Prediction of fetal growth restriction using estimated fetal weight vs a combined screening model in the third trimester.

OBJECTIVES: To compare the performance of third-trimester screening, based on estimated fetal weight centile (EFWc) vs a combined model including maternal baseline characteristics, fetoplacental ultrasound and maternal biochemical markers, for the prediction of small-for-gestational-age (SGA) neonates and late-onset fetal growth restriction (FGR). METHODS: This was a nested case-control study within a prospective cohort of 1590 singleton gestations undergoing third-trimester (32 + 0 to 36 + 6 weeks' gestation) evaluation. Maternal baseline characteristics, mean arterial pressure, fetoplacental ultrasound and circulating biochemical markers (placental growth factor (PlGF), lipocalin-2, unconjugated estriol and inhibin A) were assessed in all women who subsequently delivered a SGA neonate (n = 175), defined as birth weight < 10th centile according to customized standards, and in a control group (n = 875). Among SGA cases, those with birth weight < 3rd centile and/or abnormal uterine artery pulsatility index (UtA-PI) and/or abnormal cerebroplacental ratio (CPR) were classified as FGR. Logistic regression predictive models were developed for SGA and FGR, and their performance was compared with that obtained using EFWc alone. RESULTS: In SGA cases, EFWc, CPR Z-score and maternal serum concentrations of unconjugated estriol and PlGF were significantly lower, while mean UtA-PI Z-score and lipocalin-2 and inhibin A concentrations were significantly higher, compared with controls. Using EFWc alone, 52% (area under receiver-operating characteristics curve (AUC), 0.82 (95% CI, 0.77-0.85)) of SGA and 64% (AUC, 0.86 (95% CI, 0.81-0.91)) of FGR cases were predicted at a 10% false-positive rate. A combined screening model including a-priori risk (maternal characteristics), EFWc, UtA-PI, PlGF and estriol (with lipocalin-2 for SGA) achieved a detection rate of 61% (AUC, 0.86 (95% CI, 0.83-0.89)) for SGA cases and 77% (AUC, 0.92 (95% CI, 0.88-0.95)) for FGR. The combined model for the prediction of SGA and FGR performed significantly better than did using EFWc alone (P < 0.001 and P = 0.002, respectively). CONCLUSIONS: A multivariable integrative model of maternal characteristics, fetoplacental ultrasound and maternal biochemical markers modestly improved the detection of SGA and FGR cases at 32-36 weeks' gestation when compared with screening based on EFWc alone. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Performance of third-trimester combined screening model for prediction of adverse perinatal outcome.

OBJECTIVE: To explore the potential value of third-trimester combined screening for the prediction of adverse perinatal outcome (APO) in the general population and among small-for-gestational-age (SGA) fetuses. METHODS: This was a nested case-control study within a prospective cohort of 1590 singleton gestations undergoing third-trimester evaluation (32 + 0 to 36 + 6 weeks' gestation). Maternal baseline characteristics, mean arterial blood pressure, fetoplacental ultrasound and circulating biochemical markers (placental growth factor (PlGF), lipocalin-2, unconjugated estriol and inhibin A) were assessed in all women who subsequently had an APO (n = 148) and in a control group without perinatal complications (n = 902). APO was defined as the occurrence of stillbirth, umbilical artery cord blood pH < 7.15, 5-min Apgar score < 7 or emergency operative delivery for fetal distress. Logistic regression models were developed for the prediction of APO in the general population and among SGA cases (defined as customized birth weight < 10th centile). RESULTS: The prevalence of APO was 9.3% in the general population and 27.4% among SGA cases. In the general population, a combined screening model including a-priori risk (maternal characteristics), estimated fetal weight (EFW) centile, umbilical artery pulsatility index (UA-PI), estriol and PlGF achieved a detection rate for APO of 26% (area under receiver-operating characteristics curve (AUC), 0.59 (95% CI, 0.54-0.65)), at a 10% false-positive rate (FPR). Among SGA cases, a model including a-priori risk, EFW centile, UA-PI, cerebroplacental ratio, estriol and PlGF predicted 62% of APO (AUC, 0.86 (95% CI, 0.80-0.92)) at a FPR of 10%. CONCLUSIONS: The use of fetal ultrasound and maternal biochemical markers at 32-36 weeks provides a poor prediction of APO in the general population. Although it remains limited, the performance of the screening model is improved when applied to fetuses with suboptimal fetal growth. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Contingent versus routine third-trimester screening for late fetal growth restriction.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Correlation between histological signs of placental underperfusion and perinatal morbidity in late-onset small-for-gestational-age fetuses.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Angiogenic factors at diagnosis of late-onset small-for-gestational age and histological placental underperfusion.

OBJECTIVE: This study was designed to explore the association between angiogenic factors levels at diagnosis of small-for-gestational age (SGA) and placental underperfusion (PUP). METHODS: In a cohort of SGA singleton pregnancies, each delivered at >34 weeks, uterine (UtA), umbilical (UA), and middle cerebral (MCA) arteries were evaluated by Doppler upon diagnosis of SGA status. In addition, maternal circulating concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were assayed by ELISA, and each placenta was evaluated for histologic signs of PUP using a hierarchical and standardized classification system. Logistic regression was applied to analyze independent relationships (at diagnosis) between angiogenic factors and Doppler parameters. RESULTS: A total of 122 suspected SGA pregnancies were studied, 70 (57.4%) of which ultimately met PUP criteria. In this group, 85 placental findings qualified as PUP. Both mean UtA pulsatility index z-values (1.26 vs. 0.84; p = 0.038) and PlGF multiples of normal median (0.21 vs. 0.55; p = 0.002) differed significantly in pregnancies with and without PUP, respectively. By logistic regression, PlGF alone was independently predictive of PUP (OR = 0.11 [95% CI 0.025-0.57]; p = 0.008). DISCUSSION: Histologic placental abnormalities in term SGA neonates reflect latent insufficiency in uteroplacental blood supply. The heightened risk of adverse perinatal outcomes in this context underscores a need for new Doppler or biochemical prenatal markers of placental disease. Angiogenic factors may be pivotal identifying SGA neonates. CONCLUSIONS: Diminished circulating levels of placental growth factor, determined upon discovery of SGA status, are associated with histologic evidence of PUP.

