Association of umbilical vein flow with abnormal fetal growth and adverse perinatal outcome in low-risk population: multicenter prospective study.

OBJECTIVES: To investigate the relationship of umbilical vein flow (UVF) measured close to term with abnormal fetal growth and adverse perinatal outcome in a cohort of pregnancies at low risk of placental insufficiency. METHODS: This was a prospective multicenter observational study conducted across two tertiary maternity units. Patients with a singleton appropriate-for-gestational-age fetus between 35 and 38 weeks' gestation were included. Pregnancies at higher risk of placental insufficiency or with fetal anomalies were excluded. At ultrasound examination, the abdominal circumference (AC), umbilical vein diameter and peak velocity of the umbilical vein were measured, and, using these variables, a new variable, UVF/AC, was calculated. The primary outcome was the occurrence of severely stunted fetal growth, defined as a greater than 40-percentile drop between estimated fetal weight at the third-trimester ultrasound and birth weight between the third-trimester ultrasound and delivery. The occurrence of adverse perinatal outcome, defined as one of the following: neonatal acidosis (umbilical artery pH < 7.15 and/or base excess > 12 mmol/L) at birth, 5-min Apgar score < 7, neonatal resuscitation or neonatal intensive care unit admission, was analyzed as a secondary outcome. RESULTS: Between April 2021 and March 2023, 365 women were included in the study. The mean UVF/AC at enrolment was 6.4 ± 2.6 mL/min/cm, and 35 (9.6%) cases were affected by severely stunted fetal growth. Severely stunted fetal growth was associated with a lower mean UVF/AC (5.4 ± 2.6 vs 6.5 ± 2.6 mL/min/cm; P = 0.02) and a higher frequency of UVF/AC < 10th percentile (8/35 (22.9%) vs 28/330 (8.5%); P = 0.01). Moreover, UVF/AC showed an area under the receiver-operating-characteristics curve (AUC) of 0.65 (95% CI, 0.55-0.75; P = 0.004) in predicting the occurrence of severely stunted fetal growth, and the optimal cut-off value of UVF/AC for discriminating between normal and severely stunted fetal growth was 7.2 mL/min/cm. This value was associated with a sensitivity and specificity of 0.77 (95% CI, 0.60-0.90) and 0.33 (95% CI, 0.28-0.39), and positive and negative predictive values of 0.11 (95% CI, 0.07-0.15) and 0.93 (95% CI, 0.87-0.97), respectively. Regarding the occurrence of adverse perinatal outcome, this was associated independently with maternal age (adjusted odds ratio (aOR), 0.93 (95% CI, 0.87-0.99); P = 0.04), UVF/AC Z-score (aOR, 0.53 (95% CI, 0.30-0.87); P = 0.01) and augmentation of labor (aOR, 2.69 (95% CI, 1.28-5.69); P = 0.009). UVF/AC showed an AUC of 0.65 (95% CI, 0.56-0.73; P = 0.005) in predicting the occurrence of adverse perinatal outcome, and the optimal cut-off value of UVF/AC for discriminating between normal and adverse perinatal outcome was 6.7 mL/min/cm. This value was associated with a sensitivity and specificity of 0.70 (95% CI, 0.54-0.83) and 0.40 (95% CI, 0.34-0.45), and positive and negative predictive values of 0.14 (95% CI, 0.09-0.19) and 0.91 (95% CI, 0.85-0.95), respectively. CONCLUSIONS: Our data demonstrate an association between reduced UVF close to term, severely stunted fetal growth and adverse perinatal outcome in a cohort of low-risk pregnant women, with a moderate ability to rule out and a poor ability to rule in either outcome. Further studies are needed to establish whether the assessment of UVF can improve the identification of fetuses at risk of subclinical placental insufficiency and adverse perinatal outcome. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Longitudinal Doppler Assessments in Late Preterm Fetal Growth Restriction.

PURPOSE: To assess the longitudinal variation of the ratio of umbilical and cerebral artery pulsatility index (UCR) in late preterm fetal growth restriction (FGR). MATERIALS AND METHODS: A prospective European multicenter observational study included women with a singleton pregnancy, 32+ 0-36+ 6, at risk of FGR (estimated fetal weight [EFW] or abdominal circumference [AC] < 10th percentile, abnormal arterial Doppler or fall in AC from 20-week scan of > 40 percentile points). The primary outcome was a composite of abnormal condition at birth or major neonatal morbidity. UCR was categorized as normal (< 0.9) or abnormal (≥ 0.9). UCR was assessed by gestational age at measurement interval to delivery, and by individual linear regression coefficient in women with two or more measurements. RESULTS: 856 women had 2770 measurements; 696 (81 %) had more than one measurement (median 3 (IQR 2-4). At inclusion, 63 (7 %) a UCR ≥ 0.9. These delivered earlier and had a lower birth weight and higher incidence of adverse outcome (30 % vs. 9 %, relative risk 3.2; 95 %CI 2.1-5.0) than women with a normal UCR at inclusion. Repeated measurements after an abnormal UCR at inclusion were abnormal again in 67 % (95 %CI 55-80), but after a normal UCR the chance of finding an abnormal UCR was 6 % (95 %CI 5-7 %). The risk of composite adverse outcome was similar using the first or subsequent UCR values. CONCLUSION: An abnormal UCR is likely to be abnormal again at a later measurement, while after a normal UCR the chance of an abnormal UCR is 5-7 % when repeated weekly. Repeated measurements do not predict outcome better than the first measurement, most likely due to the most compromised fetuses being delivered after an abnormal UCR.

