Fetal neurosonography and infant neurobehavior following conception by assisted reproductive technology with fresh or frozen embryo transfer.

OBJECTIVE: We aimed to explore fetal cortical brain development by neurosonography in fetuses conceived by assisted reproductive technology (ART), including frozen and fresh embryo transfer (ET), compared with those conceived spontaneously (SC), and to investigate its association with infant neurobehavior at 12 months of age. METHODS: This was a prospective cohort study of 210 singleton pregnancies, including 70 SC pregnancies, 70 conceived by in-vitro fertilization (IVF) following frozen ET and 70 conceived by IVF after fresh ET. Fetal neurosonography was performed at 32 ± 2 gestational weeks to assess cortical development. Sulci depths were measured offline and normalized by biparietal diameter (BPD). Ages and Stages Questionnaires (ASQ) were completed postnatally, at 12 ± 1 months of corrected age. Neurosonographic findings were adjusted by regression analysis for maternal age, ethnicity, parity, fetal sex and fetal-weight centile and gestational age at scan, and ASQ scores were adjusted for maternal age, ethnicity, parity, educational level and employment status, gestational age at birth, breastfeeding, infant sex and infant age at the ASQ evaluation. RESULTS: Overall, in comparison to the SC fetuses, fetuses conceived by ART showed statistically significant differences in cortical development, with reduced parieto-occipital sulci depth adjusted for BPD (mean ± SD: fresh ET, 12.5 ± 2.5 vs frozen ET, 13.4 ± 2.6 vs SC, 13.4 ± 2.6, P < 0.001), cingulate sulci depth adjusted for BPD (median (interquartile range (IQR)): fresh ET, 5.8 (4.2-7.4) vs frozen ET, 5.8 (4.1-7.5) vs SC, 6.5 (4.8-7.8), P = 0.001) and calcarine sulci depth adjusted for BPD (median (IQR): fresh ET, 13.5 (10.1-16.1) vs frozen ET, 14.5 (12.1-15.8) vs SC, 16.4 (14.3-17.9), P < 0.001), together with lower Sylvian fissure grading score. Changes in cortical development were more pronounced in the fresh ET than in the frozen ET group. ART infants showed lower ASQ scores as compared to SC infants, particularly in the fresh ET group (mean ± SD global ASQ Z-score: fresh ET, -0.3 ± 0.4 vs frozen ET, -0.2 ± 0.4 vs SC, 0 ± 0.4, P < 0.001). CONCLUSIONS: Fetuses conceived by ART show a distinctive pattern of cortical development and suboptimal infant neurodevelopment, with more pronounced changes in those conceived following fresh ET. These findings support the existence of in-utero brain reorganization associated with ART and warrant follow-up studies to assess its long-term persistence. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Fetal neurosonography at 31-35 weeks reveals altered cortical development in pre-eclampsia with and without small-for-gestational-age fetus.

