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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 < 10(th) 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.

Background Being born small-for-gestational age (SGA, 10 percent of all births) is associated with increased risk of cardiovascular mortality (1,2) in adulthood together with lower exercise tolerance (3), but mechanistic pathways are unclear. Central obesity is known to worsen cardiovascular outcomes, but it is uncertain how it affects the heart in adults born SGA. Purpose We aimed to assess whether central obesity makes young adults born SGA more susceptible to cardiac remodelling and dysfunction. Methods A perinatal cohort study including 80 young adults born SGA (birth weight below 10th centile) and 75 adults with normal birth weight (controls). Current waist-to-hip ratio was used as a surrogate of central obesity. Cardiac structure and function were assessed by cardiac magnetic resonance. Statistical shape analysis was used to study the regional geometric variability of the biventricular surfaces produced by central obesity and SGA, and synthetic surfaces representative of obese and non obese were generated for both SGA and controls. Results Figure 1 shows the superimposed representative surfaces of obese and non-obese according to our model, for controls (right column) and SGA (left column). Both SGA and waist-to-hip were highly associated to cardiac shape (F=3.94 p Conclusions SGA young adults show unique cardiac adaptation to central obesity, which is associated with a decrease in stroke volume. Preventive strategies aiming to reduce cardiometabolic risk in SGA population may be warranted. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union Horizon 2020 Programme

Study question Do spontaneously conceived (SC) fetuses from subfertile couples present signs of cardiac remodeling as those observed after in vitro fertilization (IVF) treatments? Summary answer SC fetuses from subfertile couples do not associate cardiac remodeling, and their cardiac structure and function are similar to those of SC from fertile couples. What is known already Fetuses and children from IVF associate cardiac remodeling and suboptimal function, including dilated atria, more globular and thicker ventricles, reduced longitudinal motion and impaired relaxationin uteroand after birth. Fetal cardiac changes have been demonstrated both after fresh and frozen embryo transfer. The SC fetuses used as ‘controls’ in our previous publications were conceived by fertile couples thus making it difficult to separate the contribution of infertilityper sefrom the IVF procedures on cardiac programming. There are no previous cardiovascular studies investigating the independent effects of infertility in SC fetuses from subfertile couples (time-to-pregnancy (TTP) over 12 months). Study design, size, duration Prospective cohort study of 289 singleton pregnancies recruited from 2017 to 2021, including 96 SC pregnancies from fertile couples (TTP less than 12 months), 97 SC from subfertile couples (TTP over 12 months) and 96 from IVF after fresh ET. Fetal echocardiography was performed in all pregnancies. Epidemiological data and perinatal outcomes were collected in all pregnancies. Participants/materials, setting, methods IVF pregnancies from our centre were identified as eligible at pregnancy diagnosis. Eligible SC pregnancies from fertile and subfertile couples who attended our Maternal-Fetal Unit were invited to participate at third trimester, being matched to the IVF pregnancies by maternal age. Fetal echocardiography was performed at 29-34 weeks of pregnancy to assess cardiac structure and function. Echocardiographic comparisons were adjusted by nulliparity, birthweight centile, gestational age and estimated fetal weight at scan. Main results and the role of chance Parental age, ethnicity, body mass index and smoking exposure, median gestational age and estimated fetal weight were similar in all study groups. There were no significant differences in infertility duration or aetiology between the subfertile and the IVF populations (TTP: subfertile median 30 months [IQR 20-54] versus IVF: 47 [25-61]; p-value=0.052). While both fertile and subfertile SC groups presented similar fetal cardiac results, IVF fetuses showed larger atria (right atria-to-heart ratio: IVF mean 18.9% [SD 3.4] versus subfertile 17.8% [3.5] versus fertile 17.6% [3.3]; adjusted P-value Limitations, reasons for caution The fetal cardiac changes reported here are subclinical, with most cardiovascular parameters lying within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with long-term cardiovascular disease remains to be proven. Wider implications of the findings Subfertility per se does not seem to be associated to fetal cardiac remodeling, which have been previously described in IVF fetuses. Future studies are warranted to further investigate the factors related to fetal cardiac changes associated to ART. Trial registration number Not a trial

