental/umbilical cord anomaly, an-/oligohydramnios) and 189 cases with transient findings (defined as ultrasound findings which resolved <24 weeks gestation) were found, with one case having an unknown outcome. 0.9% (n=1164) of all cases with a normal FTAS were diagnosed with a fetal anomaly in the second trimester. Test performance included a sensitivity of 84.6% (126/149) for first-trimester major congenital anomalies and 31.6% (537/1701) for all types of anomalies. Specificity for all anomalies was 99.2% (98 055/98 830); positive predictive value 40.9% (537/1 312); negative predictive value 98.8% (98 055/99 219); positive likelihood ratio 40.3; negative likelihood ratio 0.7; false positive rate 0.8% (775/98 830) and false negative rate 68.4% (1 164/1 701). The median time to diagnosis for structural anomalies was 20 days (6-43 days; median GA 16+3), for genetic anomalies 17 days (8.5-27.5 days; median GA 15+6 weeks) and for first-trimester major congenital anomalies 9 days (5-22 days; median GA 14+6 weeks). CONCLUSIONS: The performance of a newly introduced nationwide FTAS in a low-risk population showed a high sensitivity for first-trimester major congenital anomalies and a lower sensitivity for all anomalies combined. The program was accompanied by a referral rate of 1.0%, of which 59.1% involved cases where anomalies were either not confirmed or resolved before 24 weeks gestation. Timing of diagnosis was around 16 weeks gestation for referred cases. To evaluate the balance between benefits and potential harm of the FTAS within a nationwide prenatal screening program, it is essential to assess the effectiveness of the program over time and to consider the perspectives of both women and their partners, as well as healthcare professionals.
ABSTRACT
OBJECTIVE: To evaluate which cytogenetic characteristics of confined placental mosaicism (CPM) detected in the first trimester chorionic villi and/or placentas in terms of chromosome aberration, cell lineage involved and trisomy origin will lead to fetal growth restriction and low birthweight. METHODS: Cohort study using routinely collected perinatal data and cytogenetic data of non-invasive prenatal testing, the first trimester chorionic villi sampling and postnatal placentas. RESULTS: 215 CPM cases were found. Fetal growth restriction (FGR) and low birthweight below the 10th percentile (BW < p10) were seen in 34.0% and 23.1%, respectively. Excluding cases of trisomy 16, 29.1% showed FGR and 17.9% had a BW < p10. The highest rate of FGR and BW < p10 was found in CPM type 3, but differences with type 1 and 2 were not significant. FGR and BW < p10 were significantly more often observed in cases with meiotic trisomies. CONCLUSION: There is an association between CPM and FGR and BW < p10. This association is not restricted to trisomy 16, neither to CPM type 3, nor to CPM involving a meiotic trisomy. Pregnancies with all CPM types and origins should be considered to be at increased risk of FGR and low BW < p10. A close prenatal fetal monitoring is indicated in all cases of CPM.
Subject(s)
Placenta , Trisomy , Pregnancy , Female , Humans , Placenta/metabolism , Trisomy/diagnosis , Trisomy/genetics , Mosaicism , Fetal Growth Retardation/diagnosis , Fetal Growth Retardation/genetics , Cohort Studies , Birth Weight , Retrospective Studies , Chromosomes, Human, Pair 16ABSTRACT
OBJECTIVE: To evaluate perinatal and postnatal outcomes of fetuses with an isolated small head circumference (HC) on expert ultrasound examination in the second trimester for further recommendations in prenatal care. STUDY DESIGN: In a retrospective cohort we included singleton-pregnancies with a fetal HC > -3.0 SD and ≤ -1.64 SD determined on expert ultrasound examination between 18 and 24 weeks of gestational age. Three subgroups were determined: "isolated small HC (ISHC)", "small HC plus abdominal circumference (AC) ≤ p10 (SHC+)" and "small HC plus AC ≤ p10 and Doppler abnormalities (SHC + D)". After ultrasound examination, genetic testing was sometimes offered and postnatally genetic tests were performed on indication. RESULTS: We included 252 pregnancies: 109 ISHC, 104 SHC+, and 39 SHC + D. In the ISHC and SHC+ subgroup, 96 % of the fetuses were born alive and did not die neonatal. In the SH + D group this was only 38 %. In the SHC+ subgroup, less fetuses were delivered vaginal (non-instrumental) compared to the ISHC subgroup (61 % vs. 73 %, p < 0.01). In the ISHC and SHC+ subgroup s some fetuses were diagnosed with congenital defects (4 % vs. 10 %, p = 0.08) and with a genetic anomaly (6.4 % vs. 7.7 %, p = 0.13) after 24 weeks or postnatally. In SHC + D subgroups 5 % presented with congenital defects and 2.6 % with a genetic anomaly. CONCLUSION: We conclude that fetuses with a small HC without structural anomalies on second trimester expert ultrasound require follow-up and special medical attention. We recommend differentiating between ISHC, SHC+, and SHC + D for prenatal counseling. Genetic testing and referral to a clinical geneticist should be considered.
