Infant outcome after active management of early-onset fetal growth restriction with absent or reversed umbilical artery blood flow.

OBJECTIVE: To describe the short- and long-term outcomes of infants with early-onset fetal growth restriction (FGR) and umbilical artery absent or reversed end-diastolic flow (AREDF), delivered before 30 weeks' gestation and managed proactively. METHODS: This was a retrospective cohort study of fetuses delivered for fetal indication before 30 completed weeks' gestation that had early-onset FGR (defined as estimated fetal weight more than 2 SD below the mean) with AREDF in the umbilical artery (FGR group), at the level-3 perinatal unit in Lund, Sweden, between 1998 and 2015. Perinatal outcome and neurodevelopment at ≥ 2 years of age in surviving infants were compared with those of a group of infants without small-for-gestational-age birth weight or any known fetal Doppler changes delivered before 30 weeks in Lund during the corresponding time period (non-FGR group). In the FGR group, the main indication for delivery was the Doppler finding of AREDF in the umbilical artery. RESULTS: There were 139 fetuses (of which 26% were a twin/triplet) in the FGR group and 946 fetuses (of which 28% were a twin/triplet) in the non-FGR group. The FGR infants had a median birth weight of 630 g (range, 340-1165 g) and gestational age at birth of 187 days (range, 164-209 days), as compared with 950 g (range, 470-2194 g) and 185 days (range, 154-209 days), respectively, in the non-FGR group. The rate of fetal mortality did not differ between the two groups (5.0% and 5.4% in the FGR and non-FGR groups, respectively). All seven intrauterine deaths in the FGR group occurred before 26 weeks' gestation. In the FGR group compared with the non-FGR group, severe intraventricular hemorrhage was less frequent and bronchopulmonary dysplasia and septicemia were more frequent (P = 0.008, P < 0.001 and P = 0.017, respectively). In the FGR group, the survival rate at 2 years (83% of liveborn infants) and the rate of cerebral palsy (7%) did not differ significantly from those in the non-FGR group (82% and 8%, respectively). The rate of survival without neurodevelopmental impairment was higher in the non-FGR group (83%) than in the FGR group (62%) (P < 0.001), as well as in infants in the FGR group delivered at or after 26 weeks (72%) compared with those delivered before 26 weeks (40%) (P = 0.003). Within the FGR group, outcomes were similar between twins and singletons and, in those who survived beyond 2 years, outcomes were similar between fetuses with absent and those with reversed end-diastolic flow in the umbilical artery. CONCLUSIONS: Infants delivered very preterm after severe FGR with AREDF in the umbilical artery had a similar rate of survival as did non-FGR infants of corresponding gestational age; however, they were at higher risk of neurodevelopmental impairment, the risk being most pronounced following birth before 26 weeks. Gestational age remains an important factor associated with the prognosis of early-onset FGR; nevertheless, the present results support the hypothesis, which should be tested prospectively, that fetuses with early-onset FGR and umbilical artery AREDF may benefit from early intervention rather than expectant management, and that umbilical artery Doppler findings could be incorporated into clinical protocols for cases very early in gestation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Extent of absent end-diastolic flow in umbilical artery and outcome of pregnancy.

