Aortic isthmus Doppler velocimetry: role in assessment of preterm fetal growth restriction

Intrauterine fetal growth restriction (IUGR) is an important pregnancy complication associated with significant adverse clinical outcome, stillbirth, perinatal morbidity and cerebral palsy. To date, no uniformly accepted management protocol of Doppler surveillance that reduces mortality and cognitive morbidity has emerged. Aortic isthmus (AoI) evaluation has been proposed as a potential monitoring tool for IUGR fetuses. In this review, the current knowledge of the relationship between AoI Doppler velocimetry and preterm fetal growth restriction is reviewed. Relevant technical aspects and reproducibility data are reviewed as we discuss AoI Doppler and its place within the existing repertoire of Doppler assessments in placental insufficiency. The AoI is a link between the right and left ventricles which perfuse the lower and upper body, respectively. The clinical use of AoI waveforms for monitoring fetal deterioration in IUGR has been limited, but preliminary work suggests that abnormal AoI impedance indices are an intermediate step between placental insufficiency-hypoxemia and cardiac decompensation. Further prospective studies correlating AoI indices with arterial and venous Doppler indices and perinatal outcome are required before encorporating this index into clinical practice. Copyright © 2010 John Wiley & Sons, Ltd.     

Severe early-onset fetal growth restriction: What do we tell the prospective parents?

Fetal growth restriction (FGR) is a common complication of pregnancy, associated with higher risk of perinatal mortality and adverse health and developmental outcomes for surviving infants. True FGR relates to a pathological restriction of fetal growth resulting from complex interactions between maternal, placental, fetal, and environmental factors. Early-onset FGR (onset <32 weeks' gestation) is often first suspected at routine mid-trimester sonographic assessment of fetal morphology, or identified as part of the placental syndrome, commonly maternal pre-eclampsia. Prenatal investigations may identify the cause of FGR. Timing of delivery is guided by serial sonographic surveillance of fetal growth and well-being and maternal condition, balancing the risk of stillbirth with the benefits of advancing gestation. This is particularly pertinent to severe early-onset FGR, a leading iatrogenic cause of very preterm birth. Prognosis is largely determined by the severity of FGR and its causes, gestation at birth, and birthweight. Pregnancy termination may be considered. Antenatal care and delivery in a tertiary center, provided by a multi-disciplinary team with expertise in managing high-risk pregnancies, are imperative to optimizing outcomes.     

Selective intrauterine growth restriction in monochorionic diamniotic twin pregnancies

Selective intrauterine growth restriction (sIUGR) occurs in 10 to 15% of monochorionic (MC) twins, and it is associated with a substantial increase in perinatal mortality and morbidity. Clinical evolution is largely influenced by the existence of intertwin placental anastomoses: pregnancies with similar degrees of fetal weight discordance are associated with remarkable differences in clinical behavior and outcome. We have proposed a classification of sIUGR into three types according to umbilical artery (UA) Doppler findings (I-normal, II-absent/reverse end-diastolic flow, III-intermittent absent/reverse end-diastolic flow), which correlates with distinct clinical behavior, placental features and may assist in counseling and management. In terms of prognosis, sIUGR can roughly be divided in two groups: type I cases, with a fairly good outcome, and types II and III, with a substantial risk for a poor outcome. Management of types II and III may consist in expectant management until deterioration of the IUGR fetus is observed, with the option of cord occlusion if this occurs before viability. Alternatively, active management can be considered electively, including cord occlusion or laser coagulation. Both therapies seem to increase the chances of intact survival of the larger fetus, while they entail, or increase the chances of, intrauterine demise of the IUGR fetus. Copyright © 2010 John Wiley & Sons, Ltd.     

Discordant growth in twins

Discordant growth in twins contributes significantly to rates of perinatal morbidity and mortality. These rates vary according to chorionicity, timing of onset and severity. We have reviewed English language literature in Medline since 1980. It is clear that diagnosis of discordant growth has improved due to the use of serial ultrasound examination. Following the detection of differences in fetal size, diagnosis is facilitated by umbilical artery and fetal Doppler studies. Management options vary according to chorionicity, timing of onset and umbilical-fetal Doppler studies. The mode of delivery in discordant twins remains controversial. We conclude that ultrasound surveillance of twin gestations, combining serial biometry and selective Doppler studies, is effective in the recognition of siginificant intrauterine growth restriction in co-twins. Differences in etiology and management underscore the imortance of establishing chorionicity routinely as soon as twin gestation is diagnosed. Copyright © 2005 John Wiley & Sons, Ltd.     

