Fetal Growth Restriction Pregnancies Research Articles

Enhanced Nitrite-Mediated Relaxation of Placental Blood Vessels Exposed to Hypoxia Is Preserved in Pregnancies Complicated by Fetal Growth Restriction.

Nitric oxide (NO) is essential in the control of fetoplacental vascular tone, maintaining a high flow−low resistance circulation that favors oxygen and nutrient delivery to the fetus. Reduced fetoplacental blood flow is associated with pregnancy complications and is one of the major causes of fetal growth restriction (FGR). The reduction of dietary nitrate to nitrite and subsequently NO may provide an alternative source of NO in vivo. We have previously shown that nitrite induces vasorelaxation in placental blood vessels from normal pregnancies, and that this effect is enhanced under conditions of hypoxia. Herein, we aimed to determine whether nitrite could also act as a vasodilator in FGR. Using wire myography, vasorelaxant effects of nitrite were assessed on pre-constricted chorionic plate arteries (CPAs) and veins (CPVs) from normal and FGR pregnancies under normoxic and hypoxic conditions. Responses to the NO donor, sodium nitroprusside (SNP), were assessed in parallel. Nitrate and nitrite concentrations were measured in fetal plasma. Hypoxia significantly enhanced vasorelaxation to nitrite in FGR CPAs (p < 0.001), and in both normal (p < 0.001) and FGR (p < 0.01) CPVs. Vasorelaxation to SNP was also potentiated by hypoxia in both normal (p < 0.0001) and FGR (p < 0.01) CPVs. However, compared to vessels from normal pregnancies, CPVs from FGR pregnancies showed significantly lower reactivity to SNP (p < 0.01). Fetal plasma concentrations of nitrate and nitrite were not different between normal and FGR pregnancies. Together, these data show that nitrite-mediated vasorelaxation is preserved in FGR, suggesting that interventions targeting this pathway have the potential to improve fetoplacental blood flow in FGR pregnancies.

1159 Evaluation of fetal growth restriction in pregnancies complicated by buprenorphine therapy

To determine if a single growth ultrasound in the third trimester is as effective as serial growth ultrasounds to diagnose fetal growth restriction (FGR) in pregnancies exposed to buprenorphine therapy. This is a retrospective cohort study of pregnant women on buprenorphine opioid replacement therapy who delivered a singleton fetus at a tertiary care center between January 1, 2014 to December 31, 2019. Women were included if they had a growth ultrasound with MFM in the third trimester and at least one additional MFM ultrasound. Women served as their own control. The primary outcome was FGR, defined as estimated fetal weight less than the 10th percentile by Hadlock, on a single third trimester growth ultrasound compared to serial growth ultrasounds. Mantel-Haenszel Chi-square test was used to compare the proportion of patients diagnosed with FGR on a single ultrasound to serial ultrasounds. There were 294 pregnant women on buprenorphine therapy included in this study. The majority of the patients were single (81%), non-Hispanic white females (97%) who used tobacco (95%). Patients received an average of 3.7 ultrasounds > 20 weeks. When serial growth ultrasounds were performed, 79 fetuses were diagnosed with FGR (Table 1). Of the 79 cases, 73 fetuses were found to have FGR by evaluating a single third trimester growth ultrasound (p=0.57). The mean earliest gestational age of diagnosis of FGR was at 31w6d (SD±4w2d). In pregnant women on buprenorphine maintenance therapy, a single third trimester growth ultrasound is as effective in detecting fetal growth restriction when compared to serial growth ultrasounds. These data suggest that a single fetal growth assessment in the third trimester is sufficient for pregnant women on buprenorphine therapy. We recommend considering one growth ultrasound between 31-32 weeks to evaluate for fetal growth restriction in this population.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

957 Obstetric outcomes in patients undergoing expectant management for severe preeclampsia in fetal growth-restricted pregnancies

This study aimed to evaluate the obstetric outcomes of patients with pregnancies undergoing expectant management for preeclampsia with severe features (SPE) with or without fetal growth restriction (FGR) from 23 to 34 weeks’ gestation. This is a single-site, retrospective cohort study of patients with SPE who delivered from 2013 to 2019. Singleton, non-anomalous gestations expectantly managed for SPE for ≥ 24 hours and delivered between 23 to 34 weeks were included in the study. Pregnancies complicated by FGR, defined as estimated fetal weight (EFW) or abdominal circumference (AC) <10th percentile (Hadlock), were compared with those with EFW or (AC) ≥10%. The primary outcome was gestational age (GA) at delivery. Secondary outcomes included: days of expectant management, delivery indication, cesarean delivery, birth weight and neonatal length of stay. A bivariate analysis was performed to assess differences between the two groups. Of 207 women who met inclusion criteria, 89 were diagnosed with FGR and 114 were not diagnosed with FGR according to MFM ultrasound. Gestational age at delivery was earlier in the FGR pregnancies (29.6 ± 2.9 weeks vs. 30 ± 2.8 weeks; p=0.003). Significant differences were noted in all secondary outcomes except for days of expectant management (p=0.36) and delivery indication, mostly maternal (p=0.069; Table 1). Despite a similar latency period from diagnosis-to-delivery, women with SPE and FGR were diagnosed and delivered at earlier gestational ages, more frequently by cesarean section, had lower birth weights and longer NICU admissions compared to SPE women with no FGR. Additional studies with a larger sample size are needed to re-evaluate if more stringent guidelines are needed for patients undergoing expectant management in FGR pregnancies.