Third-trimester ultrasound for antenatal diagnosis of placenta accreta spectrum in women with placenta previa: results from the ADoPAD study.

OBJECTIVE: To evaluate the performance of third-trimester ultrasound for the diagnosis of clinically significant placenta accreta spectrum disorder (PAS) in women with low-lying placenta or placenta previa. METHODS: This was a prospective multicenter study of pregnant women aged ≥ 18 years who were diagnosed with low-lying placenta (< 20 mm from the internal cervical os) or placenta previa (covering the internal cervical os) on ultrasound at ≥ 26 + 0 weeks' gestation, between October 2014 and January 2019. Ultrasound suspicion of PAS was raised in the presence of at least one of these signs on grayscale ultrasound: (1) obliteration of the hypoechogenic space between the uterus and the placenta; (2) interruption of the hyperechogenic interface between the uterine serosa and the bladder wall; (3) abnormal placental lacunae. Histopathological examinations were performed according to a predefined protocol, with pathologists blinded to the ultrasound findings. To assess the ability of ultrasound to detect clinically significant PAS, a composite outcome comprising the need for active management at delivery and histopathological confirmation of PAS was considered the reference standard. PAS was considered to be clinically significant if, in addition to histological confirmation, at least one of these procedures was carried out after delivery: use of hemostatic intrauterine balloon, compressive uterine suture, peripartum hysterectomy, uterine/hypogastric artery ligation or uterine artery embolization. The diagnostic performance of each ultrasound sign for clinically significant PAS was evaluated in all women and in the subgroup who had at least one previous Cesarean section and anterior placenta. Post-test probability was assessed using Fagan nomograms. RESULTS: A total of 568 women underwent transabdominal and transvaginal ultrasound examinations during the study period. Of these, 95 delivered in local hospitals, and placental pathology according to the study protocol was therefore not available. Among the 473 women for whom placental pathology was available, clinically significant PAS was diagnosed in 99 (21%), comprising 36 cases of placenta accreta, 19 of placenta increta and 44 of placenta percreta. The median gestational age at the time of ultrasound assessment was 31.4 (interquartile range, 28.6-34.4) weeks. A normal hypoechogenic space between the uterus and the placenta reduced the post-test probability of clinically significant PAS from 21% to 5% in women with low-lying placenta or placenta previa in the third trimester of pregnancy and from 62% to 9% in the subgroup with previous Cesarean section and anterior placenta. The absence of placental lacunae reduced the post-test probability of clinically significant PAS from 21% to 9% in women with low-lying placenta or placenta previa in the third trimester of pregnancy and from 62% to 36% in the subgroup with previous Cesarean section and anterior placenta. When abnormal placental lacunae were seen on ultrasound, the post-test probability of clinically significant PAS increased from 21% to 59% in the whole cohort and from 62% to 78% in the subgroup with previous Cesarean section and anterior placenta. An interrupted hyperechogenic interface between the uterine serosa and bladder wall increased the post-test probability for clinically significant PAS from 21% to 85% in women with low-lying placenta or placenta previa and from 62% to 88% in the subgroup with previous Cesarean section and anterior placenta. When all three sonographic markers were present, the post-test probability for clinically significant PAS increased from 21% to 89% in the whole cohort and from 62% to 92% in the subgroup with previous Cesarean section and anterior placenta. CONCLUSIONS: Grayscale ultrasound has good diagnostic performance to identify pregnancies at low risk of PAS in a high-risk population of women with low-lying placenta or placenta previa. Ultrasound may be safely used to guide management decisions and concentrate resources on patients with higher risk of clinically significant PAS. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Evaluation of fetal cardiac function in pregnancies with well-controlled gestational diabetes.

OBJECTIVE: To evaluate fetal ventricular diastolic function in pregnancies of women with gestational diabetes (GD), to determine whether minimal anomalies of glucose metabolism may influence fetal cardiac function. STUDY DESIGN: Fetal ventricular filling time was measured by transabdominal ultrasound in singleton pregnancies between 34 and 37 weeks of gestation. We used a measurement which consists in the ratio between the diastolic time and the whole cardiac cycle time. RESULTS: The study included 35 women with a GD and 217 non-diabetic. Right ventricular filling time (RVFT) was significantly lower in the GD group (mean of RVFT = 39.2 ± 4.4 vs 43.6 ± 4.6; p < 0.01). Likewise, left ventricular filling time (LVFT) was shorter in the GD group compared to the non-GD group, though the difference was not significant (mean of LVFT = 43.6 ± 4.6 vs 44.6 ± 5.5; p = 0.33). CONCLUSIONS: Fetal right cardiac function is altered also in pregnancies where gestational diabetes is well controlled.

