Absent End-diastolic Flow Research Articles

Investigation of Serum Pregnancy-Specific Beta-1-Glycoprotein and Relationship with Fetal Growth Restriction.

ObjectiveThe most used definition for fetal growth restriction (FGR) is a fetus whose estimated weight is below the 10th percentile for its gestational age. Pregnancy-specific beta-1-glycoprotein (PSG-1) is an immunomodulator found in maternal serum during pregnancy. This study aimed to determine the serum levels of PSG-1 and clarify the potential role of this molecule in the etiopathogenesis of FGR.MethodsEighty women carrying fetuses with FGR and 80 healthy pregnant women were included in the study. Demographic data, laboratory values, and Doppler Ultrasonography (USG) results of all cases were recorded. Venous blood samples were taken from all cases before birth. PSG-1 values were studied by the ELISA method. An Independent Samples T-test was used to evaluate the results. The correlations between parameters were evaluated based on Spearman's rank correlation coefficient. P-values <0.05 were considered statistically significant.ResultsWhen the groups were evaluated for serum PSG-1 levels, the median serum PSG-1 level was lower in pregnant women carrying fetuses with FGR than in controls (0.05 < p>0.10). Median serum PSG-1 was lower in patients with absent end diastolic flow (AEDF) in the umbilical artery in Doppler ultrasound scans than in patients without AEDF, but the difference was not statistically significant (p>0.05). In patients with serum PSG-1 values below 12.93 with 50% sensitivity and 76% specificity, the risk of FGR was higher.ConclusionsSerum PSG-1 levels may be lower in complicated pregnancies due to problems related to placental insufficiency and FGR.

Retrograde Flow in the Aortic Isthmus: Trigger to Deliver Growth Restricted Fetuses Between 30 and 34 Weeks of Gestation?

Abstract Objective To evaluate the association of aortic isthmus (AoI) circulation assessed by doppler imaging in growth restricted fetuses with perinatal outcome. Design Prospective longitudinal observational study. Setting Tertiary referral center. Population Fetal growth restriction (FGR) (n = 38) between 24 and 36 weeks’ gestation. Methods Doppler examination of the aortic isthmus, umbilical artery (UA), middle cerebral artery, and ductus venosus (DV) was performed. The relationship between perinatal outcomes and antegrade (n = 25) and retrograde flow (n = 13) in the AoI and other Doppler parameters was analysed. Results Retrograde AoI group had higher rates of adverse perinatal outcome (92.3% vs. 72%) with 63.1% sensitivity and 87.5% specificity. Overall perinatal mortality (intrauterine death and neonatal death) was higher in the retrograde group (23%). No perinatal mortality was seen in the antegrade AoI group. Cases with absent end diastolic flow (AEDF) or reverse end diastolic flow (REDF) in the UA and retrograde flow in the AoI and normal DV flow had 40% prenatal mortality as 25% in those with abnormal DV Doppler. Conclusion Retrograde blood flow in the AoI is associated with adverse perinatal outcome, particularly intrauterine fetal demise, neonatal death, Respiratory Distress Syndrome (RDS) and increased duration of Neonatal Intensive Care Unit (NICU) stay. Even if DV flow is normal, adverse outcome might be suspected in fetuses with AEDF/REDF in the UA and retrograde flow in the AoI. Consequently, retrograde flow in the AoI might be considered as an additional trigger for delivering FGR fetuses at 30–34 weeks with AREDF in the UA. Larger longitudinal studies are, however, required to vaidate this.

Risk stratification for early-onset fetal growth restriction in women with abnormal serum biomarkers: a retrospective cohort study

Abnormal maternal serum biomarkers (AMSB), identified through the aneuploidy screening programme, are frequent incidental findings in pregnancy. They are associated with fetal growth restriction (FGR), but previous studies have not examined whether this association is with early-onset (< 34 weeks) or late-onset (> 34 weeks) FGR; as a result there is no consensus on management. The aims of this study were to determine the prevalence and phenotype of FGR in women with AMSB and test the predictive value of placental sonographic screening to predict early-onset FGR. 1196 pregnant women with AMSB underwent a 21–24 week “placental screen” comprising fetal and placental size, and uterine artery Doppler. Multivariable regression was used to calculate a predictive model for early-onset FGR (birthweight centile < 3rd/< 10th with absent umbilical end-diastolic flow, < 34 weeks). FGR prevalence was high (10.3%), however early-onset FGR was uncommon (2.3%). Placental screening effectively identified early-onset (area under the curve (AUC) 0.93, 95% confidence interval (CI) 0.87–1.00), but not late-onset FGR (AUC 0.70, 95% CI 0.64–0.75). Internal validation demonstrated robust performance for detection/exclusion of early-onset FGR. In this cohort, utilisation of our proposed algorithm with targeted fetal growth and Doppler surveillance, compared with universal comprehensive surveillance would have avoided 1044 scans, potentiating significant cost-saving for maternity services.