Association of Doppler parameters with placental signs of underperfusion in late-onset small-for-gestational-age pregnancies.

OBJECTIVE: To elucidate the association between Doppler parameters and histological signs of placental underperfusion in late-onset small-for-gestational-age (SGA) babies. METHODS: 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 weight < 10(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. RESULTS: 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%; P < 0.001) 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 UVBF > 82 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-PI > 95(th) percentile (risk 94.4%). CONCLUSIONS: 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.

Placental findings in late-onset SGA births without Doppler signs of placental insufficiency.

OBJECTIVES: To describe placental pathological findings in late-onset small-for-gestational age (SGA) births for which Doppler signs of placental insufficiency are lacking. METHODS: A series of placentas were evaluated from singleton pregnancies of SGA births (birth weight below the 10th percentile) delivered after 34 weeks with normal umbilical artery Doppler (pulsatility index below the 95th percentile), that were matched by gestational age with adequate-for-gestational age (AGA) controls. Using a hierarchical and standardized system, placental lesions were classified histologically as consequence of maternal underperfusion, fetal underperfusion or inflammation. RESULTS: A total of 284 placentas were evaluated (142 SGA and 142 AGA). In the SGA group, 54.2% (77/142) of the placentas had weights below the 3rd percentile for GA while it was a 9.9% (14/142) in the AGA group (p < 0.001). Only 21.8% (31/142) of SGA placentas were free of histological abnormalities, while it was 74.6% (106/142) in the AGA group (p < 0.001). In the abnormal SGA placentas (111/142) there were a total of 161 lesions, attributable to MUP in 64% (103/161), FUP in 15.5% (25/161), and inflammation in 20.5% (33/161). DISCUSSION: In most placentas of term SGA neonates with normal UA Doppler histological abnormalities secondary to maternal underperfusion prevail, reflecting latent insufficiency in uteroplacental blood supply. This is consistent with the higher risk of adverse perinatal outcome reported in this population and underscores a need for new markers of placental disease. CONCLUSIONS: A significant proportion of late-onset SGA births with normal umbilical artery Doppler may still be explained by placental insufficiency.

Added value of umbilical vein flow as a predictor of perinatal outcome in term small-for-gestational-age fetuses.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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-PI > 1.46 (risk 15.6%); MCA-PI ≤ 1.46 and UV blood flow > 68 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 flow > 68 mL/min/kg or UV flow ≤ 68 mL/min/kg and MCA-PI > 1.23 (risk ≤ 10%); and UV flow ≤ 68 mL/min/kg and MCA-PI ≤ 1.23 (risk 39.1%). CONCLUSION: 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.

Prediction of preterm birth using the cervical consistency index.

OBJECTIVES: To assess the diagnostic power of a new cervical consistency index (CCI) obtained using transvaginal sonography for the prediction of spontaneous preterm birth (PTB) and to establish reference ranges for this new variable. METHODS: Included in this prospective cross-sectional study were 1115 singleton pregnancies at 5-36 weeks of gestation. Anteroposterior cervical diameter was measured before (AP) and after (AP') application of pressure on the cervix using the transvaginal probe. The index was calculated using the formula: CCI=((AP'/AP) × 100). Cervical length was also measured. The outcomes evaluated were spontaneous PTB before 32, 34 and 37 weeks. Logistic regression and analysis of receiver-operating characteristics (ROC) curves were performed to evaluate the diagnostic power of CCI and cervical length (adjusted for gestational age). Intraclass correlation coefficients (ICCs) and Bland-Altman analysis were used to evaluate intra- and interobserver variability. RESULTS: In the 1031 women with follow-up, the rate of spontaneous PTB before 32 weeks was 0.87%, before 34 weeks was 2.13% and before 37 weeks was 7.76% (n=80). There were 31 (3.01%) iatrogenic PTBs before 37 weeks. An inverse linear correlation between gestational age and CCI was observed, with regression equation: CCI (in %)=89.8 - 1.35 × (GA in weeks); r(2)=0.66, P<0.001. Cervical length showed an inverse quadratic, though non-significant, relationship with gestational age: CL (in mm)=31.084 - 0.0278× (GA in weeks)(2) + 1.0772× (GA in weeks); r(2)=0.076, P<0.14. The intra- and interobserver ICCs for CCI were 0.99 (95% CI, 0.988-0.994) and 0.98 (95% CI, 0.973-0.987), respectively. The area under the ROC curve for CCI in the prediction of spontaneous PTB before 32 weeks was 0.947, for spontaneous PTB before 34 weeks it was 0.943 and for spontaneous PTB before 37 weeks it was 0.907. For a 5% screen-positive rate, CCI had a sensitivity of 67%, 64% and 45% for prediction of spontaneous PTB before 32, 34 and 37 weeks, respectively, with equivalent values of 11%, 9% and 11% for cervical length. CONCLUSIONS: CCI shows a clear inverse linear relationship with GA. Assessment of CCI is reproducible and is effective in the prediction of spontaneous PTB. This new variable appears to provide better prediction of spontaneous PTB than does cervical length.