Effects of Antenatal Betamethasone on Fetal Doppler Indices and Short Term Fetal Heart Rate Variation in Early Growth Restricted Fetuses.

PURPOSE: To investigate the effects of the antenatal administration of betamethasone on fetal Doppler and short term fetal heart rate variation (CTG-STV) in early growth restricted (FGR) fetuses. MATERIALS AND METHODS: Post hoc analysis of data derived from the TRUFFLE study, a prospective, multicenter, randomized management trial of severe early onset FGR. Repeat Doppler and CTG-STV measurements between the last recording within 48 hours before the first dose of betamethasone (baseline value) and for 10 days after were evaluated. Multilevel analysis was performed to analyze the longitudinal course of the umbilico-cerebral ratio (UC ratio), the ductus venosus pulsatility index (DVPIV) and CTG-STV. RESULTS: We included 115 fetuses. A significant increase from baseline in CTG-STV was found on day + 1 (p = 0.019) but no difference thereafter. The DVPIV was not significantly different from baseline in any of the 10 days following the first dose of betamethasone (p = 0.167). Multilevel analysis revealed that, over 10 days, the time elapsed from antenatal administration of betamethasone was significantly associated with a decrease in CTG-STV (p = 0.045) and an increase in the DVPIV (p = 0.001) and UC ratio (p < 0.001). CONCLUSION: Although steroid administration in early FGR has a minimal effect on increasing CTG-STV one day afterwards, the effects on Doppler parameters were extremely slight with regression coefficients of small magnitude suggesting no clinical significance, and were most likely related to the deterioration with time in FGR. Hence, arterial and venous Doppler assessment of fetal health remains informative following antenatal steroid administration to accelerate fetal lung maturation.

The effect of delayed umbilical cord clamping on cord blood gas analysis in vaginal and caesarean-delivered term newborns without fetal distress: a prospective observational study.

OBJECTIVE: To determine variations in cord blood gas (CBG) parameters after 3-minute delayed cord clamping (DCC) in vaginal deliveries (VDs) and caesarean deliveries (CDs) at term without fetal distress. DESIGN: Prospective observational study. SETTING: University hospital. SAMPLE: CBG from 97 VDs and 124 CDs without fetal distress. METHODS: Comparison of paired arterial-venous CBG parameters drawn at birth from the unclamped cord and after 3-minutes DCC for VDs and CDs. MAIN OUTCOME MEASURES: Base excess, bicarbonate, haematocrit and haemoglobin from both arterial and venous cord blood, lactate, neonatal outcomes, partial pressure of oxygen (pO2 ), partial pressure of carbon dioxide (pCO2 ), pH, and postpartum haemorrhage. RESULTS: Arterial cord blood pH, bicarbonate ( HCO3- , mmol/l), and base excess (BE, mmol/l) decreased significantly after 3-minute DCC both in VDs (pH = 7.23 versus 7.27; P < 0.001; HCO3-  = 23.3 versus 24.3; P = 0.004; BE = -5.1 versus -2.9; P < 0.001) and CDs (pH = 7.28 versus 7.34; P < 0.001; HCO3-  = 26.2 versus 27.2; P < 0.001; BE = -1.5 versus 0.7; P < 0.001). After 3-minute DCC, pCO2 increased in CDs only (57 versus 51; P < 0.001), whereas lactate increased more in CDs compared with VDs (lactate, +1.1 [0.9, 1.45] versus +0.5 [-0.65, 2.35]; P = 0.01). Postpartum maternal haemorrhage, neonatal maximum bilirubin concentration, and need for phototherapy were similar between the two groups. Newborns born by CD more frequently required postnatal clinical monitoring or admission to a neonatal intensive care unit. CONCLUSIONS: After 3-minute DCC, the acid-base status shifted towards mixed acidosis in CDs and prevalent metabolic acidosis in VDs. CDs were associated with a more pronounced increase in arterial lactate, compared with VDs. TWEETABLE ABSTRACT: By 3-minute DCC, acid-base status shifts towards mixed and metabolic acidosis in caesarean and vaginal delivery, respectively.

Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis.

