Neurosonographic assessment of the corpus callosum as imaging biomarker of abnormal neurodevelopment in late-onset fetal growth restriction.

OBJECTIVE: To explore corpus callosum (CC) developmental differences by ultrasound in late-onset small fetuses compared with adequate for gestational age (AGA) controls. STUDY DESIGN: Ninety four small (estimated fetal weight <10th centile) and 71 AGA fetuses were included. Small fetuses were further subdivided into fetal growth restriction (IUGR, n = 64) and small for gestational age (SGA, n = 30) based on poor perinatal outcome factors, that is, birth weight <3rd centile and/or abnormal cerebroplacental ratio and/or uterine artery Doppler. The entire cohort was scanned to assess CC by transvaginal neurosonography obtaining axial, coronal and midsagittal images. CC length, thickness, total area and the areas after a subdivision in 7 portions were evaluated by semiautomatic software. Furthermore, the weekly average growth of the CC in each study group was calculated and compared. RESULTS: Small fetuses showed significantly shorter (small fetuses: 0.49 vs. AGA: 0.52; p < 0.01) and smaller CC (1.83 vs. 2.03; p < 0.01) with smaller splenium (0.47 vs. 0.55; p < 0.01) compared to controls. The CC growth rate was also reduced when compared to controls. Changes were more prominent in small fetuses with abnormal cerebroplacental Doppler suggesting fetal growth restriction. CONCLUSIONS: Neurosonographic assessment of CC showed significantly altered callosal development, suggesting in-utero brain reorganization in small fetuses. This data support the potential value of CC assessment by US to monitor brain development in fetuses at risk.

Survey on the current trends in managing intrauterine growth restriction.

OBJECTIVE: To provide a snapshot of the current trends in managing intrauterine growth restriction (IUGR) and to assess the agreement on the gestational age and the way of delivery in different clinical scenarios. METHODS: A PubMed search was performed to identify all original articles on IUGR in the last 6 years. The most active 20 authors were selected as experts and were invited to respond to a survey on their preferred gestational age for elective delivery in several IUGR cases depending on Doppler measurements (including umbilical artery (UA), middle cerebral artery, cerebroplacental ratio, uterine artery and ductus venosus), biophysical profile and cardiotocography. RESULTS: 15 of the 20 selected experts agreed to participate in the survey, of which 3 failed to meet the deadline to complete the survey. Management of IUGR was relatively uniform for abnormal UA, uterine artery or cerebroplacental ratio. Although average gestational age at delivery reflected a clear progression with accepted markers of severity, discrepancies of up to 4 weeks were found for abnormal middle cerebral artery Doppler and absent end-diastolic velocity in the UA, and of up to 8 weeks for reverse end-diastolic velocity in the UA and abnormalities in the ductus venosus Doppler. CONCLUSIONS: Management of IUGR is still far from being uniform among centers, with most controversy surrounding the management of early-onset IUGR. There is a need of prospective studies to address this issue.

Neurodevelopmental outcomes of near-term small-for-gestational-age infants with and without signs of placental underperfusion.

OBJECTIVE: To evaluate 2-year neurodevelopmental outcomes of near-term, small-for-gestational-age (SGA) newborns segregated by presence or absence of histopathology reflecting placental underperfusion (PUP). PATIENTS AND METHODS: A cohort of consecutive near-term (≥ 34.0 weeks) SGA newborns with normal prenatal umbilical artery Doppler studies was selected. All placentas were inspected for evidence of underperfusion and classified in accordance with established histologic criteria. Neurodevelopmental outcomes at 24 months (age-corrected) were then evaluated, applying the Bayley Scale for Infant and Toddler Development, Third Edition (Bayley-III) to assess cognitive, language, and motor competencies. The impact of PUP on each domain was measured via analysis of covariance, logistic and ordinal regression, with adjustment for smoking, socioeconomic status, gestational age at birth, gender, and breastfeeding. RESULTS: A total of 83 near-term SGA deliveries were studied, 46 (55.4%) of which showed signs of PUP. At 2 years, adjusted neurodevelopmental outcomes were significantly poorer in births involving PUP (relative to SGA infants without PUP) for all three domains of the Bayley scale: cognitive (105.5 vs 96.3, adjusted-p = 0.03), language (98.6 vs 87.8, adjusted-p<0.001), and motor (102.7 vs 94.5, adjusted-p = 0.007). Similarly, the adjusted likelihood of abnormal cognitive, language, and motor competencies in instances of underperfusion was 9.3-, 17.5-, and 1.44-fold higher, respectively, differing significantly for the former two domains. CONCLUSIONS: In a substantial fraction of near-term SGA babies without Doppler evidence of placental insufficiency, histologic changes compatible with PUP are still identifiable. These infants are at greater risk of abnormal neurodevelopmental outcomes at 2 years.

Evaluation of an optimal gestational age cut-off for the definition of early- and late-onset fetal growth restriction.