Why we succeed and fail in detecting fetal growth restriction: A population-based study.

The objective of this study was to explore the association between detection of fetal growth restriction and maternal-, healthcare provider- and organizational factors. A historical, observational, multicentre study. All women who gave birth to a child with a birthweight <2.3rd centile from 1 September 2012 to 31 August 2015 in Zealand, Denmark, were included. The population was identified through the Danish Fetal Medicine Database. Medical charts were reviewed to obtain data regarding maternal characteristics and information on the healthcare professionals. Date of authorization for the midwives and obstetricians involved was extracted from the Danish Health Authorization Registry. Multivariable Cox regression models were used to identify predictors of antenatal detection of fetal growth restriction, and analyses were adjusted for hospital, body mass index, parity, the presence of at least one risk factor and experience of the first midwife, number of midwife visits, number of visits to a doctor, the experience of the consultant midwife or the educational level of the doctor, the number of scans and gaps in continuity of midwife-care. Antenatal detection was defined as an ultrasound estimated fetal weight <2.3rd centile (corresponding to -2 standard deviations) prior to delivery. Among 78 544 pregnancies, 3069 (3.9%) had a fetal growth restriction. Detection occurred in 31% of fetal growth-restricted pregnancies. Clinical experience (defined as years since graduation) of the first consultation midwife was positively associated with detection, with a hazard ratio [HR] of 1.15, 95% confidence interval [CI] 1.03-1.28), for every 10years of additional experience. The hazard of detection increased with the number of midwife consultations (HR 1.15, 95% CI 1.05-1.26) and with multiparity (HR 1.28, 95% CI 1.03-1.58). After adjusting for all covariates, an unexplained difference between hospitals (P=.01) remained. The low-risk nullipara may constitute an overlooked group of women at increased risk of antenatal non-detection of fetal growth restriction. Being screened by experienced midwives during early pregnancy and having access to multiple midwife consultations may improve future diagnosis.

Ten-year experience of protocol-based management of small-for-gestational-age fetuses: perinatal outcome in late-pregnancy cases diagnosed after 32 weeks.

To report our 10-year experience of protocol-based management of small-for-gestational-age (SGA) fetuses, based on standardized clinical and Doppler criteria, in late-pregnancy cases. A retrospective cohort was constructed of consecutive singleton pregnancies referred for late-onset (> 32 weeks) SGA (defined as estimated fetal weight (EFW) < 10th centile) that were classified as fetal growth restriction (FGR) or low-risk SGA, based on the severity of smallness (EFW < 3rd centile) and the presence of Doppler abnormalities (uterine artery pulsatility index (UtA-PI) ≥ 95th centile or cerebroplacental ratio (CPR) < 5th centile). Low-risk SGA pregnancies were followed at 2-week intervals and delivered electively at 40 weeks. FGR pregnancies were followed at 1-week intervals, or more frequently if there were signs of fetal deterioration, and were delivered electively after 37 + 0 weeks' gestation. The occurrence of stillbirth and composite adverse outcome (CAO; defined as neonatal death, metabolic acidosis, need for endotracheal intubation or need for admission to the neonatal intensive care unit) was analyzed in low-risk SGA and FGR pregnancies. A total of 1197 pregnancies with EFW < 10th centile were identified and classified at diagnosis as low-risk SGA (n = 619; 51.7%) or FGR (n = 578; 48.3%). Of these, 160 were delivered before 37 weeks' gestation; for obstetric reasons in 93 (58.1%) cases, severe pre-eclampsia in 33 (20.6%), FGR with severe hypoxia in 47 (29.4%) and stillbirth in four (2.5%) (indications are non-exclusive). During follow-up, 52/574 (9.1%) low-risk SGA pregnancies were reclassified as FGR, whereas 22/463 (4.8%) FGR pregnancies were reclassified as low-risk SGA. Overall, there were no stillbirths in the low-risk SGA group and four in the FGR group, all of which occurred before 37 weeks. There were no instances of neonatal death in pregnancies delivered ≥ 37 weeks. The risk of CAO was higher in those meeting antenatal criteria for FGR at 37 weeks than in those classified as low-risk SGA (32/493 (6.5%) vs 15/544 (2.8%); odds ratio, 2.5 (95%CI, 1.3-4.6)). In FGR pregnancies, the adjusted odds ratio (95% CI) for CAO was 6.3 (1.8-21.1) in those with EFW < 3rd centile, while it was 3.2 (1.5-6.8) and 4.2 (1.9-8.9) in those with UtA-PI ≥ 95th centile and CPR < 5th centile, respectively, as compared to FGR pregnancies without each of these criteria. Protocol-based risk stratification with different management and monitoring schemes for late pregnancy with a suspected SGA baby, based on clinical and Doppler criteria, enables identification and tailored assessment of high-risk FGR, while allowing expectant management with safe perinatal outcome for low-risk SGA fetuses. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Effect of Pentaerythrityltetranitrate (PETN) on the Development of Fetal Growth Restriction in Pregnancies with Impaired Uteroplacental Perfusion at Mid Gestation – A Double Blinded Randomised Multicentre Trial