Subject(s)
Prenatal Care , Ultrasonography, Prenatal , Pregnancy , Infant, Newborn , Female , Humans , Pregnancy Trimester, Second , Retrospective Studies , Fetus , Gestational Age , Counseling , Fetal Growth RetardationABSTRACT
In the TRIDENT-2 study, all pregnant women in the Netherlands are offered genome-wide non-invasive prenatal testing (GW-NIPT) with a choice of receiving either full screening or screening solely for common trisomies. Previous data showed that GW-NIPT can reliably detect common trisomies in the general obstetric population and that this test can also detect other chromosomal abnormalities (additional findings). However, evidence regarding the clinical impact of screening for additional findings is lacking. Therefore, we present follow-up results of the TRIDENT-2 study to determine this clinical impact based on the laboratory and perinatal outcomes of cases with additional findings. Between April 2017 and April 2019, additional findings were detected in 402/110,739 pregnancies (0.36%). For 358 cases, the origin was proven to be either fetal (n = 79; 22.1%), (assumed) confined placental mosaicism (CPM) (n = 189; 52.8%), or maternal (n = 90; 25.1%). For the remaining 44 (10.9%), the origin of the aberration could not be determined. Most fetal chromosomal aberrations were pathogenic and associated with severe clinical phenotypes (61/79; 77.2%). For CPM cases, occurrence of pre-eclampsia (8.5% [16/189] vs 0.5% [754/159,924]; RR 18.5), and birth weight <2.3rd percentile (13.6% [24/177] vs 2.5% [3,892/155,491]; RR 5.5) were significantly increased compared to the general obstetric population. Of the 90 maternal findings, 12 (13.3%) were malignancies and 32 (35.6%) (mosaic) pathogenic copy number variants, mostly associated with mild or no clinical phenotypes. Data from this large cohort study provide crucial information for deciding if and how to implement GW-NIPT in screening programs. Additionally, these data can inform the challenging interpretation, counseling, and follow-up of additional findings.
Subject(s)
Prenatal Diagnosis , Trisomy , Cohort Studies , Female , Follow-Up Studies , Humans , Mosaicism , Placenta , Pregnancy , Prenatal Diagnosis/methodsABSTRACT
RESEARCH QUESTION: Does periconceptional maternal folate status influence the size of human embryonic head and brain structures? DESIGN: The study population was selected from the Rotterdam Periconceptional Cohort conducted at the Erasmus MC. Three-dimensional (3D) ultrasound scans were performed at 9 and 11 weeks of gestational age. Using 3D ultrasound datasets, head volume, head circumference, diencephalon (DTD), mesencephalon (MTD) and left/right telencephalon (TTL/TTR) measurements were performed offline using a virtual reality technique and specialized 3D software. Maternal venous blood samples were taken at study entry to determine red blood cell (RBC) folate. Linear regression models were applied to investigate associations between RBC folate status and embryonic head and brain structures adjusted for gestational age, alcohol use, smoking, maternal age and mode of conception. RESULTS: RBC folate measurements were available for 144 of the 166 singleton pregnancies eligible for analysis. RBC folate quartiles were defined: 466-1078 nmol/l (Q1), 1079-1342 nmol/l (Q2), 1343-1594 nmol/l (Q3), 1595-2919 nmol/l (Q4), with Q3 being used as reference. At 11 weeks of gestational age, head volume was largest in Q1 (ßâ¯=â¯0.866; P = 0.004) and Q4 (ßâ¯=â¯0.764; Pâ¯=â¯0.007). In addition, head circumference at 11 weeks of gestational age was significantly larger in Q4 (ßâ¯=â¯2.745; P = 0.03). There were no statistical significantly associations between the RBC folate quartiles and the sizes of the DTD, MTD, TTL and TTR. CONCLUSIONS: U-shaped associations were shown between the periconceptional maternal RBC folate status and embryonic head volume and head circumference. The clinical implication of these findings needs further investigation.