OBJECTIVE: To investigate if the extent of absent end-diastolic flow (AEDF) on umbilical artery (UA) Doppler velocimetry predicts pregnancy outcome. METHODS: This was a retrospective observational study based on data from 25 000 Doppler examinations of UA flow performed between 1998 and 2017 at the Blood Flow Laboratory, Level III Perinatal Center, Lund, Sweden. All pregnancies with AEDF in the UA were identified, and the duration of AEDF as a proportion of the total duration of the cardiac cycle (Ta /Ttot ratio) was measured in digital images of the Doppler spectrum recorded at the last examination showing AEDF before delivery. Clinical data on pregnancies and neonatal outcomes were extracted from the regional perinatal database and the hospital patient records. The predictive performance of the Ta /Ttot ratio for intrauterine death and any (intrauterine or postnatal) death was assessed. RESULTS: A total of 170 fetuses (122 (72%) singletons and 48 (28%) twins) were included in the study. Median gestational age at birth was 189.5 days (range, 163-279 days) (i.e. 27 + 0 weeks (range, 23 + 2 to 39 + 6 weeks)), birth weight was 650 g (range, 320-3326 g) and deviation from expected birth weight (standard deviation score) was -2.975 (range, -6.38 to 0.69). There were 15 (9%) intrauterine and 26 (15%) postnatal deaths. The principal outcome variables and their relationship with Doppler velocimetry results did not differ significantly between singletons and twins, giving a rationale for using the Ta /Ttot ratio in the total study group. Mean Ta /Ttot ratio was 0.42 ± 0.08 and 0.34 ± 0.08 in stillborn and liveborn fetuses, respectively (P = 0.002). For fetuses examined before 30 weeks' gestation, a Ta /Ttot ratio cut-off of 0.30 predicted intrauterine death with 92% sensitivity and a negative predictive value (NPV) of 98% (area under receiver-operating-characteristics curve (AUC), 0.74) and predicted any death with 83% sensitivity and a NPV of 85% (AUC, 0.66). CONCLUSIONS: In fetuses with AEDF in the UA, duration of absent flow for at least 30% of the total cardiac cycle length might predict the risk of fetal demise, even when assessed before 30 weeks' gestation. This finding is particularly relevant to growth-restricted fetuses. After evaluation in further studies, the extent of AEDF might facilitate obstetric decision-making in very preterm growth-restricted fetuses. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe.

OBJECTIVE: To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation. DESIGN: Incidence estimation based on literature review and published national and EU statistics. SETTING AND POPULATION: European Union. METHODS: Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched. RESULTS: The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93-3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07-3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population. CONCLUSIONS: Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life-threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits. TWEETABLE ABSTRACT: Placental insufficiency meets the European Medicines Agency requirements for orphan disease designation.

Timing of antenatal corticosteroid administration and survival in extremely preterm infants: a national population-based cohort study.

OBJECTIVE: To explore the association between administration-to-birth interval of antenatal corticosteroids (ACS) and survival in extremely preterm infants. DESIGN: Population-based prospective cohort study. SETTING: All obstetric and neonatal units in Sweden from 1 April 2004 to 31 March 2007. POPULATION: All live-born infants (n = 707) born at 22-26 completed weeks of gestation. METHODS: The relationship between time from first administration of ACS to delivery and survival was investigated using Cox proportional hazards regression analysis. MAIN OUTCOME MEASURES: Neonatal (0-27 days) and infant (0-365 days) survival, and infant survival without major neonatal morbidity (intraventricular haemorrhage grade ≥ 3, retinopathy of prematurity stage ≥ 3, periventricular leukomalacia, necrotising enterocolitis, or severe bronchopulmonary dysplasia). RESULTS: Five-hundred and ninety-one (84%) infants were exposed to ACS. In the final adjusted model, infant survival was lower in infants unexposed to ACS [hazard ratio (HR) = 0.26; 95% confidence interval 0.15-0.43], in infants born <24 h [HR = 0.53 (0.33-0.87)] and >7 days after ACS [HR = 0.56 (0.32-0.97)], but not in infants born 24-47 h after ACS [HR = 1.60 (0.73-3.50)], as compared with infants born 48 h to 7 days after administration. The findings were similar for neonatal survival. Survival without major neonatal morbidity among live-born infants was 14% in unexposed infants and 30-39% in steroid-exposed groups, indicating that any ACS exposure was valuable. CONCLUSIONS: Administration of ACS 24 h to 7 days before extremely preterm birth was associated with significantly higher survival than in unexposed infants and in infants exposed to ACS at shorter or longer administration-to-birth intervals. TWEETABLE ABSTRACT: Timing of antenatal corticosteroids is important for extremely preterm infants' survival.

Pre-eclampsia- an additional risk factor for cognitive impairment at school age after intrauterine growth restriction and very preterm birth.