Effect of Pentaerythrityltetranitrate (PETN) on the Development of Fetal Growth Restriction in Pregnancies with Impaired Uteroplacental Perfusion at Mid Gestation – A Double Blinded Randomised Multicentre Trial

Characterization of Placental Microvascular Architecture by MV-Flow Imaging in Normal and Fetal Growth-Restricted Pregnancies.

To observe the microvascular architecture in the placental bed and explore the feasibility and clinical utility of MV-Flow imaging (Samsung Medison Co, Ltd, Seoul, Korea) during normal pregnancy and fetal growth restriction (FGR). Placental microvascular structure ultrasound imaging by MV-Flow was performed on 227 unaffected and 17 FGR fetuses between 11 and 41 weeks' gestation. A placental vascular index (VIMV ) was acquired by application of various MV-Flow regions of interest (ellipse, rectangle, and manual trace). Unaffected control and FGR groups were assessed for umbilical artery, middle cerebral artery, and uterine artery pulsatility indices and the cerebroplacental ratio calculated by ultrasound. No significant difference in the VIMV by varying regions of interest or placental regions was observed in the control group. The VIMV in the first trimester was lower than that in the second and third trimesters, with 5th through 95th percentile normal VIMV reference values of 18.39 to 63.79 for 13.6 weeks and earlier, 28.53 to 66.64 for 14 weeks to 27 weeks 6 days, and 21.95 to 67.45 for 28 weeks and later. The VIMV values in the FGR group were lower than those in the control group in the upper, middle, and lower parts of the placenta (mean ± SD, 24.9 ± 13.9 versus 45.0 ± 13.4; P < .01; 30.5 ± 16.1 versus 44.7 ± 14.3; P < .01; and 29.9 ± 17.4 versus 47.6 ± 12.2; P < .01, respectively). Higher umbilical artery and uterine artery pulsatility indices and a lower cerebroplacental ratio were found in the FGR group compared with the control group (P < .01). MV-Flow technology can display and quantify placental microvascular architecture at the level of the stem villi and villous leaves, and the VIMV provides for quantification of tissue vascularity. MV-Flow is a potentially powerful and promising tool to explore placental microvascular perfusion and provide new information on a host of pregnancy-related conditions.

Altered Levels of Decidual Immune Cell Subsets in Fetal Growth Restriction, Stillbirth, and Placental Pathology.

Immune cells are critically involved in placental development and functioning, and inadequate regulation of the maternal immune system is associated with placental pathology and pregnancy complications. This study aimed to explore numbers of decidual immune cells in pregnancies complicated with fetal growth restriction (FGR) and stillbirth (SB), and in placentas with histopathological lesions: maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), delayed villous maturation (DVM), chorioamnionitis (CA), and villitis of unknown etiology (VUE). Placental tissue from FGR (n = 250), SB (n = 64), and healthy pregnancies (n = 42) was included. Histopathological lesions were classified according to criteria developed by the Amsterdam Placental Workshop Group. Tissue slides were stained for CD68 (macrophages), CD206 (M2-like macrophages), CD3 (T cells), FOXP3 [regulatory T (Treg) cells], and CD56 [natural killer (NK) cells]. Cell numbers were analyzed in the decidua basalis using computerized morphometry. The Mann-Whitney U-test and Kruskal Wallis test with the Dunn's as post-hoc test were used for statistical analysis. Numbers of CD68+ macrophages were higher in FGR compared to healthy pregnancies (p < 0.001), accompanied by lower CD206+/CD68+ ratios (p < 0.01). In addition, in FGR higher numbers of FOXP3+ Treg cells were seen (p < 0.01) with elevated FOXP3+/CD3+ ratios (p < 0.01). Similarly, in SB elevated FOXP3+ Treg cells were found (p < 0.05) with a higher FOXP3+/CD3+ ratio (p < 0.01). Furthermore, a trend toward higher numbers of CD68+ macrophages was found (p < 0.1) in SB. Numbers of CD3+ and FOXP3+ cells were higher in placentas with VUE compared to placentas without lesions (p < 0.01 and p < 0.001), accompanied by higher FOXP3+/CD3+ ratios (p < 0.01). Elevated numbers of macrophages with a lower M2/total macrophage ratio in FGR suggest a role for a macrophage surplus in its pathogenesis and could specifically indicate involvement of inflammatory macrophages. Higher numbers of FOXP3+ Treg cells with higher Treg/total T cell ratios in VUE may be associated with impaired maternal-fetal tolerance and a compensatory response of Treg cells. The abundant presence of placental lesions in the FGR and SB cohorts might explain the increase of Treg/total T cell ratios in these groups. More functionality studies of the observed altered immune cell subsets are needed.

