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FIGO (International Federation of Gynecology and Obstetrics) initiative on fetal growth: Best practice advice for screening, diagnosis, and management of fetal growth restriction
2021; Elsevier BV; Volume: 152; Issue: S1 Linguagem: Inglês
10.1002/ijgo.13522
ISSN1879-3479
AutoresNir Melamed, Ahmet Baschat, Yoav Yinon, Apostolos Athanasiadis, Federico Mecacci, F. Figueras, Vincenzo Berghella, Amala Nazareth, Muna Tahlak, David McIntyre, Fabrício da Silva Costa, Anne‐Beatrice Kihara, Eran Hadar, Fionnuala M. McAuliffe, Mark A. Hanson, Ronald C.W., Rachel Gooden, Eyal Sheiner, Anil Kapur, Hema Divakar, Diogo Ayres‐de‐Campos, Liran Hiersch, Liona C. Poon, John Kingdom, Roberto Romero, Moshe Hod,
Tópico(s)Gestational Diabetes Research and Management
ResumoFetal growth restriction (FGR) is defined as the failure of the fetus to meet its growth potential due to a pathological factor, most commonly placental dysfunction. Worldwide, FGR is a leading cause of stillbirth, neonatal mortality, and short- and long-term morbidity. Ongoing advances in clinical care, especially in definitions, diagnosis, and management of FGR, require efforts to effectively translate these changes to the wide range of obstetric care providers. This article highlights agreements based on current research in the diagnosis and management of FGR, and the areas that need more research to provide further clarification of recommendations. The purpose of this article is to provide a comprehensive summary of available evidence along with practical recommendations concerning the care of pregnancies at risk of or complicated by FGR, with the overall goal to decrease the risk of stillbirth and neonatal mortality and morbidity associated with this condition. To achieve these goals, FIGO (the International Federation of Gynecology and Obstetrics) brought together international experts to review and summarize current knowledge of FGR. This summary is directed at multiple stakeholders, including healthcare providers, healthcare delivery organizations and providers, FIGO member societies, and professional organizations. Recognizing the variation in the resources and expertise available for the management of FGR in different countries or regions, this article attempts to take into consideration the unique aspects of antenatal care in low-resource settings (labelled "LRS" in the recommendations). This was achieved by collaboration with authors and FIGO member societies from low-resource settings such as India, Sub-Saharan Africa, the Middle East, and Latin America. Aspects of FGR addressed in this article include prediction, diagnosis, investigation, management, and postpartum counselling. The main recommendations are given below and are summarized in Table 1 (section 8) and in the management algorithms for high-resource settings (Figure 1a) and low-resource settings (Figure 1b) (section 4). This article is directed at multiple stakeholders with the intention of bringing attention to the assessment of fetal growth, with a particular focus on the screening, diagnosis, and management of FGR, which is a leading cause of stillbirth and neonatal mortality and morbidity. This article proposes to standardize and provide guidance for the screening, prevention, diagnosis, and management of FGR. The intended target audience includes: Healthcare providers: all those qualified to care for pregnant women (obstetricians, maternal-fetal medicine specialists, general practitioners, midwives, nurses, advance practice clinicians, radiologists, sonographers, pediatricians, and neonatologists). Healthcare delivery organizations and providers: governments, federal and state legislators, healthcare management organizations, health insurance organizations, international development agencies, and nongovernmental organizations. Professional organizations: international, regional, and national professional organizations of obstetricians and gynecologists, obstetric ultrasound, family practitioners, pediatricians, neonatologists, and worldwide national organizations dedicated to the care of pregnant women and their offspring. In assessing the quality of evidence and grading of strength of recommendations, the article follows the terminology proposed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group.5 This system uses consistent language and graphical descriptions for the strength and quality of the recommendations and the evidence on which they are based. Recommendations are classified as strong or conditional (weak) (Table S1).6 The strength of recommendation is dependent not only on the quality of evidence, but also on factors such as risk–benefit, cost, resource allocation, values, and preferences. Thus, some recommendations may be based on low-quality evidence but still represent a benefit that outweighs the risks and burdens, and therefore may be strongly recommended. The overall quality of evidence was assessed for each of the recommendations and expressed using four levels of quality: very low, low, moderate, and high (Table S2).7 Considerations for quality of evidence include primarily the study design and methodology. As such, evidence based on randomized controlled trials is considered high-quality evidence, observational studies provide moderate or low quality of evidence, and all others are very low. However, other parameters must be considered while assessing the level of evidence: risk of bias, study limitations, consistency of results, precision, publication bias, indirectness of evidence, and scarcity of evidence. For the quality of evidence, cross-filled circles are used: ⊕○○○ denotes very low-quality evidence; ⊕⊕○○ low quality; ⊕⊕⊕○ moderate quality; and ⊕⊕⊕⊕ high-quality evidence. FGR is a common pregnancy