Fetal umbilical artery absent end-diastolic flow and decreased cerebral-placental ratio and pregnancy outcome and prognosis of survival children

Fetal umbilical artery absent end-diastolic flow and decreased cerebral-placental ratio and pregnancy outcome and prognosis of survival children

Umbilical and Middle Cerebral Artery Doppler Measurements in Fetuses With Congenital Heart Block

In fetal congenital complete heart block, the slow fetal heart rate prolongs the diastolic phase of the cardiac cycle, which may affect Doppler measurements that are typically used to quantify placental function. We here describe the umbilical artery (UA) and middle cerebral artery (MCA) Dopplers in a cohort of fetuses with heart block, hypothesizing that values will be increased but nevertheless remain associated with placental function and fetal outcome. We retrospectively reviewed Doppler measurements of the UA and MCA pulsatility index (PI) and resistance index in fetuses with complete heart block. The cerebroplacental ratio (CPR) was calculated as a marker of central redistribution. Measurements were transformed to Z scores and compared between fetuses born with a normal weight (appropriate for gestational age [AGA]) to those with fetal growth restriction (FGR) and correlated with a composite adverse outcome consisting of FGR, fetal death, or preterm birth prior to 34weeks' gestation. Fifty-four fetuses were included. There were 36 (67%) live births, 8 (22%) stillbirths, and 10 (19%) pregnancy terminations. Of those born alive, 14 (39%) had FGR. The UA PI decreased with gestational age and was higher in FGR compared with AGA fetuses (P<.001). Twenty-three percent of AGA fetuses developed absent end-diastolic flow in the UA. The MCA PI did not change with gestation and did not differ between AGA and FGR fetuses. The CPR was lower in FGR than in AGA fetuses (-2.43±0.85 vs -1.44±1.04, P=.006). The UA PI and resistance index were strongly correlated with the composite adverse outcome (P<.001). The UA and MCA PI are significantly elevated in fetuses with complete heart block. The UA Doppler indices and CPR nevertheless still reflect placental function. Longitudinal measurements may be useful in monitoring well-being in fetuses with heart block.

VP37.17: Impact of antenatal corticosteroids on umbilical artery Dopplers in growth‐restricted twin pregnancies

Assess the impact of antenatal corticosteroids (ACS) on umbilical artery Dopplers (UAD) in fetuses from twin pregnancies with growth restriction (FGR) and previously identified abnormal UAD. Retrospective cohort study of fetuses from twin pregnancies with FGR and absent end-diastolic flow (AEDF) on UAD in which ACS were given from November 2014 to October 2018 at a single centre. Monochorionic twin pregnancies with Twin–twin transfusion syndrome were excluded. Two twin pregnancies in the cohort had growth restriction of both fetuses and each fetus was treated as a separate subject. The cohort was divided into groups based on whether UAD performed within 7 days of ACS improved (return of diastolic flow), stayed the same (remained absent), or worsened (reversed end diastolic flow). Perinatal outcomes following ACS were analysed with ANOVA and Fisher's exact test when appropriate. There were 37 fetuses with FGR from 35 twin pregnancies (19 dichorionic-diamniotic, 15 monochorionic-diamniotic and 1 monochorionic-monoamniotic) during the study period. Following ACS, 21( 57%) of UAD improved and 16 (43%) were unchanged. Worsening of the UAD was not noted. No differences were noted in baseline maternal demographics or incidence of pre-existing maternal disease between groups. No difference in gestational age FGR diagnosis, ACS administration or delivery was noted. No perinatal deaths occurred in this cohort. Those with improved UAD were likely to have a higher birthweight (p = 0.002) and shorter NICU stay (p = 0.002). No other differences in perinatal outcomes following ACS were observed. Fetuses from twin pregnancies with AEDF on UAD that receive ACS have improvement in UAD 57% of the time that is associated with improved outcomes including shorter NICU duration and increased birthweight. Doppler response to ACS can assist with optimal antepartum management.