OBJECTIVE: To report mode of delivery and immediate neonatal outcome in women infected with COVID-19. DESIGN: Retrospective study. SETTING: Twelve hospitals in northern Italy. PARTICIPANTS: Pregnant women with COVID-19-confirmed infection who delivered. EXPOSURE: COVID 19 infection in pregnancy. METHODS: SARS-CoV-2-infected women who were admitted and delivered from 1 to 20 March 2020 were eligible. Data were collected from the clinical records using a standardised questionnaire on maternal general characteristics, any medical or obstetric co-morbidity, course of pregnancy, clinical signs and symptoms, treatment of COVID 19 infection, mode of delivery, neonatal data and breastfeeding. MAIN OUTCOME AND MEASURES: Data on mode of delivery and neonatal outcome. RESULTS: In all, 42 women with COVID-19 delivered at the participating centres; 24 (57.1%, 95% CI 41.0-72.3) delivered vaginally. An elective caesarean section was performed in 18/42 (42.9%, 95% CI 27.7-59.0) cases: in eight cases the indication was unrelated to COVID-19 infection. Pneumonia was diagnosed in 19/42 (45.2%, 95% CI 29.8-61.3) cases: of these, 7/19 (36.8%, 95% CI 16.3-61.6) required oxygen support and 4/19 (21.1%, 95% CI 6.1-45.6) were admitted to a critical care unit. Two women with COVID-19 breastfed without a mask because infection was diagnosed in the postpartum period: their newborns tested positive for SARS-Cov-2 infection. In one case, a newborn had a positive test after a vaginal operative delivery. CONCLUSIONS: Although postpartum infection cannot be excluded with 100% certainty, these findings suggest that vaginal delivery is associated with a low risk of intrapartum SARS-Cov-2 transmission to the newborn. TWEETABLE ABSTRACT: This study suggests that vaginal delivery may be associated with a low risk of intrapartum SARS-Cov-2 transmission to the newborn.

Fetal cerebral Doppler changes and outcome in late preterm fetal growth restriction: prospective cohort study.

OBJECTIVES: To explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction. METHODS: This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC) < 10th percentile, abnormal arterial Doppler and/or a fall in AC growth velocity of more than 40 percentile points from the 20-week scan. Composite adverse outcome comprised both immediate adverse birth outcome and major neonatal morbidity. Using a range of cut-off values, the association of MCA pulsatility index and umbilicocerebral ratio (UCR) with composite adverse outcome was explored. RESULTS: The study population comprised 856 women. There were two (0.2%) intrauterine deaths. Median gestational age at delivery was 38 (interquartile range (IQR), 37-39) weeks and birth weight was 2478 (IQR, 2140-2790) g. Compared with infants with normal outcome, those with composite adverse outcome (n = 93; 11%) were delivered at an earlier gestational age (36 vs 38 weeks) and had a lower birth weight (1900 vs 2540 g). The first Doppler observation of MCA pulsatility index < 5th percentile and UCR Z-score above gestational-age-specific thresholds (1.5 at 32-33 weeks and 1.0 at 34-36 weeks) had the highest relative risks (RR) for composite adverse outcome (RR 2.2 (95% CI, 1.5-3.2) and RR 2.0 (95% CI, 1.4-3.0), respectively). After adjustment for confounders, the association between UCR Z-score and composite adverse outcome remained significant, although gestational age at delivery and birth-weight Z-score had a stronger association. CONCLUSION: In this prospective multicenter study, signs of cerebral blood flow redistribution were found to be associated with adverse outcome in late preterm singleton pregnancies at risk of fetal growth restriction. Whether cerebral redistribution is a marker describing the severity of fetal growth restriction or an independent risk factor for adverse outcome remains unclear, and whether it is useful for clinical management can be answered only in a randomized trial. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Multivariable evaluation of maternal hemodynamic profile in pregnancy complicated by fetal growth restriction: prospective study.

OBJECTIVE: To evaluate the association between fetal growth restriction (FGR) and maternal hemodynamic parameters using multivariable analysis, adjusting for major confounding factors, such as hypertensive disorders of pregnancy (pre-eclampsia and gestational hypertension). METHODS: A prospective cohort study was conducted between January 2013 and April 2016. Two cohorts of patients were recruited, between 24 and 39 weeks of gestation, in a high-risk outpatient setting. These cohorts comprised 49 appropriate-for-gestational-age singleton fetuses and 93 that were FGR (abdominal circumference (AC) at recruitment in the second half of pregnancy ≤ 10th percentile with a previous normal AC at 20-22 weeks). Maternal echocardiography was performed at the time of enrolment and included hemodynamic parameters of systolic and diastolic function and cardiac remodeling indices. Data were analyzed using a multivariable generalized linear model to estimate the association of FGR with maternal hemodynamic parameters after adjusting for significant confounding factors. RESULTS: In the multivariable analysis, after adjustment for hypertensive disorders of pregnancy and smoking, FGR was associated with a 14% increase in maternal total vascular resistance, 16% reduction in cardiac output, 13% reduction in left ventricular mass and 11% reduction in heart rate; similar results were observed for the corresponding indexed parameters. Hypertensive disorders of pregnancy in the absence of FGR were associated with a 25% increase in total vascular resistance, 16% increase in left ventricular mass and 14% reduction in diastolic function; similar results were observed for the corresponding indexed parameters. CONCLUSION: FGR is significantly and independently associated with several maternal hemodynamic parameters, even after adjustment for major confounding factors, such as hypertensive disorders of pregnancy. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Selective intrauterine growth restriction in monochorionic twins: changing patterns in umbilical artery Doppler flow and outcomes.

