Maternal and fetal risk factors for stillbirth : population based study

Objective: To assess the main risk factors associated with stillbirth in a multiethnic English maternity population. Design: Cohort study. Setting: National Health Service region in England. Population: 92 218 normally formed singletons including 389 stillbirths from 24 weeks of gestation, delivered during 2009-11. Main outcome measure: Risk of stillbirth. Results: Multivariable analysis identified a significant risk of stillbirth for parity (para 0 and para ≥3), ethnicity (African, African-Caribbean, Indian, and Pakistani), maternal obesity (body mass index ≥30), smoking, pre-existing diabetes, and history of mental health problems, antepartum haemorrhage, and fetal growth restriction (birth weight below 10th customised birthweight centile). As potentially modifiable risk factors, maternal obesity, smoking in pregnancy, and fetal growth restriction together accounted for 56.1% of the stillbirths. Presence of fetal growth restriction constituted the highest risk, and this applied to pregnancies where mothers did not smoke (adjusted relative risk 7.8, 95% confidence interval 6.6 to 10.9), did smoke (5.7, 3.6 to 10.9), and were exposed to passive smoke only (10.0, 6.6 to 15.8). Fetal growth restriction also had the largest population attributable risk for stillbirth and was fivefold greater if it was not detected antenatally than when it was (32.0% v 6.2%). In total, 195 of the 389 stillbirths in this cohort had fetal growth restriction, but in 160 (82%) it had not been detected antenatally. Antenatal recognition of fetal growth restriction resulted in delivery 10 days earlier than when it was not detected: median 270 (interquartile range 261-279) days v 280 (interquartile range 273-287) days. The overall stillbirth rate (per 1000 births) was 4.2, but only 2.4 in pregnancies without fetal growth restriction, increasing to 9.7 with antenatally detected fetal growth restriction and 19.8 when it was not detected. Conclusion: Most normally formed singleton stillbirths are potentially avoidable. The single largest risk factor is unrecognised fetal growth restriction, and preventive strategies need to focus on improving antenatal detection

Fetal Growth Restriction

Fetal growth defect is classified into intrauterine growth restriction (IUGR) and small-for-gestational-age (SGA) fetus based on the estimated fetal weight percentile and Doppler hemodynamic parameters. IUGR pathophysiology and etiology are complex and diverse, highlighting placental insufficiency as a paradigm, which explains its association with other entities of great clinical importance such as preeclampsia. The poor long- and short-term perinatal and postnatal results associated with this context make it necessary to establish an early diagnosis and a therapeutic strategy, which can be challenging due to the compromise between the threat of intrauterine permanence and the prematurity problem. Consequently, a systematic and protocolized diagnostic-therapeutic management, based on scientific evidence, is necessary to determine whether obstetric intervention through a preterm delivery is advisable to improve the perinatal outcomes of these patients

Current practice in the diagnosis and management of fetal growth restriction: An international survey

Introduction The aim of this survey was to evaluate the current practice in respect of diagnosis and management of fetal growth restriction among obstetricians in different countries. Material and methods An e-questionnaire was sent via REDCap with "click thru" links in emails and newsletters to obstetric practitioners in different countries and settings with different levels of expertise. Clinical scenarios in early and late fetal growth restriction were given, followed by structured questions/response pairings. Results A total of 275 participants replied to the survey with 87% of responses complete. Participants were obstetrician/gynecologists (54%; 148/275) and fetal medicine specialists (43%; 117/275), and the majority practiced in a tertiary teaching hospital (56%; 153/275). Delphi consensus criteria for fetal growth restriction diagnosis were used by 81% of participants (223/275) and 82% (225/274) included a drop in fetal growth velocity in their diagnostic criteria for late fetal growth restriction. For early fetal growth restriction, TRUFFLE criteria were used for fetal monitoring and delivery timing by 81% (223/275). For late fetal growth restriction, indices of cerebral blood flow redistribution were used by 99% (250/252), most commonly cerebroplacental ratio (54%, 134/250). Delivery timing was informed by cerebral blood flow redistribution in 72% (176/244), used from >= 32 weeks of gestation. Maternal biomarkers and hemodynamics, as additional tools in the context of early-onset fetal growth restriction (<= 32 weeks of gestation), were used by 22% (51/232) and 46% (106/230), respectively. Conclusions The diagnosis and management of fetal growth restriction are fairly homogeneous among different countries and levels of practice, particularly for early fetal growth restriction. Indices of cerebral flow distribution are widely used in the diagnosis and management of late fetal growth restriction, whereas maternal biomarkers and hemodynamics are less frequently assessed but more so in early rather than late fetal growth restriction. Further standardization is needed for the definition of cerebral blood flow redistribution