Subject(s)
Folic Acid , Ultrasonography, Prenatal , Brain/diagnostic imaging , Cohort Studies , Female , Humans , Pregnancy , Prospective Studies , Ultrasonography, Prenatal/methodsABSTRACT
BACKGROUND AND PURPOSE: Prognosis of isolated short corpus callosum is challenging. Our aim was to assess whether fetal DTI tractography can distinguish callosal dysplasia from variants of normal callosal development in fetuses with an isolated short corpus callosum. MATERIALS AND METHODS: This was a retrospective study of 37 cases referred for fetal DTI at 30.4 weeks (range, 25-34 weeks) because of an isolated short corpus callosum less than the 5th percentile by sonography at 26 weeks (range, 22-31 weeks). Tractography quality, the presence of Probst bundles, dysmorphic frontal horns, callosal length (internal cranial occipitofrontal dimension/length of the corpus callosum ratio), and callosal thickness were assessed. Cytogenetic data and neurodevelopmental follow-up were systematically reviewed. RESULTS: Thirty-three of 37 fetal DTIs distinguished the 2 groups: those with Probst bundles (Probst bundles+) in 13/33 cases (40%) and without Probst bundles (Probst bundles-) in 20/33 cases (60%). Internal cranial occipitofrontal dimension/length of the corpus callosum was significantly higher in Probst bundles+ than in Probst bundles-, with a threshold value determined at 3.75 for a sensitivity of 92% (95% CI, 77%-100%) and specificity of 85% (95% CI, 63%-100%). Callosal lipomas (4/4) were all in the Probst bundles- group. More genetic anomalies were found in the Probst bundles+ than in Probst bundles- group (23% versus 10%, P = .08). CONCLUSIONS: Fetal DTI, combined with anatomic, cytogenetic, and clinical characteristics could suggest the possibility of classifying an isolated short corpus callosum as callosal dysplasia and a variant of normal callosal development.
Subject(s)
Agenesis of Corpus Callosum , Corpus Callosum , Agenesis of Corpus Callosum/diagnostic imaging , Corpus Callosum/diagnostic imaging , Feasibility Studies , Fetus , Humans , Retrospective StudiesABSTRACT
TUBB2B codes for one of the isotypes of ß-tubulin and dominant negative variants in this gene result in distinctive malformations of cortical development (MCD), including dysgyria, dysmorphic basal ganglia and cerebellar anomalies. We present a novel family with a heterozygous missense variant in TUBB2B and an unusually mild phenotype. First, at 21 37 weeks of gestation ultrasonography revealed a fetus with a relatively small head, enlarged lateral ventricles, borderline hypoplastic cerebellum and a thin corpus callosum. The couple opted for pregnancy termination. Exome sequencing on fetal material afterwards identified a heterozygous maternally inherited variant in TUBB2B (NM_178012.4 (TUBB2B):c.530A > T, p.(Asp177Val)), not present in GnomAD and predicted as damaging. The healthy mother had only a language delay in childhood. This inherited TUBB2B variant prompted re-evaluation of the older son of the couple, who presented with a mild delay in motor skills and speech. His MRI revealed mildly enlarged lateral ventricles, a thin corpus callosum, mild cortical dysgyria, and dysmorphic vermis and basal ganglia, a pattern typical of tubulinopathies. This son finally showed the same TUBB2B variant, supporting pathogenicity of the TUBB2B variant. These observations illustrate the wide phenotypic heterogeneity of tubulinopathies, including reduced penetrance and mild expressivity, that require careful evaluation in pre- and postnatal counseling.
