Fetal Biometric Assessment and Infant Developmental Prognosis of the Tadalafil Treatment for Fetal Growth Restriction.

Background and Objectives: Tadalafil is expected to treat fetal growth restriction (FGR), a risk factor for stillbirth and neonatal morbidity. This study aimed to evaluate the fetal biometric growth pattern of fetuses with FGR treated with tadalafil by ultrasonographic assessment. Materials and Methods: This was a retrospective study. Fifty fetuses diagnosed with FGR and treated by maternal administration of tadalafil and ten controls who received conventional treatment at Mie University Hospital from 2015 to 2019 were assessed. Fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW) at the start of treatment and at two weeks and four weeks of treatment were mainly assessed by ultrasound examination. The Wilcoxon signed-rank test was used to assess the measures. The Kyoto Scale of Psychological Development (KSPD) was used to assess the developmental prognosis on tadalafil-treated children at 1.5 years of corrected age (CA) and 3 years old. Results: The median gestational age at the start of treatment was 30 and 31 weeks in the tadalafil and control groups, respectively, and the median gestational age at delivery was 37 weeks in both groups. The Z-score of HC was significantly increased at 4 weeks of treatment (p = 0.005), and the umbilical artery resistance index was significantly decreased (p = 0.049), while no significant difference was observed in the control group. The number of cases with an abnormal score of less than 70 on the KSPD test was 19% for P-M, 8% for C-A, 19% for L-S, and 11% for total area at 1.5 years CA. At 3 years old, the respective scores were 16%, 21%, 16%, and 16%. Conclusions: Tadalafil treatment for FGR may maintain fetal HC growth and infants' neuro-developmental prognosis.

The role of the brain-sparing effect of growth-restricted fetuses in newborn germinal matrix/intraventricular hemorrhage.

OBJECTIVES: The aim of the study was to evaluate the effect of the brain-sparing effect (BSE) of fetal growth restriction (FGR) in newborn germinal matrix/intraventricular hemorrhage (GM/IVH). METHODS: A total of 320 patients who delivered prior to the 34th gestational week were analyzed from data records. 201 patients were divided into two groups according to cerebro-placental ratio (CPR): early fetal growth restriction (FGR) with abnormal CPR group (n=104) and appropriate for gestational age with normal Doppler group (control) (n=97). Using the normal middle cerebral artery (MCA) Doppler as a reference, multivariate logistic regression analysis was used to assess the association between the BSE and the primary outcome. RESULTS: The rate of Grade I-II germinal matrix/intraventricular hemorrhage (GM/IVH) was 31(29.8%) in the group possessing early FGR with abnormal CPR and 7(7.2%) in the control group, showing a statistically significant difference. The rate of grade III-IV GM/IVH was 7(6.7%) in the group possessing early FGR with abnormal CPR and 2 (2.1%) in the control group, showing no statistically significant difference. We found that gestational age at delivery <32 weeks was an independent risk factor for GM/IVH. In addition, we found that other variables such as the presence of preeclampsia, fetal weight percentile <10, emergency CS delivery, 48-h completion after the first steroid administration and 24-h completion rate after MgSO4 administration were not independently associated with the primary outcome. CONCLUSIONS: Our results indicate that the rate of GM-IVH was increased in the group possessing early FGR with abnormal CPR; however, multivariate logistic regression analysis showed that BSE was not an independent risk factor for GM/IVH.

Do Doppler Changes Reflect Pathology of Placental Vascular Lesions in IUGR Pregnancies?