Magnetic resonance imaging measurement of placental perfusion and oxygen saturation in early-onset fetal growth restriction.

ObjectiveWe hypothesised that a multi-compartment magnetic resonance imaging (MRI) technique that is sensitive to fetal blood oxygenation would identify changes in placental blood volume and fetal blood oxygenation in pregnancies complicated by early-onset fetal growth restriction (FGR).DesignCase–control study.SettingLondon, UK.PopulationWomen with uncomplicated pregnancies (estimated fetal weight [EFW] >10th centile for gestational age [GA] and normal maternal and fetal Doppler ultrasound, n = 12) or early- onset FGR (EFW <3rd centile with or without abnormal Doppler ultrasound <32 weeks GA, n = 12) were studied.MethodsAll women underwent MRI examination. Using a multicompartment MRI technique, we quantified fetal and maternal blood volume and feto-placental blood oxygenation.Main outcome measuresDisease severity was stratified according to Doppler pulsatility index and the relationship to the MRI parameters was investigated, including the influence of GA at scan.ResultsThe FGR group (mean GA 27+5 weeks, range 24+2 to 33+6 weeks) had a significantly lower EFW compared with the control group (mean GA 29+1 weeks; –705 g, 95% CI –353 to –1057 g). MRI-derived feto-placental oxygen saturation was higher in controls compared with FGR (75 ± 9.6% versus 56 ± 16.2%, P = 0.02, 95% CI 7.8–30.3%). Feto-placental oxygen saturation estimation correlated strongly with GA at scan in controls (r = –0.83).ConclusionUsing a novel multimodal MRI protocol we demonstrated reduced feto-placental blood oxygen saturation in pregnancies complicated by early-onset FGR. The degree of abnormality correlated with disease severity defined by ultrasound Doppler findings. Gestational age-dependent changes in oxygen saturation were also present in normal pregnancies.

Aurora kinase mRNA expression is reduced with increasing gestational age and in severe early onset fetal growth restriction

IntroductionOxidative damage and biochemical ageing are implicated in placental dysfunction and potentially fetal death. Cellular senescence may play a role in the pathophysiology of fetal growth restriction (FGR) and preeclampsia (PE). Aurora kinases (AURKA, B and C) are important regulators of cellular division in mitosis and meiosis with implications in cellular senescence. We aimed to investigate whether aurora kinase expression is altered with placental dysfunction or placental ageing. MethodsPlacenta and blood was obtained across gestation from pregnancies complicated by PE, FGR or both PE and FGR, as well as gestation-matched control samples. Expression of AURKA, B and C mRNA was examined using real time qPCR in both the placenta and maternal circulation. ResultsPlacental aurora kinase expression decreased as gestation progressed: AURKA and AURKB were significantly reduced at 37–40 weeks, whereas AURKC was significantly reduced at 34–37 weeks, when compared to <34 weeks. In the maternal circulation, the mRNA level of AURKB was significantly reduced at >40 weeks compared to <34 weeks gestation. A significant reduction in AURKC was seen in FGR pregnancies <34 weeks compared to gestation-matched controls. ConclusionPlacental AURK expression is reduced with increased gestation. Circulating AURKB mRNA reduces at >40 weeks gestation, when compared to <34 weeks. AURKC is significantly reduced in placentas from pregnancies complicated by severe early onset (<34 weeks) FGR compared with gestation-matched controls. The functional role of aurora kinase in the placenta and in gestational age warrants further investigation.

Placental pathology in pregnancies complicated by fetal growth restriction: recurrence vs. new onset.

