Association of fetal growth restriction and stillbirth in twin compared with singleton pregnancies.

OBJECTIVE: Twin pregnancies are at an increased risk of stillbirth compared to singletons. Fetal growth restriction (FGR) is a leading cause of perinatal mortality and morbidity, in both singleton and multiple pregnancies. Whether the contribution of FGR to stillbirth in twin pregnancies differs from that in singletons is yet to be determined. The main aim of this study was to determine the association between FGR and stillbirth in twin compared to singleton pregnancies. The secondary objectives include an assessment of the contribution of FGR to stillbirths, stratified by gestational age at delivery. Furthermore, we aimed to compare the association between FGR and stillbirth in twin pregnancies using the twin-specific versus singleton birthweight charts, stratified by chorionicity. METHODS: This was a cross-sectional study including pregnancies receiving obstetric care and birth at St George's Hospital, London. The exclusion criteria included triplet and higher order pregnancies, those resulting in miscarriage or livebirths at or prior to 23+6 weeks, or had a termination of pregnancy, or with missing data on the gestational age at birth. FGR and small for gestational age (SGA) were defined as birthweight <5th and <10th centile, respectively. While standard logistic regression was used for singleton pregnancies, the association of FGR and SGA designation with stillbirth in twin pregnancies was investigated with mixed-effects logistic regression models. For twin pregnancies, intercepts were allowed to vary for twin pairs to account for inter-twin dependency. Analyses were stratified by gestational age at delivery and chorionicity. RESULTS: The study included 95,342 singleton and 3,576 twin pregnancies. There were 494 (0.52%) stillbirths in singleton and 41 (1.15%) stillbirths in twin pregnancies (17 dichorionic and 24 monochorionic). FGR and SGA were significantly associated with stillbirth in singleton pregnancies, across all gestational ages at delivery (before 32 weeks- SGA: OR 2.36; 95% CI 1.78-3.13, p<0.001 and FGR: OR 2.67; 95% CI 2.02- 3.55, p<0.001; between 32-36 weeks- SGA: OR 2.70; 95% CI 1.71-4.31, p<0.001 and FGR: OR 2.82; 95% CI 1.78- 4.47, p<0.001; above 36 weeks- SGA: OR 3.85; 95% CI 2.83 - 5.21, p<0.001 and FGR: OR 4.43; 95% CI 3.16 - 6.12, p<0.001) A greater proportion of fetuses from twin pregnancies were diagnosed as SGA and FGR when singleton compared to the twin-specific chart was used (48.43% vs. 9.12%, and 36.73% vs. 6.23%, respectively). When stratified by gestational age at delivery, both SGA and FGR determined by the twin-specific charts were associated with significantly increased odds of having a stillbirth for those delivered before 32 weeks (SGA: OR 3.87; 95% CI 1.56-9.50, p=0.003 and FGR: OR 5.26; 95% CI 2.11-13.01, p<0.001), those delivered between 32-36 weeks (SGA: OR 6.67; 95% CI 2.11-20.41, p=0.001 and FGR: OR 9.54; 95% CI 3.01-29.40, p<0.001) and those delivered beyond 36 weeks (SGA: OR 12.68 95% CI 2.47-58,15, p=0.001 and FGR: OR 23.84; 95% CI 4.62-110.25, p<0.001), whereas the association of stillbirth with either SGA or FGR was inconsistent when analysed using singleton charts (before 32 weeks- SGA: p=0.014 and FGR: p=0.005; between 32-36 weeks- SGA: p=0.036 and FGR: p=0.008; above 36 weeks- SGA: p=0.080 and FGR: p=0.063). For dichorionic twins delivered before 32 weeks, the odds of an SGA or FGR fetus having a stillbirth was increased when analysed using twin-specific charts. In contrast, monochorionic twins delivered before 32 weeks showed lower and non-significant associations with stillbirth for both SGA and FGR cases using either twin-specific or singleton charts. In dichorionic twin pregnancies delivered between 32-36 weeks, the OR for stillbirth of SGA using twin birthweight chart was 6.70 (95% CI 0.80-56.46, p=0.059), and using singleton chart was 0.92 (95% CI 0.11-7.71, p=0.934) and statistically non-significant. Similarly, the OR for stillbirth of FGR using twin birthweight chart and singleton chart was 9.59 (95% CI 1.14-81.06, p=0.025), and 1.40 (95% CI 0.17-11.76, p=0.735), respectively. On the other hand, in monochorionic twin pregnancies delivered between 32-36 weeks, the OR for stillbirth of SGA and FGR using twin birthweight chart was 9.37 (95% CI 2.20- 37.72, p=0.001), and 13.55 (95% CI 3.12 - 55.94 p < 0.001) respectively. CONCLUSIONS: Our study demonstrates a significant association between SGA, particularly for FGR, with increased odds of stillbirths in singleton pregnancies across all gestational ages. For twin pregnancies, when twin-specific charts were used, SGA and in particular FGR were associated with a significantly increased risk of stillbirth, across all gestational ages at delivery. This article is protected by copyright. All rights reserved.