VP37.13: Clinical value of TEI index as an adjunct to Doppler velocimetry in diagnosis, surveillance and management of fetal growth restriction: a case report

A 31-year-old G2P0 (0100) was noted at 30 weeks gestation to have fetal growth lag on prenatal sonography. Cerebroplacental ratio was abnormal. Placental infarcts were noted. Placental mapping further revealed a Battledore placenta. At this time, TEI index was normal at 0.35. The patient was non-diabetic and non-hypertensive. She had a previous stillbirth at 28 weeks in her previous pregnancy. Anomaly scan was reviewed, infectious disease screening was carried out and results were unremarkable. Work-up for antiphospholipid antibody syndrome was suggested but patient was unable to comply. The patient was given antenatal steroids. Close fetal surveillance was carried out, with daily CTG, BPP twice weekly and weekly Doppler velocimetry. At 32 weeks, umbilical artery Doppler showed intermittent absent end diastolic flow with elevated pusatility index (PI). MCA PI was decreased, with an abnormal cerebroplacental ratio of 0.6. TEI index was 0.53. Family conference was done, with the decision to push as near to term as possible. At 33 weeks of gestation, absent end diastolic flow in the umbilical artery was noted, with deepening A-wave of the ductus venosus, and an elevated TEI index of 0.59. NST revealed persistently minimal variability. Thus intervention was done and patient delivered a livebaby boy weighing 1.7kg. Grossly, the placenta was small weighing 300 grams and the cord was thin, measuring 1cm, inserted at the placental edge. Histopathology report revealed placenta with infarcts and umbilical cord with venous thrombosis. Both mother and baby had unremarkable postpartum course and were discharged well. This case shows how TEI index can be used to augment findings on Doppler velocimetry in the surveillance and management of preterm fetuses with IUGR, secondary to uteroplacental insufficiency. Results from these investigations can guide the clinicians in making decisions regarding the timing of delivery to ensure the best maternal and fetal outcomes.

Fetal renal artery impedance in pregnancies affected by preeclampsia.

Background Preeclampsia (PE) is a pregnancy-specific vascular endothelial disorder characterized by multi-organ system involvement. This includes the maternal kidneys, with changes such as continuous vasospasm of renal arteries and reduced renal blood flow. However, it is unclear whether similar renal vascular changes are seen in the fetus. This study sought to compare renal artery impedance in fetuses of women with and without PE. Methods This was a prospective Doppler assessment study of the fetal renal artery impedance in 48 singleton fetuses. The group with PE consisted of 24 appropriately grown fetuses in pregnancy complicated by both mild and severe PE and a control group of 24 uncomplicated pregnancies. Doppler studies included renal artery systolic/diastolic (S/D) ratio, pulsatility index (PI), resistance index (RI), and identification of end-diastolic blood flow. Results Fetuses of mothers with PE were more likely to have a lower renal artery Doppler S/D ratio (7.85 [6.4-10.2] vs. 10.8 [7.75-22.5], P = 0.03) and lower RI (0.875 [0.842-0.898] vs. 0.905 [0.872-0.957], P = 0.03). However, there was no statistically significant difference in PI. There was also no difference in the incidence of absent end-diastolic flow. Conclusion This study suggests that PE results in changes in blood flow to the renal arteries of the fetus. This may be associated with long-term adverse health effects later in adulthood.

Indication for Doppler evaluation in the management of intrauterine growth restriction of vascular origin in Sub-Saharan Africa

Objective: To assess the contribution of Doppler in foetal monitoring and decision-making during delivery in case of in-utero vascular growth retardation.&#x0D; Design: We conducted a retrospective cohort study from January 2015 to December 2017 in the Gynaecology and Obstetrics Department of the Yopougon University Hospital (Abidjan, Ivory Coast). It included 130 patients who gave birth in a setting of pre-eclampsia with intrauterine growth restriction (IUGR) from 28 weeks of amenorrhoea.&#x0D; Results: The average age of patients was 31years. Nulliparous (33% of our patients) and pauciparous (41% of our patients) women were the group most affected. The mean gestational age at the first Doppler examination was 32 weeks of amenorrhoea. Doppler abnormalities were 65% in uterine Doppler and 90% in umbilical Doppler. The meancerebrovascular ratio was reversed in 90% of the cases. Perinatal mortality was 22.3% (n = 29) with 21 foetal death in utero and 8 neonatal deaths. The time interval between absent end-diastolic or reverse flow velocity and in-utero foetal death was 3.8 days.&#x0D; Conclusion: Foetal and umbilical Doppler ultrasound greatly modified the management of intrauterine growth retardation related to hypertension.