In an attempt to shed new light on the pathogenesis of fetal growth restriction (FGR), we aimed to study pregnancy characteristics, neonatal outcomes, and placental histopathological lesions of FGR pregnancies in two different subgroups: when developed after appropriate for gestational age (AGA) pregnancy and when developed after previous pregnancy with FGR. Pregnancy and placental reports of all singleton pregnancies complicated by FGR (defined as actual birthweight below the 10th percentile according to local birthweight nomograms) between 2008 and 2018 were reviewed. Included were only cases with previous delivery. Maternal background, neonatal outcomes, and placental histopathology were compared between FGR that occurred after FGR (recurrent FGR group) and FGR that occurred after an AGA pregnancy (FGR after AGA group). Placental lesions were classified according to the current "Amsterdam" criteria. Continuous variables were compared using the Student's t test or the Mann-Whitney test as appropriate. Categorical variables were compared using Chi-square or Fisher's exact test as appropriate. A total of 334 FGR cases with a previous delivery were included in the study. Of them, 111 cases constituted the recurrent FGR group and 223 constituted the FGR after AGA group. The recurrent FGR group was characterized by higher rates of maternal diabetes during pregnancy and hypertensive diseases (9% versus 2.7%, p = 0.01 and 19.8% versus 11.6%, p = 0.04). The FGR after AGA group was characterized by a higher rate of fetal vascular malperfusion (FVM) lesions (29.6% versus 18.0%, p = 0.02), and by lower mean birthweight (1842 ± 424.9 versus 1977.4 ± 412.2, p = 0.005), as compared to the recurrent FGR group. Recurrent FGR was associated with maternal background morbidities during pregnancy which represents a chronic repeated insult, while "new" FGR cases (those followed an AGA pregnancy) were characterized by a higher rate of FVM lesions and lower birthweight which probably represent an "accident" in placentation. These findings may suggest that different mechanisms of placental dysfunction exist in the two subgroups of FGR.

Fetal Oxygen and Glucose Consumption in Human Pregnancy Complicated by Fetal Growth Restriction.

In healthy pregnancy, glucose and oxygen availability are essential for fetal growth and well being. However, how substrate delivery and fetal uptake are affected in human pregnancy complicated by fetal growth restriction (FGR) is still unknown. Here, we show that the human FGR fetus has a strikingly reduced umbilical uptake of both oxygen and glucose. In 30 healthy term and 32 FGR human pregnancies, umbilical volume flow (Qumb) and parallel umbilical vein (uv) and artery (ua) blood samples were obtained at elective Cesarean section to calculate fetal glucose and oxygen uptake as Qumb · Δ (uv-ua) differences. Umbilical blood flow was significantly lower in FGR pregnancy (-63%; P<0.001) but not when normalized for fetal body weight. FGR pregnancy had significantly lower umbilical oxygen delivery and uptake, both as absolute values (delivery: -78%; uptake: -78%) and normalized (delivery: -50%; uptake: -48%) for fetal body weight (all P<0.001). Umbilical glucose absolute delivery and uptake were significantly reduced (delivery: -68%; uptake: -72%) but only glucose uptake was decreased when normalized for fetal body weight (-30%; P<0.05). The glucose/oxygen quotient was significantly increased (+100%; P<0.05) while glucose clearance was significantly decreased (71%; P<0.001) in FGR pregnancy (both P<0.05). The human fetus in FGR pregnancy triggers compensatory mechanisms to reduce its metabolic rate, matching the proportion of substrate consumption relative to oxygen delivery as a survival strategy during complicated pregnancy.

Evaluating the accuracy and precision of sonographic fetal weight estimation models in extremely early-onset fetal growth restriction.

Birthweight is a critical predictor of survival in extremely early-onset fetal growth restriction (diagnosed pre-28weeks' gestation, with abnormal umbilical/uterine artery Doppler waveforms), therefore accurate fetal weight estimation is a crucial component of antenatal management. Currently available sonographic fetal weight estimation models were predominantly developed in populations of mixed gestational age and varying fetal weights, but not specifically tested within the context of extremely early-onset fetal growth restriction. This study aimed to determine the accuracy and precision of fetal weight estimation in this population and investigate whether model performance is affected by other factors. Cases where a growth scan was performed within 48hours of delivery (n=65) were identified from a cohort of extremely early-onset fetal growth-restricted pregnancies at a single tertiary maternity center (n=159). Fetal biometry measurements were used to calculate estimated fetal weight using 21 previously published models. Systematic and random errors were calculated for each model and used to identify the best performing model, which in turn was used to explore the relationship between error and gestation, estimated fetal weight, fetal presentation, fetal asymmetry and amniotic fluid volume. Both systematic (median 8.2%; range -44.1 to 49.5%) and random error (median 11.6%; range 9.7-23.8%) varied widely across models. The best performing model was Hadlock head circumference-abdominal circumference-femur length (HC-AC-FL), regardless of gestational age, fetal size, fetal presentation or asymmetry, with an overall systematic error of 1.5% and random error of 9.7%. Despite this, it only calculated the estimated fetal weight within 10% of birthweight in 64.6% of cases. There was a weak negative relation between mean percentage error with Hadlock HC-AC-FL and amniotic fluid volume, suggesting fetal weight is overestimated at lower liquor volumes and underestimated at higher liquor volumes (P=0.002, adjusted R2 =0.08). Hadlock HC-AC-FL is the most accurate model currently available to estimate fetal weight in extremely early-onset fetal growth restriction independent of gestation or fetal size, asymmetry or presentation. However, for 35.4% of cases in this study, estimated fetal weight calculated using this model deviates by more than 10% from birthweight, highlighting a need for an improved model.