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.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.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).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 ObstetricsGynecology published by John WileySons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

OBJECTIVE: To validate the performance of a previously constructed first-trimester predictive model for pre-eclampsia (PE) in routine care of an unselected population. METHODS: A validation cohort of 4621 consecutive women attending their routine first-trimester ultrasound examination was used to test a prediction model for PE that had been developed previously in 5170 women. The prediction model included maternal factors, uterine artery Doppler, blood pressure and pregnancy-associated plasma protein-A. Model performance was evaluated using receiver-operating characteristics (ROC) curve analysis and ROC curves from both cohorts were compared unpaired. RESULTS: Among the 4203 women included in the final analysis, 169 (4.0%) developed PE, including 141 (3.4%) cases of late-onset PE and 28 (0.7%) cases of early-onset PE. For early-onset PE, the model showed an area under the ROC curve of 0.94 (95% CI, 0.88-0.99), which did not differ significantly (P = 0.37) from that obtained in the construction cohort (0.88 (95% CI, 0.78-0.99)). For late-onset PE, the final model showed an area under the ROC curve of 0.72 (95% CI, 0.66-0.77), which did not differ significantly (P = 0.49) from that obtained in the construction cohort (0.75 (95% CI, 0.67-0.82)). CONCLUSION: The prediction model for PE achieved a similar performance to that obtained in the construction cohort when tested on a subsequent cohort of women, confirming its validity as a predictive model for PE. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

To evaluate the use of third-trimester ultrasound screening for late fetal growth restriction (FGR) on a contingent basis, according to risk accrued in the second trimester, in an unselected population.Maternal characteristics, fetal biometry and second-trimester uterine artery (UtA) Doppler were included in logistic regression analysis to estimate risk for late FGR (birth weight 3(rd) percentile, or 3(rd) -10(th) percentile plus abnormal cerebroplacental ratio or UtA Doppler, with delivery ≥ 34 weeks). Based on the second-trimester risk, strategies for performing contingent third-trimester ultrasound examinations in 10%, 25% or 50% of the cohort were tested against a strategy of routine ultrasound scanning in the entire population at 32 + 0 to 33 + 6 weeks.Models were constructed based on 1393 patients and validated in 1303 patients, including 73 (5.2%) and 82 late FGR (6.3%) cases, respectively. At the second-trimester scan, the a-posteriori second-trimester risk (a-posteriori first-trimester risk (baseline a-priori risk and mean arterial blood pressure) combined with second-trimester abdominal circumference and UtA Doppler) yielded an area under the receiver-operating characteristics curve (AUC) of 0.81 (95% CI, 0.74-0.87) (detection rate (DR), 43.1% for a 10% false-positive rate (FPR)). The combination of a-posteriori second-trimester risk plus third-trimester estimated fetal weight (full model) yielded an AUC of 0.92 (95% CI, 0.88-0.96) (DR, 74% for a 10% FPR). Subjecting 10%, 25% or 50% of the study population to third-trimester ultrasound, based on a-posteriori second-trimester risk, gave AUCs of 0.81 (95% CI, 0.75-0.88), 0.84 (95% CI, 0.78-0.91) and 0.89 (95% CI, 0.84-0.94), respectively. Only the 50% contingent model proved statistically equivalent to performing routine third-trimester ultrasound scans (AUC, 0.92 (95% CI, 0.88-0.96), P = 0.11).A strategy of selecting 50% of the study population to undergo third-trimester ultrasound examination, based on accrued risk in the second trimester, proved equivalent to routine third-trimester ultrasound scanning in predicting late FGR.

How organisms respond to environmental change is a long-standing question in evolutionary biology. Species invading novel habitats provide an opportunity to examine contemporary evolution in action and decipher the pace of evolutionary change over short timescales. Here, we characterized phenotypic evolution in the Italian plethodontid salamander, Hydromantes strinatii, following the recent colonization of an artificial cave by a forest floor population. When compared with a nearby and genetically related population in the natural forest floor and a nearby cave population, the artificial cave population displayed significant differences in overall foot shape, with more interdigital webbing relative to the other populations. Further, this population evolved significantly larger feet, which corresponded more closely to those found in other cave populations than to forest floor populations to which the cave population is closely related. Finally, we quantified the rate of evolution for both foot shape and foot area, and found that both traits displayed large and significant evolutionary rates, at levels corresponding to other classic cases of rapid evolution in vertebrates. Together, these findings reveal that the response to novel environmental pressures can be large and rapid and that the anatomical shifts observed in the artificial cave population of H. strinatii may represent a case of rapid evolution in response to novel environmental pressures.

