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.

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.

Assessment of white matter microstructural integrity in children with syndromic craniosynostosis: a diffusion-tensor imaging study.

PURPOSE: To assess whether architectural alterations exist in the white matter of patients with syndromic and complex craniosynostosis. MATERIALS AND METHODS: The medical ethics committee approved this study. Written informed consent was obtained from parents or guardians before imaging. A prospective study was performed in children with syndromic and complex craniosynostosis aged 6-14 years. Forty-five patients were included: four had Apert syndrome, 14 had Crouzon-Pfeiffer syndrome, eight had Muenke syndrome, 11 had Saethre-Chotzen syndrome, and eight had complex craniosynostosis. In addition, seven control subjects were evaluated. For diffusion-tensor imaging, an echo-planar sequence was used with a diffusion gradient (b = 1000 sec/mm(2)) applied in 25 noncollinear directions. Regions of interest (ROIs) were placed in the following white matter structures: pontine crossing tract, corticospinal tracts, medial cerebral peduncles, uncinate fasciculus (measured bilaterally), anterior commissure, frontal and occipital white matter (measured bilaterally), fornix, corpus callosum (measured in the genu and splenium), and corpus cingulum (measured bilaterally). Eigenvalues were measured in all ROIs and fractional anisotropy (FA) was calculated. RESULTS: Across all measured ROIs, FA values were generally lower in all patients combined than in the control subjects (P < .001). There were no significant differences among subgroups of patients. CONCLUSION: Diffusion-tensor imaging measurements of white matter tracts reveal significant white matter integrity differences between children with craniosynostosis and healthy control subjects. This could imply that the developmental delays seen in these patients could be caused by the presence of a primary disorder of the white matter microarchitecture.

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.

Periconceptional maternal dairy-rich dietary pattern is associated with prenatal cerebellar growth.

BACKGROUND: Maternal nutrition during pregnancy has been related to intrauterine brain development and neurodevelopmental disabilities in adult life. We aim to investigate associations between periconceptional maternal dietary patterns and prenatal cerebellar growth from the first trimester onwards. MATERIALS AND METHODS: 126 women with singleton non-malformed pregnancies were enrolled before 8 weeks of gestation in the Rotterdam periconceptional cohort between 2013 and 2015. Periconceptional maternal dietary patterns were extracted from food frequency questionnaires and associated with blood biomarkers and micronutrient intakes. Serial two-dimensional and three-dimensional ultrasound scans were performed at 9, 11, 22, 26 and 32 weeks of gestation for transcerebellar diameter (TCD) measurement. Linear mixed models were estimated to investigate associations between periconceptional maternal dietary patterns and longitudinal TCD measurements as a function of gestational age. RESULTS: We performed a median of 4 scans per pregnancy, resulting in 570 total datasets. The success rate of TCD measurements was 87% (range 65-100%), depending on gestational age. The Mediterranean, Western, egg-rich and dairy-rich dietary patterns were extracted, explaining 37.2% of the overall variance of food intake in this population. The dairy-rich dietary pattern was positively associated with cerebellar growth trajectories (ß = 0.02 (95% CI: 0.01; 0.03) √mm, p = 0.01). Maternal strong adherence to this dietary pattern increased TCD measurements by 0.8 standard deviation scores (SDs) compared to weak adherence, reflected in increased TCD estimates of 0.44 mm at 9 weeks (+6.8%), 0.88 mm at 22 weeks (+3.6%), and 1.17 mm at 32 weeks (+2.8%). No significant associations were detected for the Mediterranean, Western and egg-rich dietary patterns. CONCLUSIONS: This study shows a positive association between periconceptional maternal adherence to a dairy-rich dietary pattern and human prenatal TCD measurements as a proxy of cerebellar growth. Next step is the investigation of the impact on neurodevelopmental outcomes in the offspring.

Correction: Periconception Maternal Folate Status and Human Embryonic Cerebellum Growth Trajectories: The Rotterdam Predict Study.

[This corrects the article DOI: 10.1371/journal.pone.0141089.].

Effect of Preterm Birth on Echogenicity in Basal Ganglia.