OBJECTIVES: Doppler assessment of uteroplacental (UP) and fetoplacental (FP) circulation detects abnormal waveforms in intrauterine growth-restricted (IUGR) pregnancies. Similarly, histopathology also reveals lesions of vascular compromise in IUGR placenta. We evaluated an association between Doppler and histopathological (HP) assessment of the maternal and fetal circulation in IUGR. METHODS: IUGR cases with both Doppler and histopathology assessment were selected from our database. Doppler patterns recorded UP and FP insufficiency. The HP vascular lesions were classified as maternal vascular underperfusion and fetal thrombotic vasculopathy (FTV). IUGRs were grouped based on (i) presence of preeclampsia (PE), (ii) clinical onset (early vs late) of IUGR (early onset [EO]/late onset), and (iii) gestational age (term, T/preterm, PT). RESULTS: Abnormal Doppler waveforms were present in 69 of the total 88 IUGR cases (78.4%). The most frequent pattern was fetoplacental insufficiency (FPI) (66%) which was combined with uteroplacental insufficiency (UPI) in 49%. HP showed vascular lesions in 52.3% and most frequent was FTV (38%). PE-associated IUGR (n = 49) had higher UPI pattern (75.5% vs 43.6%, P = .004), while normotensive IUGR had higher FPI pattern (28.2% vs 8.2%, P = .01). EO-IUGR (n = 55) and PT-IUGR (n = 52) had significant abnormal Doppler waveforms (P < .05) with higher combined patterns and brain sparing. Doppler was more sensitive for fetal vascular lesions than maternal (75.8% vs 66.7%). However, 42% of cases with normal Doppler findings showed HP vascular lesions. CONCLUSION: IUGR pregnancies harbor significant vascular compromise. Fetal circulatory lesions were more common in IUGR pregnancies. In a significant number of cases with normal Doppler report, vascular lesions were identified on histopathology, emphasizing placental examination in all cases of IUGR.

Evaluation of normalization of cerebro-placental ratio as a potential predictor for adverse outcome in SGA fetuses.

BACKGROUND: Intrauterine growth restriction accounts for a significant proportion of perinatal morbidity and mortality currently encountered in obstetric practice. The primary goal of antenatal care is the early recognition of such conditions to allow treatment and optimization of both maternal and fetal outcomes. Management of pregnancies complicated by intrauterine growth restriction remains one of the greatest challenges in obstetrics. Frequently, however, clinical evidence of underlying uteroplacental dysfunction may only emerge at a late stage in the disease process. With advanced disease the only therapeutic intervention is delivery of the fetus and placenta. The cerebroplacental ratio is gaining much interest as a useful tool in differentiating the at-risk fetus in both intrauterine growth restriction and the appropriate-for-gestational-age setting. The cerebroplacental ratio quantifies the redistribution of the cardiac output resulting in a brain-sparing effect. The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect is significantly associated with an adverse perinatal outcome in the intrauterine growth restriction cohort. OBJECTIVE: The aim of the Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction study was to evaluate the optimal management of fetuses with an estimated fetal weight <10th centile. The objective of this secondary analysis was to evaluate if normalizing cerebroplacental ratio predicts adverse perinatal outcome. STUDY DESIGN: In all, 1116 consecutive singleton pregnancies with intrauterine growth restriction completed the study protocol over 2 years at 7 centers, undergoing serial sonographic evaluation and multivessel Doppler measurement. Cerebroplacental ratio was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Abnormal cerebroplacental ratio was defined as <1.0. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death. RESULTS: Data for cerebroplacental ratio calculation were available in 881 cases, with a mean gestational age of 33 (interquartile range, 28.7-35.9) weeks. Of the 87 cases of abnormal serial cerebroplacental ratio with an initial value <1.0, 52% (n = 45) of cases remained abnormal and 22% of these (n = 10) had an adverse perinatal outcome. The remaining 48% (n = 42) demonstrated normalizing cerebroplacental ratio on serial sonography, and 5% of these (n = 2) had an adverse perinatal outcome. Mean gestation at delivery was 33.4 weeks (n = 45) in the continuing abnormal cerebroplacental ratio group and 36.5 weeks (n = 42) in the normalizing cerebroplacental ratio group (P value <.001). CONCLUSION: The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect was significantly associated with an adverse perinatal outcome in our intrauterine growth restriction cohort. It was hypothesized that a normalizing cerebroplacental ratio would be a further predictor of an adverse outcome due to the loss of this compensatory mechanism. However, in this subanalysis we did not demonstrate an additional poor prognostic effect when the cerebroplacental ratio value returned to a value >1.0. Overall, this secondary analysis demonstrated the importance of a serial abnormal cerebroplacental ratio value of <1 within the <34 weeks' gestation population. Contrary to our proposed hypothesis, we recognize that reversion of an abnormal cerebroplacental ratio to a normal ratio is not associated with a heightened degree of adverse perinatal outcome.