To investigate whether signs of placental underperfusion (PUP), defined as any maternal and/or fetal vascular pathology, confer an increased risk of neonatal morbidity in late-onset small-for-gestational-age (SGA) fetuses with normal umbilical artery (UA) Doppler indices.A cohort of 126 SGA singleton fetuses with normal UA Doppler indices that were delivered after 34 weeks' gestation was studied. For each case, the placenta was evaluated histologically for signs of PUP using a hierarchical and standardized classification system. Neonatal morbidity was assessed according to the score calculated from the morbidity assessment index for newborns (MAIN), a validated outcome scale. The independent association between PUP and neonatal morbidity was evaluated using multivariable median regression analysis.In 84 (66.7%) placentae, 97 placental histological findings that qualified as signs of PUP were observed. These PUP cases had a significantly higher incidence of emergency Cesarean section for non-reassuring fetal status (44.1% vs 21.4%, respectively; P = 0.013) and neonatal metabolic acidosis at birth (33.3% vs 14.3%, respectively; P = 0.023), than did those without PUP. The median MAIN score differed significantly between those with PUP and those without (89 vs 0, respectively; P = 0.025). This difference remained significant after adjustment for potential confounders. The proportion of cases with scores indicative of mild to severe morbidity was also significantly higher in the PUP group (31% vs 14.3%, respectively; P = 0.043).In late-onset SGA fetuses with normal UA Doppler indices, signs of PUP imply a higher neonatal morbidity. These findings allow the phenotypic profiling of fetal growth restriction among the general population of late-onset SGA.

To elucidate the association between Doppler parameters and histological signs of placental underperfusion in late-onset small-for-gestational-age (SGA) babies.Umbilical, fetal middle cerebral and uterine artery pulsatility indices and umbilical vein blood flow (UVBF), which had been recorded within 7 days prior to delivery, were analyzed from a cohort of SGA singleton pregnancies delivered after 34 weeks' gestation and confirmed as having a birth weight10(th) percentile by local standards. In each case, the placenta was histologically evaluated for signs of placental underperfusion using a hierarchical and standardized classification system. The independent association of the Doppler parameters with placental underperfusion was evaluated using logistic regression and decision tree analysis.In 51 cases (53.7%), there were 61 placental histological findings indicative of placental underperfusion. These cases had a significantly higher incidence of Cesarean section for non-reassuring fetal status (52.1% vs 11.9%; P0.001) and neonatal metabolic acidosis at birth (21.6% vs 0%; P = 0.001). Significant and independent contributions to the presence of placental underperfusion lesions were provided by increased mean UtA pulsatility index (PI) (P = 0.018; odds ratio (OR) 2 (95% CI, 1.1-3.7)) and decreased UVBF normalized to estimated fetal weight (P = 0.027; OR 0.97 (95% CI, 0.95-0.99)). The combination of both parameters revealed three groups with differing risks for placental underperfusion: normalized UVBF82 mL/min/kg (risk 31.3%), normalized UVBF ≤ 82 mL/min/kg and mean UtA-PI ≤ 95(th) percentile (risk 65.5%), and normalized UVBF ≤ 82 mL/min/kg and UtA-PI95(th) percentile (risk 94.4%).In late-onset SGA pregnancies, uterine Doppler and UVBF are surrogates for placental underperfusion. These findings facilitate phenotypic profiling of cases of fetal growth restriction among the general population of late-onset SGA babies.