Elemental metabolomics in human cord blood: Method validation and trace element quantification

BackgroundTrace elements are an essential requirement for human health and development and changes in trace element status have been associated with pregnancy complications such as gestational diabetes mellitus (GDM), pre-eclampsia (PE), fetal growth restriction (FGR), and preterm birth. Elemental metabolomics, which involves the simultaneous quantification and characterisation of multiple elements, could provide important insights into these gestational disorders. MethodsThis study used an Agilent 7900 inductively coupled plasma mass spectrometer (ICP-MS) to simultaneously measure 68 elements, in 166 placental cord blood samples collected from women with various pregnancy complications (control, hypertensive, PE, GDM, FGR, pre-term, and post-term birth). ResultsThere were single element differences across gestational outcomes for elements Mg, P, Cr, Ni, Sr, Mo, I, Au, Pb, and U. Hypertensive and post-term pregnancies were significantly higher in Ni concentrations when compared to controls (control = 2.74 μg/L, hypertensive = 6.72 μg/L, post-term = 7.93 μg/L, p < 0.05), iodine concentration was significantly higher in post-term pregnancies (p < 0.05), and Pb concentrations were the lowest in pre-term pregnancies (pre-term = 2.79 μg/L, control = 4.68 μg/L, PE = 5.32 μg/L, GDM = 8.27 μg/L, p < 0.01). Further analysis was conducted using receiver operating characteristic (ROC) curves for differentiating pregnancy groups. The ratio of Sn/Pb showed the best diagnostic power in discriminating between control and pre-term birth with area under the curve (AUC) 0.86. When comparing control and post-term birth, Mg/Cr (AUC = 0.84), and Cr (AUC = 0.83) had the best diagnostic powers. In pre-term and post-term comparisons Ba was the best single element (81.5%), and P/Cu provided the best ratio (91.7%). ConclusionsThis study has shown that analysis of multiple elements can enable differentiation between fetal cord blood samples from control, hypertensive, PE, GDM, FGR, pre and post-term pregnancies. This data highlights the power of elemental metabolomics and provides a basis for future gestational studies.

Endocrine gland-derived vascular endothelial growth factor and placenta-mediated pregnancy complication

Placenta-mediated pregnancy complication (PMPC), including preeclampsia, fetal growth restriction and recurrent pregnancy loss, is caused by inadequate trophoblast invasion and abnormal remodeling of maternal spiral arteries in early pregnancy, resulting in adverse perinatal outcomes and affecting the long-term maternal and child health. However, the molecular mechanisms of PMPC remain unclear. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is highly expressed in human placenta and plays an important role in the development of a normal placenta through promoting placental angiogenesis and inhibiting trophoblast migration and invasion. EG-VEGF dysregulation is closely related to the pathogenesis of PMPC. This review described recent advances in EG-VEGF for better understanding of the underlying mechanism of PMPC and providing a potential biomarker for early diagnosis of PMPC. Key words: Pregnancy complications; Placenta diseases; Vascular endothelial growth factor, endocrine-gland-derived

OC25.07: Maternal hemodynamics in small‐for‐gestational‐age pregnancies with and without fetal growth restriction