Role of the brain-sparing effect on retinopathy of prematurity in newborns with fetal growth restriction.

INTRODUCTION: This study aimed to investigate the role of the brain-sparing effect (BSE) on retinopathy of prematurity (ROP) in fetal growth restriction (FGR). METHODS: In this retrospective study, 127 pregnant women were divided into two groups considering the cerebroplacental ratio (CPR): FGR with abnormal CPR group (n = 74) and the appropriate for gestational age with normal Doppler group (n = 53). CPR was computed using the pulsatility index (PI) and resistance index (RI) to quantitate the waveforms [middle cerebral artery (MCA) PI/umbilical artery (UA) PI and MCA RI/UA RI: a result <1 was taken into account as abnormal]. ROP screening results of newborns were recorded from electronic files. RESULTS: After adjusting for co-variants, BSE was not related to ROP (adjusted odds ratio [aOR], 1.06; 95% confidence interval [CI], 0.23-4.95). Gestational age at delivery <30 weeks (aOR, 2.55; 95% CI, 1.04-6.93) and birth weight <1500 g (aOR, 5.15; 95% CI, 1.15-25.2) were independently associated with ROP. Preeclampsia, emergency cesarean section birth, or 48 h completion after the first steroid administration were not associated with ROP. CONCLUSIONS: Gestational age at delivery <30 weeks and birth weight <1500 g are independent risk factors for ROP in FGR whereas the BSE is not a risk factor.

Prenatal Predictors of Neurobehavioral Outcome in Children with Fetal Growth Restriction at 6 Years of Age: A Retrospective Cohort Study.

(1) Background: Fetal growth restriction (FGR) increases the risk of adverse neurodevelopmental outcomes, especially in preterm newborns. This study aims to describe the behavioral results of FGR at 6 years of age and to demonstrate the relationship of certain predictive factors with this development. (2) Methods: This retrospective cohort study included 70 children born in 2015 at the University Hospital Carlos Haya, Málaga, Spain who had been exposed to FGR during pregnancy; neonatal and infant data were recorded retrospectively. Children were assessed prospectively at 6 years of age by means of a strengths and difficulties questionnaire (SDQ) to study behavioral outcomes. (3) Results: We demonstrated that there are higher behavioral disability rates in children exposed to FGR during pregnancy and, in particular, high rates of hyperactivity or conduct problems. We also proved a negative relationship between the birth weight percentile and the total behavioral scale score, along with a positive correlation between hyperactivity and the emotional and behavioral scales. Learning difficulties were more frequent in early-onset FGR than in late-onset FGR. (4) Conclusions: Our study of behavioral development has demonstrated higher behavioral disability rates in children with FGR at 6 years of age; specifically, high rates of hyperactivity or conduct problems. At the same time, we have proved a negative relationship between the birth weight percentile and the total behavioral scale score.

Cerebroplacental ratio in prediction of adverse perinatal outcome and fetal heart rate disturbances in uncomplicated pregnancy at 40 weeks and beyond.