Quality assessment of fetal middle cerebral and umbilical artery Doppler images using an objective scale within an international randomized controlled trial.

OBJECTIVES: To determine the quality of Doppler images of the fetal middle cerebral artery (MCA) and umbilical artery (UA) using an objective scale, and to determine the reliability of this scale, within a multicenter randomized controlled trial (Revealed versus concealed criteria for placental insufficiency in unselected obstetric population in late pregnancy (Ratio37)). METHODS: The Ratio37 trial is an ongoing randomized, open-label, multicenter controlled study of women with a low-risk pregnancy recruited at 20 weeks. Doppler measurements of the fetal MCA and UA were performed at 37 weeks. Twenty patients from each of the six participating centers were selected randomly, with two images evaluated per patient (one each for the MCA and UA). The quality of a total of 240 images was evaluated by six experts, scored on an objective scale of six items. Inter- and intrarater reliability was assessed using the Fleiss-modified kappa statistic for ordinal scales. RESULTS: On average, 89.2% of MCA images and 85.0% of UA images were rated as being of perfect (score of 6) or almost perfect (score of 5) quality. Kappa values for intrarater reliability of quality assessment were 0.90 (95% CI, 0.88-0.92) and 0.90 (95% CI, 0.88-0.93) for the MCA and UA, respectively. The corresponding inter-rater reliability values were 0.85 (95% CI, 0.81-0.89) and 0.84 (95% CI, 0.80-0.89), respectively. CONCLUSION: The quality of MCA and UA Doppler ultrasound images can be evaluated reliably using an objective scale. Over 85% of images, which were obtained by operators from a broad range of clinical practices within a multicenter study, were rated as being of perfect or almost perfect quality. Intra- and inter-rater reliability of quality assessment was very good. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Perinatal loss at term: role of uteroplacental and fetal Doppler assessment.

OBJECTIVE: To examine the associations of uterine artery (UtA) Doppler indices and cerebroplacental ratio (CPR) with perinatal outcome at term. METHODS: This was a retrospective cohort study conducted at a tertiary referral center that included all singleton pregnancies undergoing ultrasound assessment in the third trimester that subsequently delivered at term. Fetal biometry and Doppler assessment, including that of the umbilical artery (UA), fetal middle cerebral artery (MCA) and UtA, were recorded. Data were corrected for gestational age, and CPR was calculated as the ratio of MCA pulsatility index (PI) to UA-PI. Logistic regression analysis was conducted to examine for independent predictors of adverse perinatal outcome. RESULTS: The study included 7013 pregnancies, 12 of which were complicated by perinatal death. When compared with pregnancies resulting in perinatal survival, pregnancies complicated by perinatal death had a significantly higher proportion of small-for-gestational-age infants (25.0% vs 5%; P = 0.001) and a higher incidence of low (< 5th centile) CPR (16.7% vs 4.5%; P = 0.041). A subgroup analysis comparing 1527 low-risk pregnancies that resulted in fetal survival with pregnancies complicated by perinatal death demonstrated that UtA-PI multiples of the median (MoM), CPR < 5th centile and estimated fetal weight (EFW) centile were all associated significantly with the risk of perinatal death at term (all P < 0.05). After adjusting for confounding variables, only EFW centile (odds ratio (OR) 0.96 (95% CI, 0.93-0.99); P = 0.003) and UtA-PI MoM (OR 13.10 (95%CI, 1.95-87.89); P = 0.008) remained independent predictors of perinatal death in the low-risk cohort. CONCLUSION: High UtA-PI at term is associated independently with an increased risk of adverse perinatal outcome, regardless of fetal size. These results suggest that perinatal mortality at term is related not only to EFW and fetal redistribution (CPR), but also to indices of uterine perfusion. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Reduced fetal movements and cerebroplacental ratio: evidence for worsening fetal hypoxemia.