Small-for-gestational-age (SGA) pregnancies, and in particular those with fetal growth restriction (FGR) are associated with an increased risk of adverse outcomes. Abnormal uterine artery (UtA) Doppler and other measures of maternal hemodynamics appear to be independently associated with adverse fetal outcome. The aim of this study was to describe the maternal hemodynamic differences in normotensive, SGA pregnancies with and without FGR. This was a prospective study of SGA and control pregnancies. Measurements of maternal hemodynamics, using a non-invasive device (USCOM-1A) were obtained. Variables that are affected by gestational age and maternal characteristics were corrected for using device-specific reference ranges. Pregnancies with evidence of FGR were compared to those with SGA only and normal pregnancies using descriptive statistics. Statistical analysis was performed using the Chi-squared test and Mann-Whitney test. A total of 102 FGR, 64 SGA and 401 control pregnancies at 28-41 weeks were included in the analysis. Compared to controls, the FGR group had significantly lower median heart rate (HR) (80bpm vs 85bpm, p = 0.001), lower cardiac output (CO) (0.91MoM vs 0.98MoM, p = 0.003), and higher systemic vascular resistance (SVR) (1.2MoM vs 1.0MoM, p < 0.001). There was no significant difference in stroke volume (SV) (1.0MoM vs 0.98MoM, p = 0.647) between the FGR and normal pregnancy groups. In contrast, there were no significant differences in maternal hemodynamics between the SGA and control groups. FGR pregnancies present with maternal cardiovascular dysfunction, as evidenced by lower HR and CO as well as higher mean arterial pressure (MAP), SVR and UtA resistance. SV is unchanged in FGR pregnancy suggesting that the observed drop in CO is a consequence of lower maternal HR. Pregnancies resulting in SGA neonate, without evidence of fetal hypoxemia or adverse outcome have normal cardiovascular adaptation. Maternal HR and other hemodynamic parameters may be of value in distinguishing SGA from FGR.

Pathologic placental lesions in early and late fetal growth restriction.

The purpose of the study was to evaluate the differences in individual histopathologic placental lesions in pregnancies complicated by early-onset (<32weeks at diagnosis) and late-onset (≥32weeks at diagnosis) fetal growth restriction (FGR). A cohort study of 440 singleton pregnancies complicated by FGR, diagnosed according to standard ultrasonographic criteria, followed up and delivered at the same institution between 2010 and 2016. Placental lesions were classified according to the Amsterdam Placental Workshop Consensus Criteria. Pathologic examination of placentas from 113 healthy singleton term pregnancies served as controls. Binary and multinomial logistic regression models were used to evaluate the independent association of placental lesions with the type of FGR. In our cohort the prevalences of early and late FGR were 37.3% (164/440) and 62.7% (276/440), respectively. The overall rates of preeclampsia (69/164 vs 59/276, P<0.01) and absent/reversed umbilical artery pulsatility indices (61/164 vs 14/276, P<0.001) were higher among early FGR than late FGR. Placental characteristics from early and late FGR pregnancies differed mainly in regard to maternal vascular malperfusion scores rather than fetal scores, with preeclampsia found to be a cofactor modulating the rates and severity of associated lesions. In the binary logistic analysis, recent infarcts (OR 2.44, 95% CI 1.2-5), distal villous hypoplasia (OR 1.8, 95% CI 1.0-3.2), atherosis (OR 2.71, 95% CI 1.35-5.47), persistent endovascular trophoblasts (OR 1.67, 95% CI 1.03-2.7), and a reduced fetal/placental weight score (OR 0.27, 95% CI 0.2-0.38) were independently associated with an increased likelihood of early FGR compared with late FGR. The sensitivity, specificity, and area under the curve of the model were 60% (95% CI 51.2-66.2), 89.1% (95% CI 84.9-92.3), and 0.81 (95% CI 0.77-0.85), respectively, suggesting a fair to good predictive value. Individual placental lesions suggestive of increased rates of ischemia, defective remodeling of spiral arteries, peripheral hypoxia interfering with villus development, and reduced placental efficiency were significantly more common in early FGR than late FGR.

The impact of placental massive perivillous fibrin deposition on neonatal outcome in pregnancies complicated by fetal growth restriction

IntroductionMassive perivillous fibrin deposition (MPDD) is an uncommon placental lesion which has been associated with an increased risk of adverse pregnancy outcome in retrospective series. The purpose of the study was to evaluate the frequency and consequences of MPFD in pregnancies complicated by fetal growth restriction (FGR). Materials and methodsA cohort study of 355 pregnancies complicated by FGR diagnosed according to standard ultrasonographic criteria, enrolled, followed and delivered at a single obstetric unit. Pathological placental lesions were classified according to the Amsterdam Placental Workshop Consensus. Penalized logistic regression models were used to evaluate the association of MPFD with maternal risk factors, other pathological lesions and neonatal outcome. ResultsThe rates of moderate (25–50% of villi) and severe (>50% of villi) MPFD were 8.7% (31/355) and 3.1% (11/355), respectively. Compared to other FGR cases, MPFD pregnancies were characterized by higher placental volume (450 ± 144.5 SD as compared to 412.2 ± 151 cm3,p < 0.001) and lower birthweight/placental weight ratio (5.32 ± 1.53 compared to 6.1 ± 1.52,p < 0.001). The rates of abnormal Doppler ultrasound studies of umbilical and middle cerebral artery were similar in MPFD subjects and controls. After correction for gestational age and birthweight, MPFD was associated with an increased risk of neonatal intraventricular hemorrhage (>grade II) (OR = 5.66,95% CI = 1.69–18.97), sepsis (OR = 5.9, 95% CI = 1.27–27.12), proven necrotizing enterocolitis (OR = 9.84,95% CI = 2.49–38.8) and overall severe adverse neonatal outcome (OR = 5.71,95% CI = 2.05–15.87). ConclusionsModerate-to-severe MPFD was relatively common among FGR pregnancies and was associated with morphometric modifications of placenta and with an increased risk of severe adverse neonatal outcome.

Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial

BackgroundAffecting approximately 10% of pregnancies, fetal growth restriction (FGR), is the most important cause of perinatal mortality and morbidity. Impaired placental function and consequent mal-perfusion of the placenta is the leading cause of FGR. Although, screening for placental insufficiency based on uterine artery Doppler measurement is well established, there is no treatment option for pregnancies threatened by FGR. The organic nitrate pentaerithrityl tetranitrate (PETN) is widely used for the treatment of cardiovascular disease and has been shown to have protective effects on human endothelial cells. In a randomized placebo controlled pilot-study our group could demonstrate a risk reduction of 39% for the development of FGR, and FGR or death, by administering PETN to patients with impaired uterine artery Doppler at mid gestation. To confirm these results a prospective randomized placebo controlled double-blinded multicentre trial was now initiated.MethodThe trial has been initiated in 14 centres in Germany. Inclusion criteria are abnormal uterine artery Doppler, defined by mean PI > 1.6, at 190 to 226 weeks of gestation in singleton pregnancies. Included patients will be monitored in 4-week intervals. Primary outcome measures are development of FGR (birth weight < 10th percentile), severe FGR (birth weight < 3rd centile) and perinatal death. Placental abruption, birth weight below the 3rd, 5th and 10th centile, development of FGR requiring delivery before 34 weeks` gestation, neonatal intensive care unit admission, and spontaneous preterm delivery < 34 weeks` and 37 weeks` gestation will be assessed as secondary endpoints. Patient enrolment was started in August 2017. Results are expected in 2020.DiscussionDuring the past decade therapeutic agents with possible perfusion optimizing potential have been evaluated in clinical trials to treat FGR. Meta-analysis and sub-analysis of trials targeting preeclampsia revealed ASS to have a potential in reducing FGR. Phosphodiesterase-type-5 inhibitors have recently been tested in a worldwide RCT for therapy of established FGR, failing to show an effect on neonatal outcome. The ongoing multicenter trial will, by confirming our previous results, finally provide a therapeutic option in cases at risk for FGR.Trial registrationDRKS00011374 registered at September 29th, 2017 and NCT03669185, registered September 13th, 2018.

Early‐onset fetal growth restriction: A systematic review on mortality and morbidity

IntroductionSevere early‐onset fetal growth restriction is an obstetric condition with significant risks of perinatal mortality, major and minor neonatal morbidity, and long‐term health sequelae. The prognosis of a fetus is influenced by the extent of prematurity and fetal weight. Clinical care is individually adjusted. In literature, survival rates vary and studies often only include live‐born neonates with missing rates of antenatal death. This systematic review aims to summarize the literature on mortality and morbidity.Material and methodsA broad literature search was conducted in OVID MEDLINE from 2000 to 26 April 2019 to identify studies on fetal growth restriction and perinatal death. Studies were excluded when all included children were born before 2000 because (neonatal) health care has considerably improved since this period. Studies were included that described fetal growth restriction diagnosed before 32 weeks of gestation and antenatal mortality and neonatal mortality and/or morbidity as outcome. Quality of evidence was rated with the GRADE instrument.ResultsOf the 2604 publications identified, 25 studies, reporting 2895 pregnancies, were included in the systematic review. Overall risk of bias in most studies was judged as low. The quality of evidence was generally rated as very low to moderate, except for 3 large well‐designed randomized controlled trials. When combining all data on mortality, in 355 of 2895 pregnancies (12%) the fetus died antenatally, 192 died in the neonatal period (8% of live‐born neonates) and 2347 (81% of all pregnancies) children survived. Of the neonatal morbidities recorded, respiratory distress syndrome (34% of the live‐born neonates), retinopathy of prematurity (13%) and sepsis (30%) were most common. Of 476 children that underwent neurodevelopmental assessment, 58 (12% of surviving children, 9% of all pregnancies) suffered from cognitive impairment and/or cerebral palsy.ConclusionsWhen combining the data of 25 included studies, survival in fetal growth restriction pregnancies, diagnosed before 32 weeks of gestation, was 81%. Neurodevelopmental impairment was assessed in a minority of surviving children. Individual prognostic counseling on the basis of these results is hampered by differences in patient and pregnancy characteristics within the included patient groups.