OBJECTIVE: To explore the possible influence of pre-eclampsia on cognitive outcome in children born very preterm after intrauterine growth restriction (IUGR) and abnormal umbilical artery blood flow. METHODS: Cognitive function was evaluated at 5-8 years of age with Wechsler scales in 34 children born before 30 gestational weeks after IUGR (PT-IUGR) (11 children were exposed to maternal pre-eclampsia, 23 non-exposed) and in 34 children with no maternal pre-eclampsia and birth weight appropriate-for-gestational age (PT-AGA) matched for gestational age at birth, gender and age at examination. RESULTS: The subjects in the PT-IUGR group exposed to maternal pre-eclampsia had lower mean verbal IQ (VIQ) (mean ± SD 74 ± 16) and lower full scale IQ (FSIQ) (70 ± 19) in comparison with both the non-exposed PT-IUGR (VIQ 89 ± 15; p=0.013; FSIQ 83 ± 14, p=0.029), and, the PT-AGA group (VIQ 96 ± 15, p<0.001; FSIQ 90 ± 14, p=0.001). The differences remained significant after adjustment for known confounders. VIQ and FSIQ did not differ between the non-exposed IUGR and PT-AGA children. CONCLUSION: Fetal exposure to maternal pre-eclampsia seems to have an additional negative impact to that of IUGR on cognitive function in children born very preterm.

Umbilical artery Doppler in relation to placental pathology and FV Leiden in pregnant women and their offspring.

OBJECTIVE: Abnormal umbilical artery blood flow has been implicated in pregnancy complications and fetal demise. Its relation to histopathological changes in the placenta and to maternal or fetal thrombophilia is less well understood. The aim of this study was to evaluate the relation between umbilical artery Doppler findings, placental histopathology, and maternal and fetal coagulation factor V Leiden (FVL) status. METHODS: Two previous studies on FVL in pregnancy made the placentas of 25 women with maternal FVL carriership and 43 randomly selected non-carriers available for a histopathological examination. Umbilical artery Doppler velocimetry was performed on 54 women in late pregnancy. RESULTS: Abnormal umbilical artery Doppler velocimetry was associated with an approximately sevenfold increased risk of fetoplacental thrombotic vasculopathy (odds ratio [OR]: 7.5, 95% confidence intervals [CI]: 1.3-44.3), ischemic lesions (OR: 7.5, 95% CI: 1.2-46.1) and fetal carriership of FVL (OR: 8.2, 95% CI: 1.5-43.5), but not maternal FVL. Fetal FVL carriership was also associated with a sevenfold increased risk of ischemic lesions (OR: 6.7, 95% CI: 1.3-35). CONCLUSIONS: Our results indicate that the fetal - not the maternal - FVL carriership matters regarding the umbilical artery blood flow and placental pathology, which might explain some of the heterogeneity of studies.

Predicting risk for large-for-gestational age neonates at term: a population-based Bayesian theorem study.

OBJECTIVES: To evaluate the prediction of large-for-gestational age (LGA) term neonates using the routine third-trimester ultrasound examination and to investigate whether the prediction could be further improved by adding information on maternal characteristics. METHODS: Information on 56,792 singleton term pregnancies with a routine ultrasound examination at 32-34 weeks' gestation was retrieved from a population-based perinatal register. Estimated fetal weights (FW) were expressed as gestational age-specific standard deviation scores (Z-scores). The prediction of LGA was assessed by receiver-operating characteristics (ROC) curves, with LGA defined as birth weight Z-score > + 2. The data set with complete clinical information (n = 48,809) was divided into a development and a validation set. Using the development set, multiple logistic regression analysis was performed to identify maternal characteristics associated with LGA. The odds ratios obtained were converted into likelihood ratios. These were then applied to the validation set and the probability for LGA for each infant was estimated using the Bayesian theorem. RESULTS: The FW Z-score showed a high predictive ability for LGA (area under the ROC curve (AUC) 0.89 (95% CI, 0.89-0.90)). Prediction was further improved by using the model that included both FW Z-scores and maternal variables (AUC 0.91 (95% CI, 0.90-0.92)) (P for difference < 10(-6) ). The corresponding AUC for a model including maternal characteristics only was 0.74 (95% CI, 0.73-0.76). CONCLUSIONS: Routine third-trimester ultrasound FW estimation is effective in the prediction of LGA neonates at term. The prediction of LGA might be further improved by using a model including maternal characteristics.

Impact of maternal characteristics on fetal growth in the third trimester: a population-based study.