Blood-based biomarkers in the maternal circulation associated with fetal growth restriction

Fetal growth restriction (FGR) is associated with threefold to fourfold increased risk of stillbirth. Identifying FGR, through its commonly used surrogate—the small-for-gestational-age (SGA, estimated fetal weight and/or abdominal circumference <10th centile) fetus—and instituting fetal surveillance and timely delivery decrease stillbirth risk. Methods available to clinicians for antenatal identification of SGA fetuses have surprisingly poor sensitivity. About 80% of cases remain undetected. Measuring the symphysis-fundal height detects only 20% of SGA fetuses, and even universal third trimester ultrasound detects, at best, 57% of those born SGA. There is an urgent need to find better ways to identify this at-risk cohort. This review summarises efforts to identify molecular biomarkers (proteins, metabolites, or ribonucleic acids) that could be used to better predict FGR. Most studies examining potential biomarkers to date have utilised case-control study designs without proceeding to validation in independent cohorts. To develop a robust test for FGR, large prospective studies are required with a priori validation plans and cohorts. Given that current clinical care detects 20% of SGA fetuses, even a screening test with ≥60% sensitivity at 90% specificity could be clinically useful, if developed. This may be an achievable aspiration. If discovered, such a test may decrease stillbirth.     

Can anomalies of fetal brain circulation be useful in the management of growth restricted fetuses?

Assessment of the fetal cerebral circulation provides important information on the hemodynamic changes associated with chronic hypoxia and intrauterine growth restriction. Despite the incorporation of new US parameters, the landmark for the fetal brain hemodynamic evaluation is still the middle cerebral artery. However, new vascular territories, such as the anterior and posterior cerebral arteries, might provide additional information on the onset of the brain sparing effect. The fractional moving blood volume estimation and three-dimensional power Doppler ultrasound indices are new techniques that seem to be promising in indentifying cases at earlier stages of vascular deterioration; still, they are not available for clinical application and more information is needed on the reproducibility and advantages of three-dimensional power Doppler ultrasound blood flow indices. In the past, the brain sparing effect was considered as a protective mechanism; however, recent information challenges this concept. There is growing evidence of an association between brain sparing effect and increased risk of abnormal neurodevelopment after birth. Even in mild late-onset intrauterine growth restriction affected fetuses with normal umbilical artery blood flow, increased cerebral blood perfusion can be associated with a substantial risk of abnormal neuroadaptation and neurodevelopment during childhood. © 2012 John Wiley & Sons, Ltd.     

Antenatal detection of a single umbilical artery: does it matter?

The presence of a single umbilical artery is recognised as a soft marker for congenital anomalies, aneuploidy, earlier delivery and low birthweight. Most of the available data are derived from case series or highly selected populations and are therefore likely to be unrepresentative. In this retrospective case-comparison study, we firstly aimed to determine the incidence of a single umbilical artery in an unselected population and secondly to examine the clinical significance of this soft marker. Over a 40-month period, 107 cases were identified from a cohort of 35 066 births giving an incidence of 3.1 per 1000 total births and late pregnancy losses. The antenatal detection rate was only 30%. Compared to fetuses with normal cord vasculature, fetuses with a single umbilical artery were more likely to be delivered at an earlier gestation and to weigh less, were 1.7 times more likely to be delivered by a Caesarean section and 19% of the cases had a congenital anomaly. The perinatal mortality was 49.0 per 1000 total births, which was 6 times higher than the background hospital rate. The presence of a single umbilical artery is associated with a poorer perinatal outcome compared to that in fetuses with three vessels in the cord. Unfortunately, the antenatal detection rate is poor. Recognising the importance of this soft marker in counselling and management of pregnancies should provide the stimulus to improve detection rates. Copyright © 2003 John Wiley & Sons, Ltd.     

Intrauterine growth restriction (IUGR): biometric and Doppler assessment

Intrauterine growth restriction (IUGR) is a common complication in pregnancy and influences morbidity and mortality at all stages of life. Historically, the management of IUGR has been dependent on antenatal biophysical testing and umbilical artery Doppler studies. With recent Doppler studies of the fetal central circulation, including intracardiac flows and the ductus venosus, better timing of delivery to minimize morbidity may be possible. This review will provide the reader with tools to diagnose IUGR, more accurately date the IUGR pregnancy with poor dating criteria, and better assess the condition of the IUGR fetus. A brief review of animal models of IUGR is presented to demonstrate research directions for answering human clinical questions and potentially carrying therapeutic intervention from the bench to the bedside. Copyright © 2002 John Wiley & Sons, Ltd.     