Trisomy 12p Syndrome Presenting with Fetal Growth Restriction and Polyhydramnios

A 39-year-old nulliparous woman was referred at 36+6 weeks gestational age, and a prenatal fetal ultrasonography examination found fetal growth restriction (2,190 g <5%), polyhydramnios (amniotic fluid index: 31.76 cm), and absent end-diastolic flow in the umbilical artery. A male baby was born, and fetal dysmorphism including round face, long philtrum, low-set ears, chest retraction, edematous hands and feet, and a simian line on both hands were identified. He was diagnosed with trisomy 12p [der(18)t(12;18)(p11.2;p11.31)] by chromosomal study. The father’s chromosomes appeared normal; however, the mother’s chromosomes had a balanced translocation identified as t(12;18)(p11.2;p11.31). Patent ductus arteriosus, germinal matrix hemorrhage, and hemivertebrae were diagnosed, and respiratory distress, hyperinsulinemic hypoglycemia, and hypothyroidism were also detected. The combination of fetal growth restriction and polyhydramnios may be a significant sign of chromosomal abnormalities, and targeted sonography and a chromosomal analysis should be offered prenatally in such cases.

Indication for Doppler evaluation in the management of intrauterine growth restriction of vascular origin in Sub-Saharan Africa

Objective: To assess the contribution of Doppler in foetal monitoring and decision-making during delivery in case of in-utero vascular growth retardation.&#x0D; Design: We conducted a retrospective cohort study from January 2015 to December 2017 in the Gynaecology and Obstetrics Department of the Yopougon University Hospital (Abidjan, Ivory Coast). It included 130 patients who gave birth in a setting of pre-eclampsia with intrauterine growth restriction (IUGR) from 28 weeks of amenorrhoea.&#x0D; Results: The average age of patients was 31years. Nulliparous (33% of our patients) and pauciparous (41% of our patients) women were the group most affected. The mean gestational age at the first Doppler examination was 32 weeks of amenorrhoea. Doppler abnormalities were 65% in uterine Doppler and 90% in umbilical Doppler. The meancerebrovascular ratio was reversed in 90% of the cases. Perinatal mortality was 22.3% (n = 29) with 21 foetal death in utero and 8 neonatal deaths. The time interval between absent end-diastolic or reverse flow velocity and in-utero foetal death was 3.8 days.&#x0D; Conclusion: Foetal and umbilical Doppler ultrasound greatly modified the management of intrauterine growth retardation related to hypertension.

Utility of the modified myocardial performance index in growth-restricted fetuses.

The modified myocardial performance index (Mod-MPI) can be used to assess myocardial function. Fetal growth restriction can affect fetal myocardial function, thereby altering the Mod-MPI. The results of previous studies on the utility of the Mod-MPI in growth-restricted fetuses are conflicting. The aim of this study was to calculate the left modified-MPI in growth-restricted fetuses and to compare the results with those of healthy fetuses. This was a prospective cross-sectional case-control study. In total, 40 women with growth-restricted fetuses and 40 women with fetuses of normal weight (controls) at 29-39 gestational weeks were enrolled in the study. An experienced obstetrician calculated the Mod-MPI for each fetus. Women with systemic diseases or fetuses with chromosomal/structural abnormalities were excluded from the study. The results of Mod-MPI measurements of the two groups were compared. The mean single deepest vertical pocket (SDVP) of amniotic fluid, estimated fetal weight (EFW), and isovolumetric relaxation time (IRT) was significantly lower in the fetal growth restriction (FGR) group as compared with these parameters in the control group (P<.05). The uterine artery (UtA) pulsatility index (PI) was significantly higher in the FGR group as compared with that in the control group (P<.05). There were six cases of absent end-diastolic flow (AED) in the FGR group. There were no statistically significant between-group differences in the Mod-MPI, isovolumetric contraction time (ICT), and ejection time (ET) (P>.05). There was also no statistically significant correlation between the Mod-MPI in the fetuses with AED and the control group for Mod-MPI (P>.05). The utility of the Mod-MPI in FGR remains unclear. Future studies with larger populations are needed to determine the utility of the Mod-MPI as a predictor of cardiac compromise in FGR.