Subject(s)
Malformations of Cortical Development , Tubulin , Female , Humans , Magnetic Resonance Imaging , Male , Malformations of Cortical Development/genetics , Mutation , Phenotype , Pregnancy , Tubulin/geneticsABSTRACT
Exome sequencing (ES) enhanced the diagnostic yield of genetic testing, but has also increased the possibility of uncertain findings. Prenatal ES is increasingly being offered after a fetal abnormality is detected through ultrasound. It is important to know how to handle uncertainty in this particularly stressful period. This systematic review aimed to provide a comprehensive overview of guidelines available for addressing uncertainty related to prenatal chromosomal microarray (CMA) and ES. Ten uncertainty types associated with prenatal ES and CMA were identified and defined by an international multidisciplinary team. Medline (all) and Embase were systematically searched. Laboratory scientists, clinical geneticists, psychologists, and a fetal medicine specialist screened the papers and performed the data extraction. Nineteen papers were included. Recommendations generally emphasized the importance of trio analysis, clinical information, data sharing, validation and re-analysis, protocols, multidisciplinary teams, genetic counselling, whether to limit the possible scope of results, and when to report particular findings. This systematic review helps provide a vocabulary for uncertainties, and a compass to navigate uncertainties. Prenatal CMA and ES guidelines provide a strong starting point for determining how to handle uncertainty. Gaps in guidelines and recommendations were identified and discussed to provide direction for future research and policy making.
Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , Genomics , Prenatal Diagnosis , Clinical Decision-Making , Disease Management , Female , Genetic Association Studies/methods , Genomics/legislation & jurisprudence , Genomics/methods , Health Policy , Humans , Practice Guidelines as Topic , Pregnancy , Prenatal Diagnosis/methods , UncertaintyABSTRACT
STUDY QUESTION: Does IVF with or without ICSI (IVF/ICSI) treatment impact the development of embryonic brain structures? SUMMARY ANSWER: Our results show associations between IVF/ICSI treatment, smoking and slightly increased sizes of early human embryonic brain structures. WHAT IS KNOWN ALREADY: The number of IVF/ICSI procedures is increasing worldwide and is associated with higher risks of obstetric and perinatal complications in pregnancies. STUDY DESIGN, SIZE, DURATION: One hundred seventy-five women with a singleton pregnancy were included in the Rotterdam Periconceptional Cohort (Predict study). PARTICIPANTS/MATERIALS, SETTING, METHODS: Self-reported questionnaires, verified by a research assistant at enrollment, provided information on periconceptional maternal characteristics and mode of conception. Three-dimensional ultrasound (3D-US) examinations were performed at 9 and 11 weeks of gestational age (GA). Diencephalon total diameter (DTD), mesencephalon total diameter (MTD) and telencephalon thickness on the left and right site (TTL/TTR) were measured offline in standardized planes using 4D View software. Linear regression models with adjustment for GA, maternal age, body mass index, moment of initiation of folic acid supplement use and smoking were used to study associations between mode of conception and embryonic brain measurements at 9 and 11 weeks of GA. MAIN RESULTS AND ROLE OF CHANCE: A total of 276 3D-US scans of 166 participants, of which 50 conceived through IVF/ICSI, were included for embryonic brain measurements. Success rates of the DTD and MTD measurements were between 67% and 73% and of the TTL/TTR between 52% and 57%. In the fully adjusted model, we found that at 11 weeks of GA, the MTD (ß = 0.264, 95% CI = 0.101; 0.427, P < 0.01) and TTR (ß = 0.075, 95% CI = 0.001; 0.149, P < 0.05) sizes were larger in IVF/ICSI pregnancies. In addition, smoking also resulted in larger TTL measurements at 11 weeks of GA (ß = 0.095, 95% CI= 0.005; 0.186, P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The implications of these small deviations on brain functioning need further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Enlargement of attention for prenatal brain development and postnatal neurodevelopmental outcome after IVF/ICSI treatment. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Department of Obstetrics and Gynecology, Erasmus MC, and Sophia research foundation for Medical Research, Rotterdam, the Netherlands (SSWO grant number 644). No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.