Genetic syndromes associated with isolated fetal growth restriction

Early onset fetal growth restriction (FGR) may be due to impaired placentation, environmental or toxic exposure, congenital infections or genetic abnormalities. Remarkable research, mainly based on retrospective series, has been published on the diverse genetic causes. Those have become more and more relevant with the improvement in the accuracy of the analysis techniques and the rising of breakthrough genomewide methods such as the whole genome sequencing. However, no publication has presented an integrated view of management of those fetuses with an early and severe affection. In this review, we explored to which extent genetic syndromes can cause FGR fetuses without structural defects. The most common chromosomal abnormalities (Triploidies and Trisomy 18), submicroscopic chromosomal anomalies (22q11.2 microduplication syndrome) and single gene disorders (often associated with mild ultrasound findings) related to early and severe FGR had been analysed. Finally, we addressed the impact of epigenetic marks on fetal growth, a matter of growing importance. At the end of this review, we should be able to provide an adequate counseling to parents in terms of diagnosis, prognosis and management of those pregnancies.     

First-trimester maternal factors and biomarker screening for preeclampsia

Preeclampsia (PE), which affects about 2% of pregnancies, is a major cause of maternal and perinatal morbidity and mortality. PE can be subdivided into early onset PE with delivery <34 weeks' gestation and late onset PE with delivery ≥34 weeks. Early onset PE is associated with a higher incidence of adverse outcome. This review illustrates that effective screening for the development of early onset PE can be provided in the first-trimester of pregnancy. Screening by a combination of maternal risk factors, mean arterial pressure, uterine artery Doppler, maternal serum pregnancy-associated plasma protein-A and placental growth factor can identify about 95% of cases of early onset PE for a false-positive rate of 10%. © 2014 John Wiley & Sons, Ltd.     

Prenatal diagnosis and management of twin pregnancies complicated by a co-existing molar pregnancy

Recent advances in ultrasound and molecular genetics have increased our understanding and hence enhanced the perinatal management of complete and partial hydatidiform mole. By contrast, the management of a twin pregnancy combining a normal pregnancy with a normal fetus and a complete hydatidiform mole (CHM) remains complex and controversial due to conflicting data from different parts of the world. The aim of this review is to analyse the international literature on twin pregnancies that include a mole, present the complications and outcome of pregnancy and to discuss the perinatal management. Management is complicated and women should be counselled about the maternal and fetal complications, and the pregnancy monitored carefully by a perinatal team with experience in high-risk obstetrics and access to neonatal care. The data reviewed here suggest that a woman who decides to continue with the pregnancy including a CHM must be aware that, overall, she only has a one in four chance of live birth and in around 35% of cases she will develop persistent trophoblastic disease (PTD) after delivery. In ongoing pregnancies, there will be, in at least 20% of the cases, an early onset of pre-eclampsia (PET) and a 29% risk of fetal loss due to late miscarriage, intrauterine death and neonatal death. Maternal serum human chorionic gonadotrophin (MShCG) could be useful in predicting outcome in twin pregnancy combining normal pregnancy and CHM, but this needs to be investigated prospectively. Copyright © 2005 John Wiley & Sons, Ltd.     

Cytogenetic abnormalities among perinatal deaths demonstrating a single umbilical artery

The presence of a single umbilical artery is associated with fetal congenital malformations and cytogenetic abnormalities. The incidence of chromosomal abnormalities in perinatal deaths complicated by a single umbilical artery is unknown. We studied the proportion of cytogenetic abnormalities associated with a single umbilical artery among perinatal deaths undergoing autopsy. Of 1078 autopsies, 42 (3·9 per cent) were identified with a single umbilical artery. Chromosome analysis was attempted in 21 of the 42 cases (50 per cent). There were 16 successful chromosome analyses, of which three (18·75 per cent) were abnormal. All the chromosomally abnormal fetuses had major congenital malformations. These data suggest that in a perinatal death, the presence of a single umbilical artery does not clinically alter the a priori risk of cytogenetic abnormalities.     