OBJECTIVES: To investigate the association between maternal characteristics and fetal growth during the third trimester of pregnancy. METHODS: Using a population-based perinatal register, 48809 term singleton pregnancies were identified for which a routine ultrasound examination in the third trimester had been performed between 1995 and 2009. Fetal and infant weight were expressed as gestational age-specific standard deviation scores (z-scores) using a Swedish ultrasound-based reference curve. The growth of each fetus was assessed using the difference between the birth-weight z-score and the fetal-weight z-score estimated at the ultrasound examination, adjusted for gestational age, and divided by the time elapsed between the ultrasound examination and delivery. Analyses were performed using multivariable linear and polynomial regression analyses. RESULTS: Positive associations were found between maternal body mass index (BMI), height, pre-existing diabetes mellitus, female fetal gender and fetal growth, whereas maternal smoking had a negative association. In the univariate analyses, primiparity and parity with four or more previous children were significantly associated with reduced fetal growth, but in the multivariable analysis, no association between parity and fetal growth could be detected. Both univariate and multivariable analyses revealed a significant inverse U-shaped association between maternal age and fetal growth. CONCLUSIONS: Third-trimester fetal growth was positively associated with increasing maternal BMI, height and pre-existing diabetes mellitus, and negatively associated with maternal smoking.

Effect of various dating formulae on sonographic estimation of gestational age in extremely preterm infants.

OBJECTIVES: Gestational age (GA) is one of the most important obstetric factors and prediction of date of delivery is usually based on ultrasonographic fetal measurements. Our aim was to determine whether applying three different dating formulae to a cohort of extremely preterm infants influenced the estimation of their GA. METHODS: This was a study of 513 infants delivered before 27 gestational weeks, included in a Swedish national population study (EXPRESS), with information available on mid-trimester ultrasonographically measured biparietal diameter and femur length. We applied using these parameters three dating formulae, the Persson & Weldner formula, commonly used in Sweden, the Hadlock formula and the Mul formula, and compared their GA estimates to the clinically reported GA (recorded at delivery) and the last menstrual period (LMP)-based GA. RESULTS: The mean reported GA was 173.2 days, corresponding well to the GA according to the Persson & Weldner dating formula (173.3). The mean GA according to LMP, the Hadlock formula and the Mul formula were 176.8, 175.3 and 175.6 days, respectively. The Hadlock and Mul GA estimates differed significantly from that based on the Persson & Weldner formula (both P-values < 10(-6)). Among 68 pregnancies with a reported duration of 22 weeks, 33 (49%) had a duration of 23 weeks or more when GA was calculated according to LMP and 22 (32%) when GA was calculated according to the Hadlock formula. CONCLUSION: Estimated GA among infants delivered before 27 gestational weeks varied significantly depending on the dating formula used to calculate the estimated date of delivery; this might influence the clinical management of extremely preterm fetuses and infants.

Effect of maternal betamethasone on fetal and uteroplacental blood flow velocity waveforms.

OBJECTIVES: To investigate the effects of antenatal betamethasone on fetal and uteroplacental hemodynamics. METHODS: The study comprised 33 women with singleton high-risk pregnancies (23-33 weeks; 27 pregnancies < 30 weeks) not in labor, but at risk for preterm delivery based on fetal or maternal indications. They were treated with two doses of 12 mg betamethasone intramuscularly 24 h apart to enhance fetal lung maturity. Flow velocity waveforms were recorded with Doppler ultrasound from the umbilical artery, the fetal middle cerebral artery, the ductus venosus and both maternal uterine arteries, once before and twice after betamethasone administration. RESULTS: Twenty-one (64%) women delivered within 4 days, nine (27%) women within 5-7 days and three (9%) within 8-15 days after the first dose of betamethasone. Two days after betamethasone, a decrease in pulsatility index was found in the umbilical artery (P = 0.0002) and ductus venosus (P = 0.003). Changes in the umbilical artery waveform from reversed to absent, and from absent to positive diastolic flow, were noted in 12 of 15 cases (P < 0.01). After 4 days, umbilical artery and ductus venosus velocity waveforms in the undelivered fetuses either returned to the type of waveform observed before treatment or showed further deterioration. No significant effects of betamethasone were observed in the fetal middle cerebral artery and uteroplacental circulation. CONCLUSIONS: Maternal antenatal betamethasone resulted in a significant transient change in the velocity waveform and a decrease in the pulsatility index in the umbilical artery and ductus venosus, but did not influence uteroplacental circulation. These findings indicate a direct effect of betamethasone on fetal circulation.