Subject(s)
Fertilization in Vitro , Sperm Injections, Intracytoplasmic , Brain/diagnostic imaging , Female , Humans , Infant , Netherlands , Pregnancy , Prospective StudiesABSTRACT
The introduction of the accurate and procedurally easy non-invasive prenatal test (NIPT) raises ethical concerns that public attitudes towards prenatal screening may change, leading to societal pressure to participate in aneuploidy screening. This study examined Dutch citizens' attitudes towards a pregnant woman's decision to (1) decline NIPT in the context of two different funding policies and (2) to terminate or continue a pregnancy affected by different disorders. The attitudes of 1096 respondents were assessed with the contrastive vignette method, using two pairs of vignettes about declining NIPT and termination of pregnancy. Most respondents either agreed with a woman's decision to decline NIPT or were neutral about it, stating that this decision should be made independently by women, and does not warrant judgement by others. Interestingly, funding policies did influence respondents' attitudes: significantly more respondents disagreed with declining NIPT when it was fully reimbursed. Respondents had similar attitudes to the vignettes on termination and continuation of pregnancy in case of Down's syndrome. In case of Edwards' or Patau's syndrome, however, significantly more respondents disagreed with continuation, citing the severity of the disorder and the child's best interests. This study demonstrates broad acknowledgement of women's freedom of choice in Dutch society; a finding that may help to rebut existing concerns about societal pressure for pregnant women to participate in prenatal screening. As the reimbursement policy and the scope of NIPT may influence people's attitudes and elicit moral judgements, however, maintaining freedom of choice warrants sustained efforts by health professionals and policy makers.
Subject(s)
Attitude , Noninvasive Prenatal Testing/ethics , Peer Influence , Personal Autonomy , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Netherlands , Noninvasive Prenatal Testing/legislation & jurisprudenceABSTRACT
INTRODUCTION: The aim of this retrospective cohort study was to determine the potential diagnostic yield of prenatal whole exome sequencing in fetuses with structural anomalies on expert ultrasound scans and normal chromosomal microarray results. MATERIAL AND METHODS: In the period 2013-2016, 391 pregnant women with fetal ultrasound anomalies who received normal chromosomal microarray results, were referred for additional genetic counseling and opted for additional molecular testing pre- and/or postnatally. Most of the couples received only a targeted molecular test and in 159 cases (40.7%) whole exome sequencing (broad gene panels or open exome) was performed. The results of these molecular tests were evaluated retrospectively, regardless of the time of the genetic diagnosis (prenatal or postnatal). RESULTS: In 76 of 391 fetuses (19.4%, 95% CI 15.8%-23.6%) molecular testing provided a genetic diagnosis with identification of (likely) pathogenic variants. In the majority of cases (91.1%, 73/76) the (likely) pathogenic variant would be detected by prenatal whole exome sequencing analysis. CONCLUSIONS: Our retrospective cohort study shows that prenatal whole exome sequencing, if offered by a clinical geneticist, in addition to chromosomal microarray, would notably increase the diagnostic yield in fetuses with ultrasound anomalies and would allow early diagnosis of a genetic disorder irrespective of the (incomplete) fetal phenotype.