OBJECTIVE: To investigate the fetal cerebroplacental ratio (CPR) in women presenting with reduced fetal movements (RFM). METHODS: This was a retrospective cohort study of data collected over an 8-year period at a fetal medicine unit at a tertiary referral center. The cohort comprised 4500 singleton pregnancies presenting with RFM at or after 36 weeks' gestation and 1527 control pregnancies at a similar gestational age without RFM. Fetal biometry and Doppler parameters were recorded and converted into centiles and multiples of the median (MoM). CPR was defined as the ratio between the fetal middle cerebral artery (MCA) pulsatility index (PI) and the umbilical artery (UA) PI. Subgroup analysis for fetal size and for single vs multiple episodes of RFM was performed. RESULTS: Compared with controls, pregnancies with RFM had lower MCA-PI MoM (median, 0.95 vs 0.97; P < 0.001) and CPR MoM (median, 0.97 vs 0.99; P = 0.018). Compared with women presenting with single episodes of RFM, pregnancies with multiple episodes (≥ 2 episodes) had lower CPR MoM (median, 0.94 vs 0.98; P = 0.003). On subgroup analysis for fetal size, compared with controls, appropriate-for-gestational-age fetuses in the RFM group had lower MCA-PI MoM (median, 0.96 vs 0.97; P = 0.003) and higher rate of CPR below the 5th centile (5.3% vs 3.6%; P = 0.015). Logistic regression analysis demonstrated an association of risk of recurrent RFM with maternal age (OR, 0.96; 95% CI, 0.93-0.99), non-Caucasian ethnicity (OR, 0.72; 95% CI, 0.53-0.97), estimated fetal weight centile (OR, 1.01; 95% CI, 1.00-1.02) and CPR MoM (OR, 0.24; 95% CI, 0.12-0.47). CONCLUSION: Pregnancies complicated by multiple episodes of RFM show significantly lower CPR MoM and MCA-PI MoM compared with those with single episodes and controls. This is likely to be due to worsening fetal hypoxemia in women presenting with recurrent RFM. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Birth-weight differences at term are explained by placental dysfunction and not by maternal ethnicity.

OBJECTIVE: To investigate the influence of ethnicity, fetal gender and placental dysfunction on birth weight (BW) in term fetuses of South Asian and Caucasian origin. METHODS: This was a retrospective study of 627 term pregnancies assessed at two public tertiary hospitals in Spain and Sri Lanka. All fetuses underwent biometry and Doppler examinations within 2 weeks of delivery. The influences of fetal gender and ethnicity, gestational age (GA) at delivery, cerebroplacental ratio (CPR) and maternal age, height, weight and parity on BW were evaluated by multivariable regression analysis. RESULTS: Fetuses born in Sri Lanka were smaller than those born in Spain (mean BW = 3026 ± 449 g vs 3295 ± 444 g; P < 0.001). Multivariable regression analysis demonstrated that GA at delivery, maternal weight, CPR, maternal height and fetal gender (estimates = 0.168, P < 0.001; 0.006, P < 0.001; 0.092, P = 0.003; 0.009, P = 0.002; 0.081, P = 0.01, respectively) were associated significantly with BW. Conversely, no significant association was noted for maternal ethnicity, age or parity (estimates = -0.010, P = 0.831; 0.005, P = 0.127; 0.035, P = 0.086, respectively). The findings were unchanged when the analysis was repeated using INTERGROWTH-21st fetal weight centiles instead of BW (log odds, -0.175, P = 0.170 and 0.321, P < 0.001, respectively for ethnicity and CPR). CONCLUSION: Fetal BW variation at term is less dependent on ethnic origin and better explained by placental dysfunction. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Value of third-trimester cerebroplacental ratio and uterine artery Doppler indices as predictors of stillbirth and perinatal loss.