Compensatory Feto-Placental Upregulation of the Nitric Oxide System during Fetal Growth Restriction

Background: Fetal Growth Restriction is often associated with a feto-placental vascular dysfunction conceivably involving endothelial cells. Our study aimed to verify this pathogenic role for feto-placental endothelial cells and, coincidentally, demonstrate any abnormality in the nitric oxide system. Methods: Prenatal assessment of feto-placental vascular function was combined with measurement of nitric oxide (in the form of S-nitrosohemoglobin) and its nitrite byproduct, and of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. Umbilical vein endothelial cells were also harvested to determine their gene profile. The study comprised term pregnancies with normal (n = 40) or small-for-gestational-age (n = 20) newborns, small-for-gestational-age preterm pregnancies (n = 15), and bi-chorial, bi-amniotic twin pregnancies with discordant fetal growth (n = 12). Results: Umbilical blood nitrite (p<0.001) and S-nitrosohemoglobin (p = 0.02) rose with fetal growth restriction while asymmetric dimethylarginine decreased (p = 0.003). Nitrite rise coincided with an abnormal Doppler profile from umbilical arteries. Fetal growth restriction umbilical vein endothelial cells produced more nitrite and also exhibited reciprocal changes in vasodilator (upwards) and vasoconstrictor (downwards) transcripts. Elevation in blood nitrite and S-nitrosohemoglobin persisted postnatally in the fetal growth restriction offspring. Conclusion: Fetal growth restriction is typified by increased nitric oxide production during pregnancy and after birth. This response is viewed as an adaptative event to sustain placental blood flow. However, its occurrence may modify the endothelial phenotype and may ultimately represent an element of risk for cardiovascular disease in adult life.Fil: Pisaneschi, Silvia. Università degli Studi di Pisa; Italia. Scuola Superiore Sant’Anna; ItaliaFil: Strigini, Francesca A. L.. Università degli Studi di Pisa; ItaliaFil: Sanchez, Angel Matias. Università degli Studi di Pisa; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Begliuomini, Silvia. Università degli Studi di Pisa; ItaliaFil: Casarosa, Elena. Università degli Studi di Pisa; ItaliaFil: Ripoli, Andrea. National Research Council. Institute of Clinical Physiology, ; ItaliaFil: Ghirri, Paolo. Università degli Studi di Pisa; ItaliaFil: Boldrini, Antonio. Università degli Studi di Pisa; ItaliaFil: Fink, Bruno. Noxygen Science Transfer and Diagnostics; AlemaniaFil: Genazzani, Andrea R.. Università degli Studi di Pisa; ItaliaFil: Coceani, Flavio. Scuola Superiore Sant’Anna; ItaliaFil: Simoncini, Tommaso. Università degli Studi di Pisa; Itali

The Role of Proteoglycans in Contributing to Placental Thrombosis and Fetal Growth Restriction

Fetal growth restriction is an important pregnancy complication that has major consequences for the fetus and neonate as well as an increased risk of long-term morbidity extending into adulthood. The precise aetiology of most cases of fetal growth restriction is unknown although placental thrombosis is a common feature in many of these cases. This paper will outline the potential role of proteoglycans in contributing to placental thrombosis and fetal growth restriction

Efficacy of transverse cerebellar diameter/abdominal circumference ratio: a gestational age independent parameter in assessing fetal growth restriction

