The role of confined placental mosaicism in fetal growth restriction: A retrospective cohort study.

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.

Prenatal counseling of an isolated fetal small head circumference during the second trimester expert ultrasound examination.

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.

Clinical impact of additional findings detected by genome-wide non-invasive prenatal testing: Follow-up results of the TRIDENT-2 study.

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.

Periconceptional maternal folate status and the impact on embryonic head and brain structures: the Rotterdam Periconceptional Cohort.

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 (ß = 0.866; P = 0.004) and Q4 (ß = 0.764; P = 0.007). In addition, head circumference at 11 weeks of gestational age was significantly larger in Q4 (ß = 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.

A novel family illustrating the mild phenotypic spectrum of TUBB2B variants.

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.

How to deal with uncertainty in prenatal genomics: A systematic review of guidelines and policies.

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.

Confined placental mosaicism and the association with pregnancy outcome and fetal growth: a review of the literature.

BACKGROUND: Chromosomal mosaicism can be detected in different stages of early life: in cleavage stage embryos, in blastocysts and biopsied cells from blastocysts during preimplantation genetic testing for aneuploidies (PGT-A) and later during prenatal testing, as well as after birth in cord blood. Mosaicism at all different stages can be associated with adverse pregnancy outcomes. There is an onward discussion about whether blastocysts diagnosed as chromosomally mosaic by PGT-A should be considered safe for transfer. An accurate diagnosis of mosaicism remains technically challenging and the fate of abnormal cells within an embryo remains largely unknown. However, if aneuploid cells persist in the extraembryonic tissues, they can give rise to confined placental mosaicism (CPM). Non-invasive prenatal testing (NIPT) uses cell-free (cf) DNA released from the placenta in maternal blood, facilitating the detection of CPM. In literature, conflicting evidence is found about whether CPM is associated with fetal growth restriction (FGR) and/or other pregnancy outcomes. This makes counselling for patients by clinicians challenging and more knowledge is needed for clinical decision and policy making. OBJECTIVE AND RATIONALE: The objective of this review is to evaluate the association between CPM and prenatal growth and adverse pregnancy outcomes. All relevant literature has been reviewed in order to achieve an overview on merged results exploring the relation between CPM and FGR and other adverse pregnancy outcomes. SEARCH METHODS: The following Medical Subject Headings (MESH) terms and all their synonyms were used: placental, trophoblast, cytotrophoblast, mosaicism, trisomy, fetal growth, birth weight, small for gestational age and fetal development. A search in Embase, PubMed, Medline Ovid, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar databases was conducted. Relevant articles published until 16 July 2020 were critically analyzed and discussed. OUTCOMES: There were 823 articles found and screened based on their title/abstract. From these, 213 articles were selected and full text versions were obtained for a second selection, after which 70 publications were included and 328 cases (fetuses) were analyzed. For CPM in eight different chromosomes (of the total 14 analyzed), there was sufficient evidence that birth weight was often below the 5th percentile of fetal growth standards. FGR was reported in 71.7% of CPM cases and preterm birth (<37 weeks of delivery) was reported in 31.0% of cases. A high rate of structural fetal anomalies, 24.2%, in cases with CPM was also identified. High levels of mosaicism in CVS and presence of uniparental disomy (UPD) were significantly associated with adverse pregnancy outcomes. WIDER IMPLICATIONS: Based on the literature, the advice to clinicians is to monitor fetal growth intensively from first trimester onwards in case of CPM, especially when chromosome 2, 3, 7, 13, 15, 16 and 22 are involved. In addition to this, it is advised to examine the fetuses thoroughly for structural fetal anomalies and raise awareness of a higher chance of (possibly extreme) premature birth. Despite prematurity in nearly a fifth of cases, the long-term follow-up of CPM life borns seems to be positive. More understanding of the biological mechanisms behind CPM will help in prioritizing embryos for transfer after the detection of mosaicism in embryos through PGT-A.

IVF with or without ICSI and the impact on human embryonic brain development: the Rotterdam Periconceptional Cohort.

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.

Non-invasive prenatal testing (NIPT): societal pressure or freedom of choice? A vignette study of Dutch citizens' attitudes.

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.

The potential diagnostic yield of whole exome sequencing in pregnancies complicated by fetal ultrasound anomalies.

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.

Growth trajectories of the human fetal brain in healthy and complicated pregnancies and associations with neurodevelopmental outcome in the early life course.

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.

Social and medical need for whole genome high resolution NIPT.

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.

Implementing non-invasive prenatal testing (NIPT) in the Netherlands: An interview study exploring opinions about and experiences with societal pressure, reimbursement, and an expanding scope.

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.

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

OBJECTIVES: To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities. METHODS: This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected. RESULTS: In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95th and 99th percentile and 62% for fetuses with NT≥99th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively. CONCLUSION: Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement.

Placental studies elucidate discrepancies between NIPT showing a structural chromosome aberration and a differently abnormal fetal karyotype.

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.

Three-dimensional ultrasound imaging of fetal brain fissures in the growth restricted fetus.

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.