OBJECTIVES: To describe changes in umbilical artery (UA) Doppler flow in monochorionic diamniotic (MCDA) twins affected by selective intrauterine growth restriction (sIUGR), to correlate Doppler findings with pregnancy course and perinatal outcome, and to report postnatal follow-up. METHODS: This was a retrospective study of 140 MCDA twins with sIUGR. UA end-diastolic flow, defined as Doppler waveform pattern Type I (persistently positive), Type II (persistently absent or persistently reversed) or Type III (intermittently absent or intermittently reversed), was recorded at first examination and monitored weekly until double or single intrauterine fetal death (IUFD), bipolar cord coagulation or delivery. All neonates had an early neonatal brain scan, magnetic resonance imaging, when indicated, and neurological assessment during infancy. Rates (per 100 person-weeks) and hazard ratios (HR) of IUFD in the IUGR twin in each pregnancy were calculated considering UA Doppler pattern as a time-dependent variable. RESULTS: At first examination, there were 65 cases with UA Doppler waveform pattern Type I, 62 with Type II and 13 with Type III. Of the 65 Type-I cases, 48 (74%) remained stable, while 17 (26%) changed to either Type II absent (14%), Type II reversed (9%) or Type III (3%). Of 62 Type-II cases (47 with absent and 15 with reversed flow), 33 (53%) remained stable (18 with absent and all 15 with reversed flow). The 29 Type-II absent cases which changed became Type II reversed (24/47, 51%) or Type III (5/47, 11%). All 13 Type-III cases remained stable. Compared with Type I, the risk of IUFD (adjusted for estimated fetal weight discordance and amniotic fluid deepest vertical pocket) was highest when the pregnancy was or became Type II reversed (HR, 9.5; 95% CI, 2.7-32.7) or Type II absent (HR, 4.3; 95% CI, 1.3-14.3). Mild neurological impairment was more prevalent in the IUGR twin than in the large cotwin (7% vs 1%, P = 0.02). CONCLUSIONS: Risk stratification based on UA Doppler is useful for planning ultrasound surveillance. However, patterns can change over time, with important consequences for management and outcome. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Fetal monitoring indications for delivery and 2-year outcome in 310 infants with fetal growth restriction delivered before 32 weeks' gestation in the TRUFFLE study.

OBJECTIVE: In the TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe) study on the outcome of early fetal growth restriction, women were allocated to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate (FHR) short-term variation (STV) on cardiotocography (CTG); (2) early changes in fetal ductus venosus (DV) waveform (DV-p95); and (3) late changes in fetal DV waveform (DV-no-A). However, many infants per monitoring protocol were delivered because of safety-net criteria, for maternal or other fetal indications, or after 32 weeks of gestation when the protocol was no longer applied. The objective of the present posthoc subanalysis was to investigate the indications for delivery in relation to 2-year outcome in infants delivered before 32 weeks to further refine management proposals. METHODS: We included all 310 cases of the TRUFFLE study with known outcome at 2 years' corrected age and seven fetal deaths, excluding seven cases with inevitable perinatal death. Data were analyzed according to the allocated fetal monitoring strategy in combination with the indication for delivery. RESULTS: Overall, only 32% of liveborn infants were delivered according to the specified monitoring parameter for indication for delivery; 38% were delivered because of safety-net criteria, 15% for other fetal reasons and 15% for maternal reasons. In the CTG-STV group, 51% of infants were delivered because of reduced STV. In the DV-p95 group, 34% of infants were delivered because of abnormal DV and, in the DV-no-A group, only 10% of infants were delivered accordingly. The majority of infants in the DV groups were delivered for the safety-net criterion of spontaneous decelerations in FHR. Two-year intact survival was highest in the DV groups combined compared with the CTG-STV group (P = 0.05 for live births only, P = 0.21 including fetal death), with no difference between DV groups. A poorer outcome in the CTG-STV group was restricted to infants delivered because of FHR decelerations in the safety-net subgroup. Infants delivered because of maternal reasons had the highest birth weight and a non-significantly higher intact survival. CONCLUSIONS: In this subanalysis of infants delivered before 32 weeks, the majority were delivered for reasons other than the allocated monitoring strategy indication. Since, in the DV group, CTG-STV criteria were used as a safety net but in the CTG-STV group, no DV safety-net criteria were applied, we speculate that the slightly poorer outcome in the CTG-STV group might be explained by the absence of DV data. The optimal timing of delivery of fetuses with early intrauterine growth restriction may therefore be best determined by monitoring them longitudinally, with both DV and CTG monitoring. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Longitudinal study of computerized cardiotocography in early fetal growth restriction.