Adverse perinatal outcome in patients screen-positive for neural tube defects and fetal down syndrome

An association between various abnormal mid-trimester maternal serum analyte values and adverse perinatal outcome has been reported. From an original sample of 14 857 women, we observed five women who were ‘screen-positive’ for both neural tube defects [maternal serum alpha-fetoprotein (MSAFP) ≥2·5 multiples of the median] and Down syndrome [risk ≥1/274 using MSAFP, maternal serum unconjugated oestriol (MSuE3), maternal serum human chorionic gonadotropin (MShCG), and maternal age]. The four patients who elected to undergo amniocentesis all demonstrated both normal karyotype and normal amniotic fluid AFP levels. All five cases were associated with intrauterine growth retardation (IUGR) and abnormal pregnancy outcomes. Two cases exhibiting severe IUGR on ultrasound examination were terminated at 19·1 and 21·2 weeks, respectively; the former also exhibited fetal calcifications and positive maternal serology for toxoplasmosis. In another case, fetal demise occurred at 36 weeks' gestation in a patient who had been treated for syphilis in the second trimester. Neither infection was confirmed in fetal tissue studies. Though resulting in live births, the remaining two cases required operative deliveries; emergency Caesarean sections for fetal distress were performed at 38 and 32 weeks, respectively, the latter case being associated with severe pre-eclampsia. We conclude that elevated mid-trimester MSAFP levels concurrent with maternal serum analyte values associated with increased risk for fetal Down syndrome may presage a poor perinatal outcome, particularly IUGR and possibly congenital infection.     

Prenatal testing for Imprinting Disorders: A clinical perspective

Imprinting Disorders (ImpDis) are a group of congenital conditions caused by aberrant imprinting resulting in disturbed expression of parentally imprinted genes. ImpDis are rarely associated with major malformations, but pre- and/or postnatal growth and nutrition are often affected. In some ImpDis, behavioral, developmental, metabolic and neurological symptoms might present in the perinatal context or later in life, and in single ImpDis, there is a higher risk of tumors in childhood. Prognosis depends in part on the molecular cause of each ImpDis, but due to high clinical variability and (epi)genetic mosaicism, predicting the clinical outcome of a pregnancy solely based on the underlying molecular disturbance is difficult. Therefore, interdisciplinary care and treatment approaches play an important role in the management and decision making of affected pregnancies, especially taking into account fetal imaging in addition to genetic findings. Prenatal findings influence perinatal management, and thereby improve the prognosis of ImpDis associated with severe but sometimes transient clinical complications in the neonatal period. Therefore, prenatal diagnosis can be crucial for appropriate management not only to the pregnancy itself but might also have a life-long effect.     

Discrepancy in placental echogenicity: a sign of twin anemia polycythemia sequence

Twin anemia polycythemia sequence (TAPS) is a form of twin-to-twin transfusion syndrome that occurs very rarely and may not be diagnosed until after delivery. The condition leads to increased risk of perinatal morbidity and mortality. We present two cases of monochorionic diamniotic twins, in which the diagnosis of TAPS was made after documenting a discrepancy in the echodensities of the two portions of the placenta. Postnatal hemoglobin differences between the twins confirmed the diagnosis of TAPS. On the basis of these two cases, it appears that the heterogeneity in placental echogenicity is a sign of TAPS and Doppler measurement of middle cerebral artery peak systolic velocity is helpful for early diagnosis and management with timely delivery. © 2014 John Wiley & Sons, Ltd.     

Improvement of mesenteric superior artery Doppler velocimetry by amnio-infusion in fetal gastroschisis†

This study aimed to analyse the influence of amnio-infusion on superior mesenteric Doppler velocimetry and to correlate Doppler data with outcome in fetuses presenting with gastroschisis. Umbilical and intra- and extra-abdominal superior mesenteric artery Doppler velocimetry was measured prospectively before and after amnio-infusion in fetuses with gastroschisis. Doppler index values and changes were correlated with the following outcome parameters: importance of fibrous coating, duration of hospitalization in the neonatal intensive care unit, total duration of hospitalization, duration of parenteral feeding, duration of ventilatory assistance, and the interval to initiation of oral feeding. A significant improvement of diastolic flow was observed in the extra-abdominal superior mesenteric artery with amnio-infusion. No similar change was seen in the intra-abdominal superior mesenteric or in the umbilical artery. Pre-amnioinfusion extra-abdominal mesenteric Doppler index was correlated with maximal diameter of exteriorized bowel and slightly with duration of hospitalization in the neonatal intensive care unit, but no other relation between Doppler index and outcome parameter could be ascertained. Amnio-infusion induces modifications in the vascularization of exteriorized bowel in gastroschisis. This could partly explain the beneficial effect of this procedure on fetal gut. Copyright © 2001 John Wiley & Sons, Ltd.     