Background: It is important to identify fetal growth restriction (FGR) antenatally because it is associated with increased perinatal morbidity and mortality. There is difficulty in diagnosis of fetal growth restriction using standard ultrasonographic parameters as they are gestational age related and are not reliable in cases of symmetrical growth restriction. Therefore, there is a need for gestational age independent biometric parameter, which can diagnose fetal growth restriction in unknown gestational age and can diagnose both symmetric and asymmetric fetal growth restriction. In this study transverse cerebellar diameter (TCD)/abdominal circumference (AC) ratio used to diagnose fetal growth restriction. Objectives of the study were to evaluate the validity of TCD/AC ratio in diagnosing fetal growth restriction and to find out the cut-off value of TCD/AC ratio for diagnosis of fetal growth restriction.Methods: This study was carried out for 12 months and sample size was 100. Transverse cerebellar diameter, abdominal circumference measured between 20-22wks and 32-34weeks of gestation and transverse cerebellar diameter and abdominal circumference ratio calculated.Results: TCD/AC ratio was fairly constant throughout the pregnancy. Fetuses with TCD/AC ratio more than 2SD of the mean were found growth restricted on examination. The TCD/AC ratio more accurate in diagnosing fetal growth restriction (FGR).Conclusions: As the TCD/AC ratio is constant, it is a gestational age - independent parameter, can diagnose FGR in antenatal women with unknown gestational age. Hence, TCD/AC ratio can be a screening test to diagnose FGR in the antenatal period

Long-term cardiovascular consequences of fetal growth restriction: biology, clinical implications, and opportunities for prevention of adult disease

In the modern world, cardiovascular disease is a leading cause of death for both men and women. Epidemiologic studies consistently have suggested an association between low birthweight and/or fetal growth restriction and increased rate of cardiovascular mortality in adulthood. Furthermore, experimental and clinical studies have demonstrated that sustained nutrient and oxygen restriction that are associated with fetal growth restriction activate adaptive cardiovascular changes that might explain this association. Fetal growth restriction results in metabolic programming that may increase the risk of metabolic syndrome and, consequently, of cardiovascular morbidity in the adult. In addition, fetal growth restriction is strongly associated with fetal cardiac and arterial remodeling and a subclinical state of cardiovascular dysfunction. The cardiovascular effects ocurring in fetal life, includes cardiac morphology changes, subclinical myocardial dysfunction, arterial remodeling, and impaired endothelial function, persist into childhood and adolescence. Importantly, these changes have been described in all clinical presentations of fetal growth restriction, from severe early- to milder late-onset forms. In this review we summarize the current evidence on the cardiovascular effects of fetal growth restriction, from subcellular to organ structure and function as well as from fetal to early postnatal life. Future research needs to elucidate whether and how early life cardiovascular remodeling persists into adulthood and determines the increased cardiovascular mortality rate described in epidemiologic studies

A Core Outcome Set for the prevention and treatment of fetal GROwth restriction: deVeloping Endpoints: the COSGROVE study.

BACKGROUND: Fetal growth restriction refers to a fetus that does not reach its genetically predetermined growth potential. It is well-recognized that growth-restricted fetuses are at increased risk of both short- and long-term adverse outcomes. Systematic evaluation of the evidence from clinical trials of fetal growth restriction is often difficult because of variation in the outcomes that are measured and reported. The development of core outcome sets for fetal growth restriction studies would enable future trials to measure similar meaningful outcomes. OBJECTIVE: The purpose of this study was to develop core outcome sets for trials of prevention or treatment of fetal growth restriction. STUDY DESIGN: This was a Delphi consensus study. A comprehensive literature review was conducted to identify outcomes that were reported in studies of prevention or treatment of fetal growth restriction. All outcomes were presented for prioritization to key stakeholders (135 healthcare providers, 68 researchers/academics, and 35 members of the public) in 3 rounds of online Delphi surveys. A priori consensus criteria were used to reach agreement on the final outcomes for inclusion in the core outcome set at a face-to-face meeting with 5 healthcare providers, 5 researchers/academics, and 6 maternity service users. RESULTS: In total, 22 outcomes were included in the final core outcome set. These outcomes were grouped under 4 domains: maternal (n=4), fetal (n=1), neonatal (n=12), and childhood (n=5). CONCLUSION: The Core Outcome Set for the prevention and treatment of fetal GROwth restriction: deVeloping Endpoints study identified a large number of potentially relevant outcomes and then reached consensus on those factors that, as a minimum, should be measured and reported in all future trials of prevention or treatment of fetal growth restriction. This will enable future trials to measure similar meaningful outcomes and to ensure that findings from different studies can be compared and combined

Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers.

Fetal growth restriction is a major determinant of perinatal morbidity and mortality. Screening for fetal growth restriction is a key element of prenatal care but it is recognized to be problematic. Screening using clinical risk assessment and targeting ultrasound to high-risk women is the standard of care in the United States and United Kingdom, but the approach is known to have low sensitivity. Systematic reviews of randomized controlled trials do not demonstrate any benefit from universal ultrasound screening for fetal growth restriction in the third trimester, but the evidence base is not strong. Implementation of universal ultrasound screening in low-risk women in France failed to reduce the risk of complications among small-for-gestational-age infants but did appear to cause iatrogenic harm to false positives. One strategy to making progress is to improve screening by developing more sensitive and specific tests with the key goal of differentiating between healthy small fetuses and those that are small through fetal growth restriction. As abnormal placentation is thought to be the major cause of fetal growth restriction, one approach is to combine fetal biometry with an indicator of placental dysfunction. In the past, these indicators were generally ultrasonic measurements, such as Doppler flow velocimetry of the uteroplacental circulation. However, another promising approach is to combine ultrasonic suspicion of small-for-gestational-age infant with a blood test indicating placental dysfunction. Thus far, much of the research on maternal serum biomarkers for fetal growth restriction has involved the secondary analysis of tests performed for other indications, such as fetal aneuploidies. An exemplar of this is pregnancy-associated plasma protein A. This blood test is performed primarily to assess the risk of Down syndrome, but women with low first-trimester levels are now serially scanned in later pregnancy due to associations with placental causes of stillbirth, including fetal growth restriction. The development of "omic" technologies presents a huge opportunity to identify novel biomarkers for fetal growth restriction. The hope is that when such markers are measured alongside ultrasonic fetal biometry, the combination would have strong predictive power for fetal growth restriction and its related complications. However, a series of important methodological considerations in assessing the diagnostic effectiveness of new tests will have to be addressed. The challenge thereafter will be to identify novel disease-modifying interventions, which are the essential partner to an effective screening test to achieve clinically effective population-based screening

Maternal proteomic profiling reveals alterations in lipid metabolism in late-onset fetal growth restriction

Fetal growth restriction defined as the failure to achieve the fetal genetic growth potential is a major cause of perinatal morbidity and mortality. The role of maternal adaptations to placental insufficiency in this disorder is still not fully understood. We aimed to investigate the biological processes and protein-protein interactions involved in late-onset fetal growth restriction in particular. We applied 2D nano LC-MS/MS proteomics analysis on maternal blood samples collected at the time of delivery from 5 singleton pregnancies with late-onset fetal growth restriction and 5 uncomplicated pregnancies. Data were analyzed using R package 'limma' and Ingenuity Pathway Analysis. 25 proteins showed significant changes in their relative abundance in late-onset fetal growth restriction (p value < 0.05). Direct protein-protein interactions network demonstrated that Neurogenic locus notch homolog protein 1 (NOTCH1) was the most significant putative upstream regulator of the observed profile. Gene ontology analysis of these proteins revealed the involvement of 14 canonical pathways. The most significant biological processes were efflux of cholesterol, efflux of phospholipids, adhesion of blood cells, fatty acid metabolism and dyslipidemia. Future studies are warranted to validate the potential role of the detected altered proteins as potential therapeutic targets in the late-onset form of fetal growth restriction