Subject(s)
Abnormalities, Multiple/diagnosis , Chromosome Disorders/diagnosis , Exome Sequencing/methods , Fetal Diseases/diagnosis , Genetic Testing/methods , Prenatal Diagnosis/methods , Abnormalities, Multiple/genetics , Adult , Chromosome Disorders/genetics , Female , Fetal Diseases/genetics , Humans , Pregnancy , Retrospective Studies , Ultrasonography, Prenatal/methodsABSTRACT
BACKGROUND: There is a need for non-invasive prenatal markers of the brain to assess fetuses at risk for poor postnatal neurodevelopmental outcome. Periconceptional maternal conditions and pregnancy complications impact prenatal brain development. AIMS: To investigate associations between growth trajectories of fetal brain structures and neurodevelopmental outcome in children in the early life course. STUDY DESIGN: Periconceptional prospective observational cohort. SUBJECTS: Singleton pregnancies were included in the Rotterdam periconception cohort. Two- and three-dimensional ultrasound scans at 22, 26 and 32 weeks gestational age were analysed. OUTCOME MEASURES: Head circumference (HC), cerebellum, corpus callosum (CC), Sylvian fissure, insula and parieto-occipital fissure (POF) were measured. Neurodevelopment was evaluated using the Age-and-Stages-questionnaire-3 (ASQ-3) and the Child-Behaviour-Checklist (CBCL) at 2 years of age. Linear mixed models, used to estimate the prenatal brain growth trajectories, and linear regression models, used to evaluate the associations between prenatal brain structures and neurodevelopmental outcomes, were applied in the total study population, and in subgroups: fetal growth restriction (FGR), preterm birth (PTB), fetal congenital heart disease (CHD), and uncomplicated controls. RESULTS: Consent for participation was received from parents on behalf of their child 138/203 (68%). ASQ-3 was completed in 128/203 children (63%) and CBCL in 93/203 children (46%). Significant smaller subject-specific growth trajectories (growth rate of CC, HC, left insula, left POF and right POF and the baseline size of CC, HC, left POF and right POF) were found in the FGR subgroup, compared to the other subgroups (all p-values <0.05). In the total group (n = 138), the growth rate of the left insula was associated with poorer ASQ-3 score (ß = -869.51; p < 0.05). Healthy controls (n = 106) showed a comparable association (ß = -1209.87; p < 0.01). FGR (n = 10) showed a larger baseline size of the right Sylvian fissure in association with poorer CBCL-score (ß = 4.13; p < 0.01). In CHD (n = 12) the baseline size of the left Sylvian fissure and its growth rate were associated with respectively poorer and better CBCL-scores (ß = 3.11; p < 0.01); (ß = -171.99; p < 0.01). In PTB (n = 10) no associations were found. CONCLUSIONS: This explorative study suggests associations between ultrasound measurements of fetal brain growth and neurodevelopmental outcome at 2 years of age. In future, this non-invasive technique may improve early identification of fetuses at risk for neurodevelopmental outcome and follow-up postnatal clinical care.
Subject(s)
Brain/diagnostic imaging , Child Development , Developmental Disabilities/diagnostic imaging , Fetal Diseases/diagnostic imaging , Ultrasonography, Prenatal/statistics & numerical data , Adult , Brain/embryology , Brain/growth & development , Developmental Disabilities/epidemiology , Female , Fetal Diseases/epidemiology , Humans , Infant , Infant, Newborn , Male , Pregnancy , Pregnancy Outcome/epidemiologyABSTRACT
The noninvasive prenatal test (NIPT) as the first trimester prenatal screening (FTS) for trisomies 21, 18, and 13 is offered to all pregnant women in the Netherlands. NIPT using genome sequencing allows for an expansion of the scope of FTS and the introduction of NIPT gives rise to ethical and societal concerns about deliberated decision-making, pressure to engage in screening, and possible lack of equal access due to the financial contribution (175) to NIPT. We explored the opinions and experiences of pregnant women, who were offered FTS, about these concerns, and the possibility of a broadened scope. Nineteen pregnant women representing a diversity of backgrounds were interviewed using a semi-structured interview guide. Eight women did not opt for prenatal screening while 11 did (NIPT = 4, combined test = 7). Women experienced a free choice to accept or decline prenatal screening, despite sometimes receiving advice from others. Prior to pretest counseling, some women had already deliberated about what an abnormal test result would mean to them. Others accepted or declined FTS without deliberation. The current Dutch policy of requiring a co-payment was acceptable to some, who believed that it functioned as a threshold to think carefully about FTS. Others were concerned that a financial threshold would lead to unequal access to screening. Finally, pregnant women found it difficult to formulate opinions on the scope of FTS, because of lack of knowledge. Life expectancy, severity, and treatability were considered important criteria for the inclusion of a condition in NIPT.