Cardiac flow after fetal blood sampling in normally grown and growth-retarded fetuses

The objective of this study was to evaluate the effect of fetal blood sampling on cardiac flow velocity waveforms. Flow velocity waveforms were measured from the ascending aorta and pulmonary artery immediately before and after fetal blood sampling in 29 normally grown and 12 growth-retarded fetuses. The latter group was characterized by abnormal Doppler indices in the umbilical artery and middle cerebral artery suggestive of uteroplacental insufficiency as the causative factor of the impaired growth. The flow velocity parameters studied were the peak velocity, the time to peak velocity, and the left and right cardiac output and their ratio. In normally grown fetuses, the peak velocity and right and left cardiac output values increased significantly after fetal blood sampling, while no significant changes were observed in the other indices considered. The gestational age at the time of the procedure was positively related to the amplitude of these changes. In growth-retarded fetuses, fetal blood sampling did not induce any significant increase in cardiac output or peak velocities, while in more than 50 per cent of the fetuses these Doppler indices decreased. The amplitude of the decrease was significantly related to the severity of acidosis in the umbilical vein. In conclusion, the cardiac haemodynamic response to fetal blood sampling differs between normally grown and growth-retarded fetuses. This difference may explain the higher rate of complications occurring in the latter group of fetuses after blood sampling.     

The use of imaging technology in the assessment of the fetal inflammatory response syndrome—imaging of the fetal thymus

The fetal inflammatory response syndrome (FIRS) describes a state of extensive fetal multi organ involvement during chorioamnionitis, and is associated with grave implications on perinatal outcome. The syndrome has been linked to the preterm parturition syndrome and is associated with inflammation/infection processes in most of the fetal organs. The fetal thymus, a major organ in the developing immune system involutes during severe neonatal disease and has been shown to be smaller in fetuses with FIRS. Various methods for imaging of the fetal thymus and measurement are described. Currently the only method to diagnose FIRS prenatally is through amniocentesis. We suggest that women who are admitted with preterm labor with intact membranes and those with PPROM should have a detailed sonographic examination of the fetal thymus as a surrogate marker of fetal involvement in intrauterine infection/inflammation processes. © 2015 John Wiley & Sons, Ltd.     

Overview of low molecular weight heparin for preventative treatment of adverse obstetric outcomes related to abnormal placentation

Different proportions of cases of preterm and severe preeclampsia, placental abruption, fetal growth restriction, and fetal death share a common causal pathway of abnormal placental implantation. Documentation of an association between the risk of such adverse pregnancy outcomes (APOs) and inherited thrombophilias prompted initial studies to evaluate the benefit of anticoagulants for the prevention of recurrences both in patients with and without inherited thrombophilias. Prenatal administration of low molecular weight heparin (LMWH) has been evaluated in case control, cohort and randomized clinical trials. The evidence suggests a benefit of LMWH in the reduction of recurrences of APOs, with a number needed to treat of 6 (95% confidence interval: 4–10) to prevent one case of recurrent APOs. Such benefit is independent of the presence of inherited thrombophilias or the administration of low dose aspirin. Further studies are needed to establish the optimal duration for the prophylaxis, to better delineate the mechanism of action of LMWH and to explore the role, if any, of maternal serum markers and uterine artery Doppler findings in the modulation of the LMWH prophylaxis. © 2014 John Wiley & Sons, Ltd.     

Diagnostic yield of exome sequencing in isolated fetal growth restriction: Systematic review and meta-analysis

The aim of this study was to determine the diagnostic yield of exome sequencing (ES) above that of chromosomal microarray analysis (CMA) or karyotyping in fetuses with isolated fetal growth restriction (FGR). This was a systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Selected studies included those with (a) only fetuses with FGR in the absence of fetal structural anomalies and (b) negative CMA or karyotyping results. Only positive variants classified as likely pathogenic or pathogenic determined as causative of the fetal phenotype were considered. A negative CMA or karyotype result was treated as the reference standard. Eight studies with data on ES diagnostic yield, including 146 fetuses with isolated FGR, were identified. Overall, a pathogenic variant determined as potentially causative of the fetal phenotype was found in 17 cases, resulting in a 12% (95% CI: 7%–18%) incremental performance pool of ES. The vast majority were studied before 32 weeks'gestation. In conclusion, a monogenic disorder was prenatally found in association with apparently isolated FGR in 12% of these fetuses.