To compare the value of Doppler surveillance with maternal blood angiogenic factors at diagnosis for the prediction of adverse outcome in late-pregnancy small-for-gestational-age (SGA) fetuses.In a cohort of 198 SGA fetuses we evaluated the association of Doppler indices (mean uterine artery pulsatility index (UtA-PI) and cerebroplacental ratio (CPR)) and angiogenic factors (maternal serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF)) with the development of pre-eclampsia and adverse perinatal outcome (operative delivery for non-reassuring fetal status or neonatal metabolic acidosis).In SGA fetuses subsequently developing pre-eclampsia, mean UtA-PI (P 0.001), sFlt-1 MoM (P 0.001) and sFlt-1/PlGF MoM ratio (P 0.001) were higher, while PlGF MoM was lower (P = 0.004). In SGA fetuses with adverse perinatal outcome, CPR (P 0.002) and PlGF MoM (P 0.001) were lower, and sFlt-1/PlGF MoM ratio was higher (P = 0.001). For predicting pre-eclampsia, the areas under the receiver-operating characteristics (ROC) curves for mean UtA-PI, sFlt-1 MoM and the combination of both were 0.852, 0.839 and 0.860, respectively. For adverse perinatal outcome, the areas under the ROC curves for CPR, PlGF MoM and the combination of both were 0.652, 0.656 and 0.684, respectively. The combination of Doppler indices and angiogenic factors did not significantly improve prediction of either pre-eclampsia (P = 0.851) or adverse outcome (P = 0.579).In SGA fetuses, angiogenic factors at diagnosis and follow-up with Doppler ultrasound both predict adverse outcome with a similar performance.

To assess the effectiveness of first-trimester screening for early and late small-for-gestational-age (SGA) neonates using maternal serum biochemistry, blood pressure and uterine artery Doppler.This was a prospective study of 4970 women with a singleton pregnancy who underwent routine first-trimester screening between 2009 and 2011. A logistic regression-based predictive model for SGA, defined as birth weight10(th) percentile, divided into early- or late-onset based on gestational age at delivery before or after 34 weeks' gestation, was constructed. The model included maternal baseline characteristics: serum levels of pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin at 8-12 weeks and blood pressure and uterine artery Doppler at 11 + 0 to 13 + 6 weeks.The prevalence of early and late SGA was 0.6% and 7.9%, respectively. Association with pre-eclampsia was 67% and 8%, respectively. At a false-positive rate of 15%, the detection rate for early SGA was 73%; however it differed substantially for cases with and without pre-eclampsia (90% vs 40%). For late SGA, at false-positive rates of 15 and 50%, detection rates were 32% and 70%, respectively, and did not substantially differ between cases with and without pre-eclampsia.First-trimester screening predicts early SGA mainly because of its strong association with pre-eclampsia. Although prediction of late SGA was poorer, at a high false-positive rate it might be considered as part of a first-trimester strategy to select women requiring ultrasound assessment in the third trimester.

To compare umbilical vein (UV) flow with standard Doppler parameters in prediction of adverse perinatal outcome in late-onset small-for-gestational age (SGA) fetuses.Umbilical, uterine and middle cerebral arteries, and UV blood flow were evaluated by Doppler before delivery in a cohort of 193 term SGA fetuses. The value of the Doppler parameters to predict risk of emergency delivery for non-reassuring fetal status and neonatal metabolic acidosis was analyzed.Fifty-three (27%) fetuses had non-reassuring fetal status requiring emergency delivery, whereas 21 (11%) newborns developed neonatal metabolic acidosis. Multivariable analysis showed that significant contributions to prediction of emergency delivery for non-reassuring fetal status and neonatal metabolic acidosis were provided by middle cerebral artery (MCA) pulsatility index (PI) and UV blood flow normalized by fetal weight. Decision tree analysis defined three groups with increasing risk of need for emergency delivery for non-reassuring fetal status: MCA-PI1.46 (risk 15.6%); MCA-PI ≤ 1.46 and UV blood flow68 mL/min/kg (risk 25%); and MCA-PI ≤ 1.46 and UV flow ≤ 68 mL/min/kg (risk 53.1%); and two groups with different risks of neonatal metabolic acidosis: UV flow68 mL/min/kg or UV flow ≤ 68 mL/min/kg and MCA-PI1.23 (risk ≤ 10%); and UV flow ≤ 68 mL/min/kg and MCA-PI ≤ 1.23 (risk 39.1%).The evaluation of UV blood flow with spectral brain Doppler allows better identification of SGA fetuses with late-onset intrauterine growth restriction at risk of adverse perinatal outcome.