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.

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.

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.

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.

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.

Prenatal influence of congenital heart defects on trajectories of cortical folding of the fetal brain using three-dimensional ultrasound.

OBJECTIVE: The objective of the study is to investigate the prenatal influence of congenital heart defects (CHD) on trajectories of fetal cortical folding using three-dimensional ultrasound (3D US). METHOD: We included 20 CHD fetuses and 193 controls for studying the fetal brain at 22, 26 and 32 weeks' gestational age (GA). The Sylvian, insula and parieto-occipital fissure (POF) depths were measured using 3D US, and reliability was evaluated. Doppler indices of the umbilical artery and middle cerebral artery were measured to calculate the cerebro-placental ratio. Associations between CHD and cortical folding were estimated using linear mixed models. RESULTS: Brain fissure measurements were successful in over 80% of 3D US scans, except for the POF at 32 weeks' GA (65%). All measurements showed a good reliability (intraclass correlation coefficients > 0.84). Growth trajectories of the left insula depth (ß = -2.753, 95% CI = -5.375; -0.130, p = 0.040) and right POF (ß = -3.762, 95% CI = -7.178; -0.346, p = 0.031) were decreased in CHD compared with controls, whereas growth rates were increased (ß = 0.014, 95% CI = 0.001; 0.027, p = 0.036 and ß = 0.024, 95% CI = 0.007; 0.041, p = 0.006). In contrast to controls, we found no associations between cerebro-placental ratio and cortical folding in CHD. CONCLUSION: Fetal cortical folding can be evaluated reliably by measuring brain fissure depths. Trajectories of cortical folding between 22 and 32 weeks' GA seem to be influenced by CHD. © 2017 John Wiley & Sons, Ltd.