Discrepancy in Doppler waveforms between two umbilical arteries in fetuses with absent or reversed end-diastolic flow: A prospective observational study.

To asses the occurrence of discrepancies between the Doppler waveforms of the left and right umbilical arteries in their paravesical part in fetuses with absent or reversed end-diastolic flow in the free-floating umbilical cord. This prospective observational study included pregnant women with fetal growth restriction or twin-to-twin transfusion syndrome. Umbilical arterial Doppler waveforms were obtained from both umbilical arteries in their intra-abdominal paravesical part. Doppler findings were recorded as present end-diastolic flow (PEDF)/absent end-diastolic flow (AEDF); AEDF/AEDF; AEDF/reversed end-diastolic flow (REDF); or REDF/REDF pattern. There were 49 fetuses with AEDF or REDF at the free-floating umbilical cord. Of these, 20 (40.8%) had a discrepancy in Doppler waveforms between the two umbilical arteries, with 14 (28.6%) showing PEDF/AEDF, 17 (34.7%) AEDF/AEDF, 6 (12.2%) AEDF/REDF, and 12 (24.5%) REDF/REDF pattern. Doppler waveforms showed discrepancies between the two umbilical arteries in 40.8% of pregnant women with AEDF or REDF in the free-floating umbilical cord. The presence of end-diastolic flow in one umbilical artery cannot exclude the possibility of AEDF in the other.

Screening and managing a low-risk pregnant population using continuous-wave Doppler ultrasound in a low-income population: A cohort analytical study.

In South Africa (SA), the largest category of perinatal deaths is unexplained stillbirths. Two-thirds of these occur in the antenatal period and most fetuses are macerated, but at antenatal clinics the mothers were generally regarded as healthy, with low-risk pregnancies. Innovative methods are urgently required to detect fetuses at risk of stillbirth and manage the mothers appropriately. To determine the prevalence of raised resistance indices (RIs) of the umbilical artery in a low-risk, low-income population and ascertain whether use of this information can prevent perinatal deaths. A descriptive study was performed in Mamelodi township, east of Pretoria, SA, on pregnant women attending antenatal clinics draining to two community health centres (CHCs). These women, classified as having low-risk pregnancies, were screened for placental insufficiency using a continuous-wave Doppler ultrasound apparatus (Umbiflow) between 28 and 32 weeks' gestation. When a raised RI was detected, the mother was referred to a high-risk clinic and managed according to a standard protocol. A cohort analytical study compared women who attended antenatal care at the same clinics as the Umbiflow group but did not have an Umbiflow test with those who had an Umbiflow test. The outcomes of all the deliveries in Mamelodi were recorded. The prevalences of abnormal RIs, absent end-diastolic flow (AEDF), stillbirths and neonatal deaths were the main outcome measures. An Umbiflow RI was performed in 2 868 women, and pregnancy outcome was available for 2 539 fetuses (88.5%); 297 fetuses (11.7%) were regarded as at high risk. AEDF was found in 1.5% of the population screened with an outcome. There were 29 perinatal deaths in the Umbiflow group (low risk n=18, high risk n=11). The perinatal mortality rate for 12 168 women attending the CHCs and the antenatal clinics draining to the CHCs who did not have an RI was 21.3/1 000 births, significantly higher than that in the Umbiflow group (11.4/1000births) (risk ratio 0.58, 95% confidence interval 0.42 - 0.81). The prevalence of AEDF in this low-risk population is ~10 times higher than that previously recorded. Use of the information prevented a number of perinatal deaths, most of which would have been macerated stillbirths. Screening a low-risk pregnant population using continuous-wave Doppler ultrasound may substantially reduce the prevalence of unexplained stillbirths in SA.

Placental malperfusion in response to intrauterine inflammation and its connection to fetal sequelae.