OBJECTIVES: To explore whether, in early fetal growth restriction (FGR), the longitudinal pattern of fetal heart rate (FHR) short-term variation (STV) can be used to identify imminent fetal distress and whether abnormalities of FHR recordings are associated with 2-year infant outcome. METHODS: The original TRUFFLE study assessed whether, in early FGR, delivery based on ductus venosus (DV) Doppler pulsatility index (PI), in combination with safety-net criteria of very low STV on cardiotocography (CTG) and/or recurrent FHR decelerations, could improve 2-year infant survival without neurological impairment in comparison with delivery based on CTG monitoring only. This was a secondary analysis of women who delivered before 32 weeks and had consecutive STV data recorded > 3 days before delivery and known infant outcome at 2 years of age. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values, except the last one before delivery, were calculated. Life tables and Cox regression analysis were used to calculate the daily risk for low STV or very low STV and/or FHR decelerations (below DV group safety-net criteria) and to assess which parameters were associated with this risk. Furthermore, it was assessed whether STV pattern, last STV value or recurrent FHR decelerations were associated with 2-year infant outcome. RESULTS: One hundred and forty-nine women from the original TRUFFLE study met the inclusion criteria. Using the individual STV regression lines, prediction of a last STV below the cut-off used by the CTG monitoring group had sensitivity of 42% and specificity of 91%. For each day after study inclusion, the median risk for low STV (CTG group cut-off) was 4% (interquartile range (IQR), 2-7%) and for very low STV and/or recurrent FHR decelerations (below DV group safety-net criteria) was 5% (IQR, 4-7%). Measures of STV pattern, fetal Doppler (arterial or venous), birth-weight multiples of the median and gestational age did not usefully improve daily risk prediction. There was no association of STV regression coefficients, a low last STV and/or recurrent FHR decelerations with short- or long-term infant outcomes. CONCLUSION: The TRUFFLE study showed that a strategy of DV monitoring with safety-net criteria of very low STV and/or recurrent FHR decelerations for delivery indication could increase 2-year infant survival without neurological impairment. This post-hoc analysis demonstrates that, in early FGR, the daily risk of abnormal CTG, as defined by the DV group safety-net criteria, is 5%, and that prediction is not possible. This supports the rationale for CTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent FHR decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DV-PI is within normal range. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: post-hoc analysis of TRUFFLE study.

OBJECTIVES: In the recent TRUFFLE study, it appeared that, in pregnancies complicated by fetal growth restriction (FGR) between 26 and 32 weeks' gestation, monitoring of the fetal ductus venosus (DV) waveform combined with computed cardiotocography (CTG) to determine timing of delivery increased the chance of infant survival without neurological impairment. However, concerns with the interpretation were raised, as DV monitoring appeared to be associated with a non-significant increase in fetal death, and some infants were delivered after 32 weeks, at which time the study protocol no longer applied. This secondary sensitivity analysis of the TRUFFLE study focuses on women who delivered before 32 completed weeks' gestation and analyzes in detail the cases of fetal death. METHODS: Monitoring data of 317 pregnancies with FGR that delivered before 32 weeks were analyzed, excluding those with absent outcome data or inevitable perinatal death. Women were allocated randomly to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate short-term variation (STV) on CTG; (2) early changes in fetal DV waveform; and (3) late changes in fetal DV waveform. Primary outcome was 2-year survival without neurological impairment. The association of the last monitoring data before delivery and infant outcome was assessed by multivariable analysis. RESULTS: Two-year survival without neurological impairment occurred more often in the two DV groups (both 83%) than in the CTG-STV group (77%), however, the difference was not statistically significant (P = 0.21). Among the surviving infants in the DV groups, 93% were free of neurological impairment vs 85% of surviving infants in the CTG-STV group (P = 0.049). All fetal deaths (n = 7) occurred in the groups with DV monitoring. Of the monitoring parameters obtained shortly before fetal death in these seven cases, an abnormal CTG was observed in only one case. Multivariable regression analysis of factors at study entry demonstrated that a later gestational age, higher estimated fetal weight-to-50th percentile ratio and lower umbilical artery pulsatility index (PI)/fetal middle cerebral artery-PI ratio were significantly associated with normal outcome. Allocation to DV monitoring had a smaller effect on outcome, but remained in the model (P < 0.1). Abnormal fetal arterial Doppler before delivery was significantly associated with adverse outcome in the CTG-STV group. In contrast, abnormal DV flow was the only monitoring parameter associated with adverse outcome in the DV groups, while fetal arterial Doppler, STV below the cut-off used in the CTG-STV group and recurrent decelerations in fetal heart rate were not. CONCLUSIONS: In accordance with the findings of the TRUFFLE study on monitoring and intervention management of very preterm FGR, we found that the proportion of infants surviving without neuroimpairment was not significantly different when the decision for delivery was based on changes in DV waveform vs reduced STV on CTG. The uneven distribution of fetal deaths towards the DV groups was probably a chance effect, and neurological outcome was better among surviving children in these groups. Before 32 weeks, delaying delivery until abnormalities in DV-PI or STV and/or recurrent decelerations in fetal heat rate occur, as defined by the study protocol, is likely to be safe and possibly benefits long-term outcome. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Brain sparing effect in growth-restricted fetuses is associated with decreased cardiac acceleration and deceleration capacities: a case-control study.