Subject(s)
Genetic Testing/economics , Prenatal Diagnosis/psychology , Reimbursement Mechanisms , Adult , Female , Humans , Netherlands , Pregnancy , Prenatal Diagnosis/economics , Social ClassABSTRACT
BACKGROUND: Two technological innovations in the last decade significantly influenced the diagnostic yield of prenatal cytogenetic testing: genomic microarray allowing high resolution analysis and noninvasive prenatal testing (NIPT) focusing on aneuploidy. To anticipate future trends in prenatal screening and diagnosis, we evaluated the number of invasive tests in our center and the number of aberrant cases diagnosed in the last decade. METHODS: We retrospectively analyzed fetal chromosomal aberrations diagnosed in 2009-2018 in 8,608 pregnancies without ultrasound anomalies. RESULTS: The introduction of NIPT as the first-tier test led to a substantial decrease in the number of invasive tests and a substantially increased diagnostic yield of aneuploidies in the first trimester. However, we have also noted a decreased detection of submicroscopic aberrations, since the number of invasive tests substantially decreased. We have observed that pregnant women were interested in broader scope of prenatal screening and diagnosis than detection of common trisomies. CONCLUSION: Since the frequency of syndromic disorders caused by microdeletions/microduplications is substantial and current routine NIPT and ultrasound investigations are not able to detect them, we suggest that a noninvasive test with resolution comparable to microarrays should be developed, which will also meet patient's needs.
Subject(s)
Needs Assessment , Noninvasive Prenatal Testing/standards , Attitude , Chromosome Aberrations , Female , Genome , Humans , Noninvasive Prenatal Testing/methods , Pregnancy , Pregnant Women/psychology , Sensitivity and SpecificityABSTRACT
OBJECTIVE: Placental cytogenetic studies may reveal the origin of discordant noninvasive prenatal testing (NIPT). We performed placental studies to elucidate discordances between NIPT showing a structural chromosome aberration and the fetus having a different chromosome aberration in three cases. METHOD: Diagnostic testing with genomic SNP microarray was performed in three cases with NIPT showing a duplication on 4q (case 1), a terminal deletion of 13q (case 2), and a terminal deletion of 15q (case 3). Placental studies involved SNP array analysis of cytotrophoblast and mesenchymal core of chorionic villi of four placental quadrants. Clinical follow-up was performed as well. RESULTS: Amniotic fluid revealed a different structural chromosome aberration than predicted by NIPT: a terminal 2q deletion (case 1), a segmental uniparental isodisomy of 13q (case 2), and a terminal duplication of 15q and of 13q (case 3). Placental studies revealed the aberration detected with NIPT in the cytotrophoblast, whereas the fetal karyotype was confirmed in the placental mesenchymal core. CONCLUSION: Our study shows that targeted cytogenetic investigations for confirmation of NIPT showing a microscopically visible structural chromosome aberration should be avoided, since another aberration, even a submicroscopic one or one involving another chromosome, may be present in the fetus.
Subject(s)
Chromosome Aberrations , Karyotype , Noninvasive Prenatal Testing , Placenta/cytology , Female , Humans , PregnancyABSTRACT
OBJECTIVES: To examine differences in growth trajectories of fetal brain fissures in the growth restricted fetus (FGR) compared to controls. METHODS: We selected a subgroup of 227 women with a singleton pregnancy from the Rotterdam Periconceptional Cohort. Participants received three-dimensional ultrasound (3D-US) examinations of the fetal brain at 22, 26 and 32 weeks of gestational age (GA). The left and right Sylvian, insula and parieto-occipital fissures (POF) were measured in standardized planes. Linear mixed models with adjustment for potential confounders were applied to estimate differences between the trajectories of brain fissure depth measurements of FGR and controls. RESULTS: 22 FGR and 172 controls provided 31 and 504 3D-US respectively for longitudinal brain fissure depth measurements. Success rates for the Sylvian and insula depth measurements were over 80% and for POF over 62% at all GA. In FGR compared to controls, the trajectory of the right Sylvian fissure depth was significantly decreased (ß = -4.30, 95%CI = -8.03;-0.56, p = 0.024) while its growth rate was slightly increased (ß = 0.02, 95%CI = 0.00;0.04, p = 0.04), after adjustment for GA, head circumference, gender, educational level and parity. CONCLUSIONS: The small differences in brain fissure measurements between 22 and 32 weeks GA in FGR warrant further investigation in larger cohorts with postnatal follow-up.