Exposure to intrauterine inflammation (IUI) is associated with short- and long-term adverse perinatal outcomes. However, little data exist on utilizing placenta to prognosticate fetal injury in this scenario. Our study aimed to utilize imaging modalities to evaluate mechanisms contributing to placental injury following IUI exposure and correlated it to concomitant fetal brain injury. CD1 pregnant dams underwent laparotomies and received intrauterine injections of either lipopolysaccharide (LPS; a model of IUI) or phosphate-buffered saline (PBS). In utero ultrasound Doppler velocimetry of uterine and umbilical arteries and magnetic resonance imaging (MRI) of placental volumes with confirmatory immunohistochemical (vimentin) and histochemistry (fibrin) analyses were performed. ELISA for thrombosis markers, fibrinogen and fibrin was performed to analyze thrombi in placenta. Fetal brain immunohistochemistry was performed to detect microglial activation (ionized calcium-binding adaptor molecule 1, Iba1). On ultrasound, LPS group demonstrated elevated resistance indices, pulsatility indices and a greater occurrence of absent end-diastolic flow in the umbilical and uterine arteries. In the fetus, there was an increased cardiac Tei indices in the LPS group. MRI revealed decreased volume of placenta in the LPS group associated with placental thinning and placental endothelial damage on immunohistochemistry. Decreased fibrinogen content and more thrombi staining in placenta exposed to maternal LPS indicated the hypercoagulability. Furthermore, the expression of Iba1was significantly associated with placental thickness (r = -0.7890, Pearson correlation coefficient). Our data indicate that IUI can trigger events leading to maternal placental malperfusion and fetal vessel resistance, as well as predispose the developing fetus to cardiac dysfunction and brain damage. Furthermore, our data suggest that prenatal ultrasound can be a real-time clinical tool for assessing fetal risk for adverse neurologic outcomes following the potential IUI exposure.

Doppler changes in umbilical artery and ductus venosus during fetoscopic prenatal surgical repair of myelomeningocele.

Cardiac dysfunction has been described in 60% of fetuses undergoing open myelomeningocele (MMC) repair. Routine Doppler evaluation of the umbilical artery (UA) and ductus venosus (DV) is challenging during fetal surgery. The aim of this study was to describe Doppler changes in the UA and DV in a cohort of fetuses during fetoscopic MMC repair. This was a retrospective study of fetuses that underwent fetoscopic repair of MMC at a single institution between 2014 and 2017. Ultrasound images taken intraoperatively were analyzed to describe the changes in Doppler parameters of the UA and DV during fetoscopic MMC repair. The timing of Doppler changes was matched with the phase of surgery to determine whether a pattern to their appearance could be ascertained. Of the thirty-five cases of fetoscopic MMC repair performed during the study period, Doppler data were available for 15. Of these, UA Doppler data were obtained in 12 cases, and DV Doppler data were obtained in 13 cases. Of the 12 cases for which there were UA data, nine (75%) showed transient absence of end-diastolic flow (EDF), with five (41.7%) of them progressing to reversal of EDF. Of the 13 cases for which there were DV data, nine had elevated pulsatility index; however, none of them had absent or reversed blood flow during atrial contraction. Of the nine cases with absent EDF in the UA, this abnormality first appeared during fetoscopic repair in five (55.6%), after uterus exteriorization but before CO2 insufflation in two (22.2%), after uterus replacement but before skin closure in one (11.1%) and after CO2 insufflation but before the start of the MMC repair in one (11.1%). Doppler abnormalities in four fetuses with reversed EDF and in three with absent EDF resolved during surgery. Follow-up examination 1 day after surgery demonstrated resolution of UA and DV Doppler abnormalities in all fetuses. Transient Doppler abnormalities of the UA, without significant changes in the DV, can be seen during fetoscopic MMC repair. The clinical significance of these Doppler findings remains unclear due to their transient and intermittent nature. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

554: Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation-induced oxidative stress