INTRODUCTION: The aim of the study was to determine the usefulness of Doppler velocimetry, based on cerebroplacental ratio (C/U) evaluation, in predicting intrapartum fetal heart rate abnormalities and adverse neonatal outcome in uncomplicated pregnancies at 40 weeks and beyond. MATERIAL AND METHODS: One hundred and forty-eight women in uncomplicated pregnancies, between 40 and 42 completed weeks, were divided into control and study groups: with the absence (n = 79) and with the presence of a fetal brain-sparing effect (n = 69), respectively. Pulsatility and resistance indices in the middle cerebral, the umbilical artery and the C/U ratio were evaluated daily by Doppler ultrasonography. C/U < 1.1 was reported as suggestive of a brain-sparing effect. Abnormal flow indices were analyzed and compared to adverse pregnancy and neonatal outcome determinants. RESULTS: In the abnormal C/U group the abnormal CTG records were significantly more frequently observed (62.3%) than in normal C/U group (19.0%) (p = 0.0001). The comparison of selected Doppler indices revealed that C/U showed the highest sensitivity in prediction of both the intrapartum abnormal FHR (74.1%) and the adverse neonatal outcome (87.8%). CONCLUSIONS: The C/U index shows the highest sensitivity in prediction of FHR abnormalities and adverse neonatal outcome in uncomplicated pregnancies at 40 weeks and beyond. The C/U index is useful in clinical practice in antenatal monitoring of these women in order to select those at high risk of intra- and postpartum complications.

Doppler velocimetry of ductus venous in preterm fetuses with brain sparing effect: neonatal outcome.

OBJECTIVE: to evaluate the relationship between ductus venous (DV) and Doppler velocimetry in neonatal outcome in severe compromised preterm fetuses. METHODS: the study was designed as an observational and cross-sectional study with 52 premature neonates with brain sparing effect. The criteria of neonatal severe morbidity were: severe intraventricular hemorrhage (grades 3 or 4), retinopathy of prematurity (grade 3 or 4), cystic periventricular leukomalatia, bronchopneumo dysplasia and neonatal mortality. The fetuses were divided in two groups: group 0 - all the fetuses with ventricular systole/atrial contraction (S/A) in DV ratio values less them 3.4; group 1 - fetuses with values of S/A ratio greater than 3.4. RESULTS: 42% of fetuses showed abnormal S/A ratio in DV and 48% showed birth weight below percentile 3 for gestational age. There was no statistical significance comparing the 02 groups according to bronchopneumo dysplasia, retinopathy of prematurity (grade 3 or 4) and intraventricular hemorrhage (grade 3 or 4). Only one fetus presented cystic periventricular leukomalatia. We found statistically significant association between abnormal DV S/A ratio and neonatal mortality (CI 95%, 1.28 -38.22, p< 0.002). CONCLUSIONS: our results suggest that abnormal DV blood flow detected by Doppler examination isn't associated with severe neonatal morbidity but with neonatal mortality.

Evaluation of fetal cerebral blood flow perfusion using power Doppler ultrasound angiography (3D-PDA) in growth-restricted fetuses.

OBJECTIVE: to explore the potential of 3D Power Doppler Angiography (3D PDA) to evaluate the cerebral circulation in normal and growth restricted fetuses (IUGR). STUDY DESIGN: in a pilot study, we enrolled 51 appropriate for gestational age (AGA) pregnancies and 17 singleton pregnancies presenting IUGR, all between 22 and 38 weeks of gestation. Using 3D power Doppler ultrasound, a -volume acquisition of the fetal brain was performed. Two regions of interest (ROI) were defined within the fetal brain. Zone 1 is anterior to the cavum septi pellucidi (CSP). Zone 2 is defined by a rectangle obtained tracing a contour -between the temporal bones as wide as the CSP, corresponding to the area of the middle cerebral artery. The Flow Index (FI), the Vascularization Index (VI), the Vascularization and Flow Index (VFI) were determined in both areas in both IUGR and AGA fetuses by a single operator. IUGR fetuses were divided into three groups: Group 1, with normal pulsatility index (PI) of umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV); Group 2, IUGR fetuses with abnormal UA PI, normal MCA PI, normal DV PI; in Group 3, IUGR fetuses with abnormal UA PI, MCA PI and DV PI. RESULTS: FI and VFI values of zone 1 were increased in Group 1.Values of VFI in zone 2 were increased in Group 2. CONCLUSIONS: Our findings are in line with recent studies in growth-restricted fetuses suggesting that the anterior -cerebral artery shows Doppler signs of vasodilatation before these are observed in the MCA, demonstrating the "frontal brain sparing effect".