Subject(s)
Brain/diagnostic imaging , Brain/embryology , Fetal Growth Retardation/diagnostic imaging , Adult , Echoencephalography , Female , Fetal Development , Gestational Age , Humans , Imaging, Three-Dimensional , Pregnancy , Prospective Studies , Ultrasonography, PrenatalABSTRACT
OBJECTIVE: To investigate, from the perspective of women and partners, at what stage of a termination of pregnancy (TOP) for fetal anomalies psychosocial care (PSC) is most meaningful, what topics should be discussed, and who should provide PSC. METHOD: A cross-sectional retrospective cohort study was conducted with a consecutive series of 76 women and 36 partners, who completed a semi-structured online questionnaire. RESULTS: Overall, women expressed a greater need for PSC than their partners. Parents expressed a preference for receiving support from a maternal-fetal medicine specialist to help them understand the severity and consequences of the anomalies found and to counsel them in their decision regarding termination. Parents showed a preference for support from mental healthcare providers to help with their emotional responses. Forty-one percent of the women visited a psychosocial professional outside of the hospital after the TOP, indicating a clear need for a well-organised aftercare. CONCLUSION: Different disciplines should work together in a complementary way during the diagnosis, decision making, TOP, and aftercare stages. Parents' need for PSC should be discussed at the beginning of the process. During aftercare, attention should be paid to grief counselling, acknowledgement of the lost baby's existence, and possible future pregnancies.
Subject(s)
Abortion, Induced , Fetus/abnormalities , Parents/psychology , Patient Preference , Psychotherapy/methods , Abortion, Induced/psychology , Abortion, Induced/rehabilitation , Adult , Congenital Abnormalities/pathology , Congenital Abnormalities/psychology , Congenital Abnormalities/therapy , Counseling/methods , Cross-Sectional Studies , Depression/etiology , Depression/therapy , Female , Grief , Humans , Patient Preference/psychology , Patient Preference/statistics & numerical data , Pregnancy , Psychotherapy/statistics & numerical data , Retrospective Studies , Stress Disorders, Post-Traumatic/psychology , Stress Disorders, Post-Traumatic/therapy , Surveys and QuestionnairesABSTRACT
OBJECTIVE: Non-invasive prenatal testing (NIPT) detects placental chromosome aberrations. When amniocentesis reveals a normal karyotype, confined placental mosaicism (CPM) may be assumed. In order to confirm this, placental cytogenetic studies were performed. METHOD: NIPT was conducted in the course of the Dutch TRIDENT study. Placentas of 10 cases with NIPT results indicating an autosomal trisomy and showing a normal (N = 9) or low mosaic karyotype (N = 1) in amniotic fluid (AF) were investigated. The cytotrophoblast as well as the mesenchymal core of two to four placental chorionic villi biopsies were studied with single nucleotide polymorphism (SNP) array. Clinical outcome data were collected. RESULTS: In 10/10 cases, CPM was proven. In 3/10 cases trisomy/uniparental disomy (UPD)/biparental disomy (BPD) mosaicism was discovered. In 2/3 cases, all three cell lines were present in the placenta, whereas BPD was found in AF. In 1/3 cases trisomy 22/UPD22 was present in AF while trisomy 22/BPD22 mosaicism was found in the placenta. Five of 10 pregnancies were affected with pre-eclampsia, low birth weight, preterm delivery, and/or congenital malformations. CONCLUSION: The presence of trisomy/UPD/BPD mosaicism in 3/10 cases that we investigated proves that trisomic zygote rescue may involve multiple rescue events during early embryogenesis. UPD mosaicism, when present in crucial fetal tissues, may explain the abnormal phenotype in undiagnosed cases.
Subject(s)
Mosaicism , Placenta Diseases/genetics , Placenta/physiopathology , Prenatal Diagnosis/methods , Trisomy/diagnosis , Trisomy/genetics , Uniparental Disomy/genetics , Amniocentesis , Amniotic Fluid/physiology , Female , Genetic Testing , Humans , Karyotyping , Polymorphism, Single Nucleotide , Pregnancy , Zygote/physiologyABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0141089.].