Oxidative stress induces vasoconstriction, hypercoagulation and pathologic vascular remodeling. We hypothesized that maternally-administered melatonin may reduce oxidative stress, hypercoagulability and structural injury in placenta, and prevent fetal sequelae in a mouse model of intrauterine inflammation(IUI)-induced oxidative stress. CD1 pregnant dams were randomized to intrauterine injections of either lipopolysaccharide (LPS; a model of IUI) or phosphate-buffered saline (PBS) at E17 as follows: (1) control (C); (2) Melatonin (M); (3) LPS (L); (4) LPS with Melatonin group (LM). Doppler ultrasonography was utilized to obtain fetal and maternal hemodynamic measurements in utero. Proinflammatory mediators (NFkB, TNFα, and IL1β), oxidative stress markers (4-HNE) and antioxidant mediators (Nrf2, HO1) were analyzed in the placenta by real-time RT-qPCR and western blots. Confirmatory histochemistry (PTAH, H&E, Nissl staining) and immunohistochemical analyses (Vimentin & CD31, a vascular endothelial cell marker; and Iba1, a marker of microglial activation) were performed. The systolic/diastolic (S/D) ratio, resistance index (RI) and pulsatility index (PI) in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared to C, M, or ML groups. The rate of early diastolic notch in the UtA and the rate of absent end-diastolic flow (AEDF) in UA were significantly higher in L than C, M, or ML. Tei indices were significantly increased in L compared to C, M, or ML. The rate of abnormal Tei indices (>0.44) was significantly higher in L compared to C, M, or ML. The expression of SIRT1, Nrf2 and HO1 in the placenta were significantly decreased in L comparing to C or ML. The expression of NFkB, TNFα, and IL1β were significantly increased in L comparing to C, and ML. 4-HNE was increased in L comparing to C, M and ML. The area of vimentin in the placenta was decreased in L than C or M. PTAH staining in the placenta showed increased deposit of fibrin in L comparing to C, M, or ML. Iba1 expression was increased in fetal brains in L compared to C, M, and ML. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise and fetal neuroinflammation induced by intrauterine oxidative stress. Current results suggest that melatonin could serve as a new preventive and/or therapeutic agent to prevent fetal injury from IUI-induced oxidative stress.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Feed intolerance in preterm neonates with antenatal reverse end diastolic flow (REDF) in umbilical artery: a retrospective cohort study

Background: Feed intolerance is common in growth-restricted infants with antenatal AREDF (absent or reverse end-diastolic flow) and presumed to be more severe in those with reverse end diastolic flow (REDF). Natural history of feeding in REDF is rarely reported in the literature.Aims and objectives: To determine the incidence of feed intolerance and necrotizing enterocolitis (NEC) in neonates with antenatal REDF.Design: Preterm inborn neonates with gestation <37 weeks with antenatal REDF diagnosed between January 2015 and September 2017 were included in this retrospective cohort study. The primary outcome was the proportion of neonates having feed intolerance and NEC till discharge or death or transfer to other hospitals and time to achieve full enteral feeding (150 ml/kg/day).Results: Out of total 67 born with antenatal REDF, 8 were transferred out within 48 hours, 8 records not available and 4 excluded due to major malformations. The mean (SD) gestation and birth weight of the remaining 48 neonates were 32 (2) weeks and 1096 (291) g. The median (IQR) age of initiation of feeds was 30 (24–37) hours. Feeds were advanced by median (range) 20 (10–20) ml/kg/day in which 22 babies (45%) had at least 1 episode of feed intolerance at a median (IQR) age of 79 (40–120) hours requiring nil per oral for next 48 (18–96) hours. Full feeds were reached by median age (IQR) of nine (8–12) days. Only 3 neonates (6%) had NEC stage 2 or above as per Bell’s staging.Conclusions: Feed intolerance is common in neonates with REDF though the risk of NEC is not high.What is known on this subject?Neonates with antenatal AREDF are at increased risk of feed intolerance and necrotizing enterocolitis.Early introduction of enteral feeds in neonates with AREDF with appropriate monitoring is safe without increased risk of necrotizing enterocolitis.AEDF which progresses to REDF is associated with increased morbidity.What does this study add?Early enteral feeding as early as 24 hours can be initiated in REDF if there are no abdominal symptoms and signs.Feed intolerance is high in REDF cases.The risk of NEC is not higher than what is seen in AEDF cases.