OBJECTIVE: Placental insufficiency contributes to the risk of stillbirth. Cerebroplacental ratio (CPR) is an emerging marker of placental insufficiency. The aim of this study was to evaluate the association of third-trimester fetal CPR, uterine artery (UtA) Doppler and estimated fetal weight (EFW) with stillbirth and perinatal death. METHODS: This was a retrospective cohort study including 2812 women with a singleton pregnancy who underwent an ultrasound scan in the third trimester. EFWs were converted into centiles, and Doppler indices (UtA and CPR) were converted into multiples of the median (MoM), adjusting for gestational age. Regression analysis was performed to identify, and adjust for, potential confounders, and receiver-operating characteristics (ROC) curve analysis was used to assess the predictive value. RESULTS: When adjusting for EFW centile and UtA mean pulsatility index (UtA-PI) MoM, CPR-MoM remained an independent predictor of stillbirth (odds ratio (OR) = 0.003 (95% CI, 0.00-0.11), P = 0.003) and perinatal mortality (OR = 0.001 (95% CI, 0.00-0.03), P < 0.001). UtA-PI ≥ 1.5 MoM was significantly associated with low CPR-MoM, even after adjusting for EFW centile (OR = 5.22 (95% CI, 3.88-7.04), P < 0.001) or small-for-gestational age (SGA; OR = 4.73 (95% CI, 3.49-6.41), P < 0.001). These associations remained significant, even when excluding pregnancies with SGA or including only cases in which Doppler indices were recorded at term (P < 0.01). For prediction of stillbirth, the area under the ROC curve, using a combination of these three parameters, was 0.88 (95% CI, 0.77-0.99) with a sensitivity of 66.7%, specificity of 92.1%, positive likelihood ratio (LR) of 8.46 and negative LR of 0.36. CONCLUSIONS: Third-trimester CPR is an independent predictor of stillbirth and perinatal mortality. The role of UtA Doppler, CPR and EFW in assessing risk of adverse pregnancy outcome should be evaluated prospectively.

Poor neonatal acid-base status in term fetuses with low cerebroplacental ratio.

OBJECTIVE: To determine whether small- and appropriate-for-gestational-age (SGA and AGA) term fetuses with a low cerebroplacental ratio (CPR) have worse neonatal acid-base status than those with normal CPR. METHODS: This was a retrospective study of 2927 term fetuses divided into groups according to birth-weight centile and CPR multiple of the median. The acid-base status at birth as determined by arterial and venous umbilical cord blood pH was compared between weight-centile groups with and without low CPR. RESULTS: CPR was better correlated with umbilical cord blood pH (arterial pH, r(2) = 0.008, P < 0.0001 and venous pH, r(2) = 0.01, P < 0.0001) than was birth weight (arterial pH, r(2) = 0.001, P =0.180 and venous pH, r(2) = 0.005, P < 0.001). AGA fetuses with low CPR were more academic than were those with normal CPR (P = 0.0359 and 0.0006, respectively, for arterial and venous pH). CONCLUSIONS: The findings of this study demonstrate that low CPR in AGA fetuses is an equally important marker of low neonatal pH secondary to placental underperfusion as is being SGA. Although the relative importance of low CPR and birth weight in identifying pregnancies at risk of placental hypoxemia and adverse fetal and neonatal outcome remains to be determined, this finding may be of particular value in the prediction and prevention of stillbirth and long-term neurodevelopmental disability.

Widening of the femoral proximal diaphysis--metaphysis angle in fetuses with achondroplasia.

OBJECTIVES: It has recently been reported that fetuses with achondroplasia have a wider than expected femoral proximal diaphysis-metaphysis angle (femoral angle). The aim of this case-control study was to investigate this finding. METHODS: Cases with confirmed achondroplasia (n = 6), small-for-gestational-age fetuses (n = 70) and a group of normal fetuses (n = 377) were included in this study. The ultrasound image of the femur was examined by two independent experienced observers blinded to the diagnosis, who measured the femoral angle. These values were converted into multiples of the expected median (MoM), after adjustment for gestational age and femur length. Prevalence of various prenatal ultrasound signs of achondroplasia was determined in affected fetuses. Intra- and interobserver agreement of measurement of femoral angle was assessed using 95% limits of agreement and kappa statistics. RESULTS: The femoral angle can be measured accurately by ultrasound, and increases with both increasing gestational age and increasing femur length. The femoral angle-MoM was significantly higher in fetuses with achondroplasia than in the control group (1.36 vs 1.00 MoM, P < 0.001) and in the SGA group (1.36 vs 1.04 MoM, P < 0.001). It measured more than 130° in five of the six cases with achondroplasia (83.3%), which was the most consistent finding other than shortening of the long bones. CONCLUSIONS: The femoral angle is wider in fetuses with achondroplasia. This new ultrasound sign appears promising as an additional discriminatory marker when clinicians are faced with a case of short long bones in the third trimester.