In this study, the influence of prematurity on echogenicity of deep gray matter at 30-wk corrected age was assessed using ultrasound measurements. In an observational cohort study, ultrasound scans of 224 extremely preterm infants were prospectively collected. Gray values were assessed in putamen and globus pallidus. Intra- and inter-observer reliability was analyzed and showed excellent agreement. The globus pallidus to putamen ratio was significantly related to gestational age at birth, adjusted regression coefficient in points per wk: 1.28 (95% confidence interval [CI]: 0.38-2.19) for left and 2.12 (95% CI: 1.23-3.02) for right-side images. At 30-wk corrected age this was still the case, adjusted regression coefficient: 0.45 (95% CI: -0.57 to 1.47) for left and 1.29 (95% CI: 0.10-2.48) for right. The putamen is more hyperechoic with lower gestational age. Measuring ultrasound gray values in deep gray matter seems highly reproducible. Prematurity shows a negative correlation with echogenicity of the putamen, this persists at 30-wk corrected age, suggesting altered maturation.

Impacts on prenatal development of the human cerebellum: a systematic review.

PURPOSE: The cerebellum is essential for normal neurodevelopment and is particularly susceptible for intra-uterine disruptions. Although some causal prenatal exposures have been identified, the origin of neurodevelopmental disorders remains mostly unclear. Therefore, a systematic literature search was conducted to provide an overview of parental environmental exposures and intrinsic factors influencing prenatal cerebellar growth and development in humans. MATERIALS AND METHODS: The literature search was limited to human studies in the English language and was conducted in Embase, Medline, Cochrane, Web of Science, Pubmed and GoogleScholar. Eligible studies were selected by three independent reviewers and study quality was scored by two independent reviewers. RESULTS: The search yielded 3872 articles. We found 15 eligible studies reporting associations between cerebellar development and maternal smoking (4), use of alcohol (3), in vitro fertilization mediums (1), mercury (1), mifepristone (2), aminopropionitriles (1), ethnicity (2) and cortisol levels (1). No studies reported on paternal factors. CONCLUSIONS: Current literature on associations between parental environmental exposures, intrinsic factors and human cerebellar development is scarce. Yet, this systematic review provided an essential overview of human studies demonstrating the vulnerability of the cerebellum to the intra-uterine environment.

Periconception Maternal Folate Status and Human Embryonic Cerebellum Growth Trajectories: The Rotterdam Predict Study.

We aimed to investigate whether periconceptional maternal folate status affects human embryonic cerebellar size and growth trajectories. In a prospective periconceptional cohort participants filled out questionnaires and received weekly transvaginal 3D-ultrasounds between 7+0 and 12+6 weeks gestational age (GA). Viable non-malformed singleton pregnancies were selected for cerebellar measurements; transcerebellar diameter, (TCD), left and right cerebellar diameters (LCD, RCD). Linear mixed models were performed to estimate associations between questionnaire data on the timing of maternal folic acid supplement initiation and longitudinal cerebellar measurements as a function of crown-rump length (CRL) and GA. Maternal red blood cell folate concentrations were analysed before 8 weeks GA to validate the associations. A total of 263 serial high quality three-dimensional ultrasound scans of 135 pregnancies were studied. Preconceptional compared to postconceptional initiation of folic acid use was associated with slightly larger cerebellar diameters per millimetre increase of CRL (TCD: ß = 0.260mm, 95%CI = 0.023-0.491, p<0.05; LCD: ß = 0.171mm, 95%CI = 0.038-0.305, p<0.05; RCD: ß = 0.156mm, 95%CI = 0.032-0.280, p<0.05) and with proportional cerebellar growth (TCD/CRL:ß = 0.015mm/mm, 95%CI = 0.005-0.024, p<0.01; LCD/CRL:ß = 0.012mm/mm, 95%CI = 0.005-0.018, p<0.01; RCD/CRL:ß = 0.011mm/mm, 95%CI = 0.005-0.017, p<0.01). Cerebellar growth was significantly highest in the third quartile of maternal red blood cell folate levels (1538-1813 nmol/L). These first findings show that periconceptional maternal folate status is associated with human embryonic cerebellar development. Implications of these small but significant variations for fetal cerebellar growth trajectories and the child's neurodevelopmental outcome are yet unknown and warrant further investigation.