Placental erythropoietin expression is upregulated in growth-restricted fetuses with abnormal umbilical artery Doppler findings: a case\u2013control study of monochorionic twins

BackgroundWe previously reported that fetal plasma erythropoietin (EPO) concentrations are significantly increased in growth-restricted fetuses with abnormal umbilical artery (UA) Doppler. During hypoxia in an ovine model, the primary site of fetal EPO synthesis was switched from the kidneys to the placenta. Therefore, we designed this study to evaluate human placental EPO gene expression and the correlation to fetal serum EPO concentration in growth-restricted fetuses in a monochorionic (MC) twin model.MethodsIn MC twin pairs, selective intrauterine growth restriction (sIUGR) was defined as the presence of (i) birth weight discordance of > 20% and (ii) a smaller twin with a birth weight less than the 10th percentile. Fetal UA and middle cerebral artery (MCA) Doppler were checked within 1 week before delivery. An abnormal UA Doppler was defined as persistently absent or reverse end-diastolic flow. Cerebroplacental ratio (CPR) was defined as MCA-pulsatility index (PI)/UA-PI. Fetal plasma EPO concentrations were measured in cord blood, and EPO gene expression was assayed in each twin’s placental territory. The intertwin plasma EPO ratio was calculated as the cord plasma EPO level of the smaller (or sIUGR) twin divided by the EPO concentration of the larger (or appropriate-for-gestational-age (AGA)) twin, and the intertwin placental EPO gene expression ratio was calculated similarly.ResultsTwenty-six MC twins were analyzed, including normal twins (Group 1, n = 9), twins with sIUGR without UA Doppler abnormalities (Group 2, n = 9), and twins with sIUGR and UA Doppler abnormalities (Group 3, n = 8). The CPRs of smaller (sIUGR) fetuses were significantly decreased in Group 3 MC twins (p < 0.001), but not significantly different between Group 1 and Group 2. The highest fetal plasma EPO ratio and placental EPO gene expression ratio were identified in Group 3 MC twins (p < 0.001). The placental EPO gene expression ratios were significantly correlated with the fetal plasma EPO ratios (Pearson’s correlation test, p = 0.004).ConclusionThis study provides evidence of increased placental EPO expression in MC twin fetuses with sIUGR and abnormal UA Doppler. Future studies are needed to confirm the similar role of placental EPO in severe IUGR singletons.

Clinical implications of umbilical artery Doppler changes after betamethasone administration†

Background: Betamethasone (BMZ) is commonly administered to patients with fetal growth restriction (FGR) and abnormal umbilical artery Doppler (UAD) velocimetry due to the increased risk of preterm delivery; however, the clinical impact of UAD changes after BMZ exposure is unknown.Objective: To test the hypothesis that lack of UAD improvement after BMZ administration is associated with shorter latency and greater neonatal morbidity in patients with FGR.Study design: This was a retrospective cohort study of pregnancies complicated by FGR and abnormal UAD between 240 and 336 weeks gestation. Abnormal UAD included the following categories of increasing severity: elevated (pulsatility index >95%), absent end diastolic flow (EDF), or reversed EDF improvement was defined as any improvement in category of UAD within two weeks of BMZ. Sustained improvement was defined as improvement until the last ultrasound before delivery, whereas transient improvement was considered as unsustained. The primary outcome was latency, defined as interval from betamethasone administration to delivery. Secondary outcomes were gestational age at delivery, umbilical artery pH, and a composite of neonatal morbidity (intubation, necrotizing enterocolitis, ionotropic support, intraventricular hemorrhage, total parenteral nutrition, neonatal death). Outcomes were compared between (a) patients with and without UAD improvement and (b) patients with sustained and unsustained improvement, using univariable, multivariable and time-to-event analyses.Results: Of the 222 FGR pregnancies with abnormal UAD, 94 received BMZ and had follow-up ultrasounds. UAD improved in 48 (51.1%), with 27 (56.3%) having sustained improvement. Patients with hypertension and drug use were less likely to have UAD improvement. Patients without UAD improvement had shorter latency (21.5 days [interquartile range (IQR) 8,45] versus 35 [IQR 22,61], p = .02) and delivered at an earlier gestational age (34 weeks [IQR 31,36] versus 37 [IQR 33,37], p < .01) than those with improvement. There were no differences in umbilical artery pH between groups. Composite neonatal morbidity was higher in patients without UAD improvement, but this was not statistically significant after adjusting for confounders (aOR 2.0; 95% CI 0.08–5.1). There were no differences in outcomes between patients with sustained versus unsustained improvement.Conclusions: UAD improved in half of patients following BMZ. Lack of UAD improvement was associated with shorter latency and earlier gestational age at delivery, but no difference in composite neonatal morbidity. UAD response to BMZ may be useful to further risk stratify FGR pregnancies.