OBJECTIVE: To explore the pattern of fetal cortical development in pregnancies complicated by pre-eclampsia (PE), with and without a small-for-gestational-age (SGA) fetus, compared to uncomplicated pregnancies. METHODS: This was a prospective observational study including singleton pregnancies complicated by normotensive SGA (birth weight < 10th centile) (n = 77), PE with an appropriate-for-gestational-age (AGA) fetus (n = 76) or PE with a SGA fetus (n = 67), and 128 uncomplicated pregnancies (normotensive AGA) matched by gestational age at ultrasound. All pregnancies underwent detailed neurosonography, using a transabdominal and transvaginal approach, at 31-35 weeks' gestation to assess the depth of the insula, Sylvian fissure, parieto-occipital sulcus, cingulate sulcus and calcarine sulcus. All measurements were adjusted for biparietal diameter (BPD). In addition, a grading score of cortical development was assigned to each brain structure, ranging from Grade 0 (no development) to Grade 5 (maximum development). Univariate and multiple regression analyses were conducted. RESULTS: Similar to findings in previous studies, normotensive pregnancies with a SGA fetus showed significant differences in cortical development compared with controls, with reduced Sylvian fissure depth adjusted for BPD (14.5 ± 2.4 vs 16.6 ± 2.3; P < 0.001) and increased insula depth adjusted for BPD (33.2 ± 2.0 vs 31.8 ± 2.0; P < 0.001). Interestingly, a similar cortical development pattern was observed in PE pregnancies with a SGA fetus and in PE pregnancies with an AGA fetus, manifested by reduced Sylvian fissure depth adjusted for BPD (14.2 ± 2.3 and 14.3 ± 2.3 vs 16.6 ± 2.3; P < 0.001 for both) and greater insula depth adjusted for BPD (33.2 ± 2.1 and 32.8 ± 1.7 vs 31.8 ± 2.0; P < 0.001 for both) compared with controls. No significant differences were observed in parieto-occipital, cingulate sulcus or calcarine sulcus depth across the study groups. The Sylvian fissure was scored as Grade 4 in significantly more (93.2% vs 59.5%) and as Grade 5 in significantly fewer (2.7% vs 37.3%) PE pregnancies with an AGA fetus compared with controls (P < 0.05 for both). These differences remained significant even after statistical adjustment for potential confounders, including ethnicity, low socioeconomic status, nulliparity, chronic hypertension, pregestational diabetes, assisted reproductive technologies, smoking and fetal gender, with the application of Benjamini-Hochberg procedure for multiple comparisons. CONCLUSIONS: PE with or without SGA is associated with a differential fetal cortical development pattern which is similar to that described previously in small fetuses. Future research is warranted to elucidate better the mechanism(s) underlying these changes. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal neurosonography detects differences in cortical development and corpus callosum in late-onset small fetuses.

OBJECTIVE: To explore whether neurosonography can detect differences in cortical development and corpus callosal length in late-onset small fetuses subclassified into small-for-gestational age (SGA) or growth restricted (FGR). METHODS: This was a prospective cohort study in singleton pregnancies, including normally grown fetuses (birth weight between the 10th and 90th centiles) and late-onset small fetuses (estimated fetal weight < 10th centile, diagnosed after 32 weeks of gestation and confirmed by birth weight < 10th centile). Small fetuses were subclassified into SGA (birth weight between the 3rd and 9th centiles and normal fetoplacental Doppler) and FGR (birth weight < 3rd centile and/or abnormal cerebroplacental ratio and/or abnormal uterine artery Doppler). Neurosonography was performed at 33 ± 1 weeks of gestation to assess the depth of the insula, Sylvian fissure and parieto-occipital sulcus in the axial views and corpus callosal length in the midsagittal plane. Measurements were performed offline using Alma Workstation software and were adjusted by biparietal diameter or cephalic index. Linear regression analysis was used to assess the association between the neurosonographic variables and study group, adjusting for confounding factors such as gender, gestational age at neurosonography, nulliparity and pre-eclampsia. RESULTS: In total, 318 fetuses were included, of which 97 were normally grown and 221 were late-onset small fetuses that were further subdivided into late-onset SGA (n = 67) or late-onset FGR (n = 154). Compared to controls, both SGA and FGR cases showed significantly increased insular depth adjusted for biparietal diameter (median (interquartile range), controls 0.329 (0.312-0.342) vs SGA 0.339 (0.321-0.347) vs FGR 0.336 (0.325-0.349); P = 0.006). A linear tendency to reduced Sylvian fissure depth adjusted for biparietal diameter was also observed across the study groups (mean ± SD, controls 0.148 ± 0.021 vs SGA 0.142 ± 0.025 vs FGR 0.139 ± 0.022; P = 0.003). However, differences were significant only between the FGR and control groups. Corpus callosal length adjusted for cephalic index was significantly reduced in FGR cases compared with both controls and SGA cases, while there was no difference between SGA cases and controls (median (interquartile range), controls 0.500 (0.478-0.531) vs SGA 0.502 (0.487-0.526) vs FGR 0.475 (0.447-0.508); P = 0.005). No differences were found in parieto-occipital sulcus depth between the three study groups. CONCLUSION: Neurosonography seems to be a sensitive tool to detect subtle structural differences in brain development in late-onset small fetuses. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.