OBJECTIVE: Phase rectified signal averaging (PRSA) is a new method of fetal heart rate variability (fHRV) analysis that quantifies the average acceleration (AC) and deceleration capacity (DC) of the heart. The aim of this study was to evaluate AC and DC of fHR [recorded by trans-abdominal fetal electrocardiogram (ta-fECG)] in relation to Doppler velocimetry characteristics of intrauterine growth restriction (IUGR). DESIGN: Prospective case-control study. SETTING: Single third referral centre. POPULATION: IUGR (n = 66) between 25 and 40 gestational weeks and uncomplicated pregnancies (n = 79). METHODS: In IUGR the nearest ta-fECG monitoring to delivery was used for PRSA analysis and Doppler velocimetry parameters obtained within 48 hours. AC and DC were computed at s = T = 9. The relation was evaluated between either AC or DC and Doppler velocimetry parameters adjusting for gestational age at monitoring, as well as the association between either AC or DC and IUGR with or without brain sparing. RESULTS: In IUGRs there was a significant association between either AC and DC and middle cerebral artery pulsatility index (PI; P = 0.01; P = 0.005), but the same was not true for uterine or umbilical artery PI (P > 0.05). Both IUGR fetuses with and without brain sparing had lower AC and DC than controls, but this association was stronger for IUGRs with brain sparing. CONCLUSIONS: Our study observed for the first time that AC and DC at PRSA analysis are associated with middle cerebral artery PI, but not with uterine or umbilical artery PI, and that there is a significant decrease of AC and DC in association with brain sparing in IUGR fetuses from 25 weeks of gestation to term. TWEETABLE ABSTRACT: Brain sparing in IUGR fetuses is associated with decreased acceleration and deceleration capacities of the heart.

Bedside diagnosis of two major clinical phenotypes of hypertensive disorders of pregnancy.

OBJECTIVE: To investigate the hypothesis that fetal abdominal circumference (AC) and uterine artery (UtA) Doppler pulsatility index (PI) could be used to select two homogeneous subgroups of women affected by hypertensive disorders of pregnancy (HDP), characterized by the coexistence of maternal hypertension with and without intrauterine growth restriction (IUGR). METHODS: This was a multicenter retrospective study of cases affected by HDP in whom fetal AC and UtA-PI had been measured at admission to fetomaternal medicine units. Maternal characteristics, pregnancy complications and outcome were recorded. These data allowed us to model the characteristics of fetal growth in cases affected by HDP, and to design composite indicators of risk factors for maternal metabolic syndrome and of severity for maternal functional organ damage. RESULTS: Measurements of fetal AC and UtA-PI allowed us to define a group of HDP cases with appropriate-for-gestational-age (AGA) fetuses (HDP-AGA), diagnosed by normal fetal AC and UtA-PI (n = 205), and a group of HDP cases with IUGR fetuses (HDP-IUGR), diagnosed by fetal AC < 5(th) centile and UtA-PI > 95(th) centile (n = 124). Curves fitted to the birth weights of these two groups were significantly different, but gestational age at admission for HDP (< 34 or ≥ 34 weeks) did not show an independent association with birth weight. When birth weight was expressed as a Z-score with respect to local reference charts, the average corresponded to the 6(th) and 48(th) centiles, respectively. The occurrence of HDP-AGA (as compared with HDP-IUGR) was significantly associated with risk factors for maternal metabolic syndrome (odds ratio, 2.79 (95% CI, 1.57-4.97)), independent of gestational age. The same risk factors yielded non-significant odds ratios for the development of late-onset (vs early-onset) HDP. Women with HDP-IUGR had worse clinical outcomes. CONCLUSIONS: This study provides new information based on simple prenatal bedside examinations that might help to differentiate HDP-IUGR from HDP-AGA fetuses. These groups are associated with different fetal growth patterns and risk factors, independent of gestational age at onset of the disease. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia.