OBJECTIVE: The terms early- and late-onset fetal growth restriction (FGR) are commonly used to distinguish two phenotypes characterized by differences in onset, fetoplacental Doppler, association with preeclampsia (PE) and severity. We evaluated the optimal gestational age (GA) cut-off maximizing differences among these two forms. PATIENTS AND METHODS: A cohort of 656 consecutive singleton pregnancies with FGR was created. We used the decision tree analysis to evaluate the GA cut-off that best discriminated perinatal mortality, association with PE and adverse perinatal outcome (fetal demise, early neonatal death, neonatal acidosis at birth, and 5-min Apgar score <7). RESULTS: We identified 32 weeks at diagnosis as the optimal cut-off, resulting in two groups with 7.1 and 0%, p < 0.001 perinatal mortality, 35.1 and 12.1%, p < 0.001 association with PE, and 13.4 and 4.6%, p < 0.001 composite adverse perinatal outcome. Abnormal versus normal umbilical artery (UA) Doppler classified two groups with 10.6 and 0.2%, p < 0.001 perinatal mortality, 50.0 and 11.8%, p < 0.001 association with PE, and 18.2 and 4.2%, p < 0.001 composite adverse perinatal outcome. CONCLUSIONS: UA Doppler discriminated better the two forms of FGR with average early- and late-onset presentation, higher association with PE and poorer outcome. In the absence of UA information, a GA cut-off of 32 weeks at diagnosis maximizes differences between early- and late-onset FGR.

Increased fetal brain perfusion and neonatal neurobehavioral performance in normally grown fetuses.

OBJECTIVE: To explore the association between fetal cerebroplacental ratio (CPR) and frontal brain perfusion at third trimester with neonatal neurobehavioral performance in normally grown fetuses. METHODS: CPR and frontal brain perfusion measured by fractional moving blood volume (FMBV) were assessed in 258 consecutive healthy fetuses at routine third trimester scan (32-35.6 weeks). Neonates were evaluated with the Neonatal Behavioral Assessment Scale. The association between Doppler parameters and neurobehavior was analyzed by MANCOVA (multiple analysis of covariance) and logistic regression, with adjustment for smoking, socioeconomic class, mode of delivery, gestational age at birth, postnatal days at examination and gender. RESULTS: Fetuses with increased FMBV (in the upper quartile) had lower neurobehavioral scores in all areas, reaching significance in motor (5.6 vs. 5.8; p = 0.049), social (6 vs. 6.4; p = 0.006) and attention (5.3 vs. 5.9; p = 0.032). Fetuses with increased FMBV had higher risk of abnormal (<10th centile) motor (OR 3.3; 95% CI 1.36-8.1), social (OR 2.9; 95 CI% 1.33-6.5) and attention (OR 2.5; 95% CI 1.1-5.8) scores. Fetuses with lower CPR (in the lower quartile) did not differ in their neurobehavioral scores from those with normal values. CONCLUSIONS: Normally grown fetuses with increased frontal brain perfusion have poorer neurobehavioral competences, suggesting a disrupted neurological maturation. The results support the existence of forms of placental insufficiency not detected by current definitions of growth restriction.

A large network of interconnected signaling pathways in human ovarian follicles is supported by the gene expression activity of the granulosa cells.

Human follicular fluid (hFF), as an extra oocyte microenvironment, is essential to the biological processes of oocyte development. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 426 proteins as consistently present in hFF from different participants. According to our gene chip data, the granulosa cells in the follicle locally produce 235 of these proteins. These data suggest that the granulosa cells actively participate in the follicular development by synthesizing important molecules to support the activity of pathways that are essential to oocyte development and genomic preservation. The computational Ingenuity Pathway Analysis (IPA) suggests that the identified proteins have well-established functions in the pathways of steroidogenesis, cell-to-cell signaling and interaction, molecular transport, the antioxidative system, interleukin 1 (IL-1) and IL-6 signaling, liver X receptor/retinoid X receptor (LXR/RXR) activation, and the interconnective insulin-like growth factor and lipid metabolism networks. The hFF peptide composition is likely to serve not only the inflammatory follicular state as has been previously suggested; rather, it is a highly diverse and multifunctional environment with several interconnected pathways. These results provide us with important knowledge related to the environment in which the oocyte develops as well as the molecular basis for controlling the process independently of blood supply.

Follicular fluid-specific distribution of vascular endothelial growth factor isoforms and sFlt-1 in patients undergoing IVF and their correlation with treatment outcomes.

OBJECTIVE: To investigate the distribution of vascular endothelial growth factor (VEGF) isoforms and soluble form of VEGF receptor 1 (sFlt-1) in the follicular fluid (FF) of in vitro fertilization (IVF) patients in relationship to age, body mass index (BMI), diagnosis of polycystic ovary syndrome (PCOS), and their correlation with IVF outcomes. DESIGN: Prospective study. MAIN OUTCOME MEASURES: VEGF( 121) and VEGF(165) isoforms were detected using Western blotting and pixel density analysis. The concentration of sFlt-1 was determined by enzyme-linked immunosorbent assay (ELISA). In vitro fertilization outcomes measured included number of oocytes retrieved, fertilization rate, and clinical pregnancy. Statistical analysis used the Kruskal-Wallis and Mann-Whitney U test where appropriate. RESULTS: There was a statistically significant association between higher VEGF(165) levels and the diagnosis of PCOS, BMI ≥ 30, and age ≥40 years. In vitro fertilization cycles resulting in pregnancy were linked to statistically lower VEGF(165) levels in the FF. No statistically significant trend was identified in levels of VEGF(121) or sFlt-1 relative to patient characteristics or IVF outcomes. CONCLUSION: Our results suggest that elevated VEGF(165) levels are associated with less favorable patient characteristics and clinical IVF outcomes.