Changes in fetal Doppler indices as a marker of failure to reach growth potential at term.

OBJECTIVE: To evaluate whether changes in the middle cerebral artery (MCA), umbilical artery (UA) and cerebroplacental ratio (CPR) Doppler indices at term might be used to identify those appropriate-for-gestational-age (AGA) fetuses that are failing to reach their growth potential (FRGP). METHODS: This was a retrospective cohort study of data obtained in a single tertiary referral center over a 10-year period from 2002 to 2012. The UA pulsatility index (PI), MCA-PI and CPR were recorded between 37+0 and 41+6 weeks within 14 days before delivery. The Doppler parameters were converted into multiples of the median (MoM), adjusting for gestational age, and their correlation with birth-weight (BW) centiles was evaluated by means of regression analysis. Doppler indices were also grouped according to BW quartiles and compared using Kruskal-Wallis and Dunn's post-hoc tests. RESULTS: The study included 11576 term fetuses, with 8645 (74.7%) classified as AGA. Within the AGA group, fetuses with lower BW had significantly higher UA-PI, lower MCA-PI and lower CPR MoM values. Large-for-gestational-age (LGA) fetuses were considered as the group least likely to be growth-restricted. The CPR MoM < 5(th) centile (0.6765 MoM) in these fetuses was used as a threshold for diagnosing FRGP. Using this definition, in the AGA pregnancies the percentage of fetuses with FRGP was 1% in the 75-90(th) BW centile group, 1.7% in the 50-75(th) centile group, 2.9% in the 25-50(th) centile group and 6.7% in the 10-25(th) centile group. CONCLUSION: AGA pregnancies may present with fetal cerebral and placental blood flow redistribution indicative of fetal hypoxemia. Fetal Doppler assessment may be of value in detecting AGA pregnancies that are subject to placental insufficiency, fetal hypoxemia and FRGP. Future studies are needed to evaluate the appropriate threshold for the diagnosis of FRGP and the diagnostic performance of this new approach for the management of growth disorders.

Reproducibility of the fetal cerebral vessels assessment in full and late term pregnancies.

Objective: Data concerning feasibility of the fetal cerebral Doppler examination in full term and late term pregnancy is lacking. Our purpose was to perform an evaluation of these arteries with power Doppler ultrasound, calculating the percentage of identification and measurement and the intraobserver reproducibility.Methods: This was a cross sectional study evaluating a population of 578 normally grown fetuses divided according to the week of examination. The first group included fetuses examined at week 40 (N = 323) and the second fetuses examined at week 41 (N = 255). The three major branches of the internal carotid artery (anterior, middle and posterior cerebral arteries, ACA, middle cerebral artery (MCA), posterior cerebral arteries (PCA)) and their anastomosis (A1, A2, P1, P2) were examined with power Doppler ultrasonography by three independent ultrasonographers. The proportion of vessel identified and measured was calculated and the reproducibility among the three operators was investigated.Results: The major arteries at the circle of Willis were fully identified/measured in 65/56 and 62/48% of fetuses at 40 and 41 weeks. The MCA obtained the higher percentage of identification and measurement at both periods (> 80 and >70%). The entire set of anastomosis were less frequently identified/measured at both periods (50/< 50% of cases), especially in the A2 segment. The best agreement was obtained in the MCA and the worst in the PCA-P1 segment.Conclusions: At 40 and 41 weeks, the fetal cerebral vessels, especially the MCA, are suitable for power Doppler evaluation, providing an interesting tool to evaluate fetal hemodynamics in full and late term pregnancy.