Intrauterine growth restriction (IUGR) and pregnancy hypertensive disorders such as preeclampsia (PE) associated with IUGR share a common placental phenotype called "placental insufficiency", originating in early gestation when high availability of energy is required. Here, we assess mitochondrial content and the expression and activity of respiratory chain complexes (RCC) in placental cells of these pathologies. We measured mitochondrial (mt)DNA and nuclear respiratory factor 1 (NRF1) expression in placental tissue and cytotrophoblast cells, gene and protein expressions of RCC (real-time PCR and Western blotting) and their oxygen consumption, using the innovative technique of high-resolution respirometry. We analyzed eight IUGR, six PE, and eight uncomplicated human pregnancies delivered by elective cesarean section. We found lower mRNA levels of complex II, III, and IV in IUGR cytotrophoblast cells but no differences at the protein level, suggesting a posttranscriptional compensatory regulation. mtDNA was increased in IUGR placentas. Both mtDNA and NRF1 expression were instead significantly lower in their isolated cytotrophoblast cells. Finally, cytotrophoblast RCC activity was significantly increased in placentas of IUGR fetuses. No significant differences were found in PE placentas. This study provides genuine new data into the complex physiology of placental oxygenation in IUGR fetuses. The higher mitochondrial content in IUGR placental tissue is reversed in cytotrophoblast cells, which instead present higher mitochondrial functionality. This suggests different mitochondrial content and activity depending on the placental cell lineage. Increased placental oxygen consumption might represent a limiting step in fetal growth restriction, preventing adequate oxygen delivery to the fetus.

Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE).

OBJECTIVES: Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early-onset fetal growth restriction. Yet, the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching. The objective of this study was to describe perinatal morbidity and mortality following early-onset fetal growth restriction based on time of antenatal diagnosis and delivery. METHODS: We report cohort outcomes for a prospective multicenter randomized management study of fetal growth restriction (Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE)) performed in 20 European perinatal centers between 2005 and 2010. Women with a singleton fetus at 26-32 weeks of gestation, with abdominal circumference < 10(th) percentile and umbilical artery Doppler pulsatility index > 95(th) percentile, were recruited. The main outcome measure was a composite of fetal or neonatal death or severe morbidity: survival to discharge with severe brain injury, bronchopulmonary dysplasia, proven neonatal sepsis or necrotizing enterocolitis. RESULTS: Five-hundred and three of 542 eligible women formed the study group. Mean ± SD gestational age at diagnosis was 29 ± 1.6 weeks and mean ± SD estimated fetal weight was 881 ± 217 g; 12 (2.4%) babies died in utero. Gestational age at delivery was 30.7 ± 2.3 weeks, and birth weight was 1013 ± 321 g. Overall, 81% of deliveries were indicated by fetal condition and 97% were by Cesarean section. Of 491 liveborn babies, outcomes were available for 490 amongst whom there were 27 (5.5%) deaths and 118 (24%) babies suffered severe morbidity. These babies were smaller at birth (867 ± 251 g) and born earlier (29.6 ± 2.0 weeks). Death and severe morbidity were significantly related to gestational age, both at study entry and delivery and also with the presence of maternal hypertensive morbidity. The median time to delivery was 13 days for women without hypertension, 8 days for those with gestational hypertension, 4 days for pre-eclampsia and 3 days for HELLP syndrome. CONCLUSIONS: Fetal outcome in this study was better than expected from contemporary reports: perinatal death was uncommon (8%) and 70% survived without severe neonatal morbidity. The intervals to delivery, death and severe morbidity were related to the presence and severity of maternal hypertensive conditions.

Bipolar cord coagulation for selective feticide in complicated monochorionic twin pregnancies: 118 consecutive cases at a single center.

OBJECTIVE: To review the experience of performing selective feticide with bipolar cord coagulation (BCC) in complicated monochorionic (MC) twin pregnancies at a single center. METHODS: This was a retrospective analysis of BCC performed using 3-mm bipolar forceps under ultrasound control in cases complicated by twin-to-twin transfusion syndrome, selective growth restriction, discordant anomaly or twin reversed arterial perfusion sequence. RESULTS: The series comprised 118 cases with a median gestational age at the time of the procedure of 22 (range, 16-30) weeks. There were 14 (12%) intrauterine deaths of the cotwin, eight (7%) miscarriages and one (1%) termination of pregnancy. When BCC was performed before 19 weeks of gestation, the rate of miscarriage was 45%, whereas it was 3% (P < 0.001) when BCC was performed after 19 weeks. Preterm prelabor rupture of membranes (PPROM) occurred in 45 (38%) cases. The median interval between BCC and PPROM was 4 (interquartile range, 2-9) weeks. In 15 (13%) cases, PPROM occurred within 2 weeks after the procedure. Median gestational age at delivery was 34 (range, 24-41) weeks. The median birth weight was 2103 (range, 480-3875) g. Neonatal death occurred in 11 (9%) cases, and two (2%) children had severe neurologic morbidity. The overall survival rate was 71% (84/118). CONCLUSION: BCC is an effective procedure in complicated MC twin pregnancies for selective feticide or when one fetus is severely jeopardized and delivery is not yet an option. Better outcomes can be achieved when this procedure is performed after 19 weeks.