complication that worldwide is a leading cause of stillbirth, neonatal mortality, and short- and long-term neonatal morbidity.8-15 The definition, diagnosis, and optimal management of FGR have generated controversy as clinicians strive for more harmonized care. The purpose of this article is to provide a summary of the available evidence and provide recommendations regarding the early prediction and prevention, diagnosis, investigation, monitoring, and timing of delivery of pregnancies complicated by FGR, with the overall goal to decrease the risk of stillbirth and neonatal mortality and morbidity associated with this pregnancy complication. Given the variation in resources and expertise available for the assessment and monitoring of pregnancies complicated by FGR in different countries or regions, we have included, in addition to the standard of care or "best" recommendations, specific recommendations for low-resource settings, which are marked as in the recommendation tables. Management algorithms for women in high-resource and low-resource settings are summarized in Figure 1a,b, respectively. FGR is defined as the failure of the fetus to meet its growth potential due to a pathological factor, most commonly placental dysfunction. Clinically, this is reflected by a drop in fetal size percentiles over the course of gestation. However, fetal growth potential is difficult to determine, and serial assessments of fetal size to detect a drop in fetal weight percentile are usually not available. Instead, care providers most commonly have only a "snapshot" of fetal weight estimation at a given point in time. Therefore, in clinical practice, small for gestational age (SGA), defined as estimated fetal weight (EFW) or abdominal circumference below a certain threshold such as the 10th or 3rd percentile, is most commonly used to suspect FGR. The use of SGA as a proxy for FGR has several limitations that need to be recognized. First, most SGA fetuses are constitutionally healthy small fetuses, whose smallness is merely the result of their predetermined growth potential (i.e. false-positive diagnosis of FGR). Second, some growth-restricted fetuses, depending on their original growth potential and timing of insult, may remain above the percentile threshold described above and may thus not be SGA (i.e. false-negative diagnosis of FGR). Third, the use of SGA as a proxy for FGR is limited by the accuracy of sonographic fetal weight estimation, which has an estimation error of up to ±15%–20%. Finally, the diagnosis of SGA is highly dependent on the growth chart being used, which can therefore have a considerable effect on the proportion of fetuses or infants flagged as SGA in a given population. It should be noted that there is inconsistency in the literature regarding the terminology described above, where some use the term FGR to describe a fetus with an estimated weight below the 10th percentile for gestational age and the term SGA to describe an infant with birth weight below the 10th percentile for gestational age. However, for the purpose of this article, the term SGA is used to indicate an EFW or birth weight below the 10th percentile for gestational age, and the term FGR to refer to a small fetus that has failed to achieve its growth potential because of a pathologic process. The major member societies of FIGO follow a definition using the 10th percentile as a means of diagnosing an SGA fetus, which then leads to further testing, assessment, and follow-up. There are proposals to address the limitations of this definition, but their validity regarding reduction in adverse outcomes needs to be tested. For example, in an attempt to overcome some of the limitations described above, a consensus-based definition for placenta-mediated FGR has been proposed via a Delphi procedure.1 To decrease the likelihood of false-positive and false-negative diagnosis of FGR, the consensus definition was based on a combination of measures of fetal size (fetal weight estimation and abdominal circumference) and abnormal Doppler findings in the umbilical, uterine, and middle cerebral arteries, as described in Box 1. The implementation of this definition is limited by the lack of a recommendation on which growth chart should be used to define the 10th and 3rd percentiles for EFW and fetal abdominal circumference. In addition, further research is needed to correlate this definition with adverse perinatal outcomes. Early-onset FGR (<32 weeks) Late-onset FGR (≥32 weeks) Abbreviations: AC, fetal abdominal circumference; AREDV, absent or reversed end-diastolic velocity; CPR, cerebroplacental ratio; EFW, estimated fetal weight; PI, pulsatility index; UA, umbilical artery; UtA, uterine artery. Adapted from Gordijn et al.1 It has been suggested that FGR should be broadly classified, based on gestational age at the time of diagnosis, into early-onset FGR (<32 weeks) and late-onset FGR (≥32 weeks). The rationale underlying this classification is based on differences between these two phenotypes of FGR in severity, natural history, Doppler findings, association with hypertensive complications, placental findings, and management.16-18 Early-onset FGR has a prevalence of 0.5%–1%, is usually more severe, and is more likely to be associated with abnormal umbilical artery Doppler than late-onset FGR. The underlying placental pathology is frequently similar to that observed in cases of early-onset pre-eclampsia (maternal vascular malperfusion), which explains the strong association of early-onset FGR with pre-eclampsia. Therefore, early-onset FGR is usually easier to detect, and the natural history tends to follow a predictable sequence of Doppler changes in the umbilical artery and ductus venosus. The main challenge in cases of early-onset FGR is management (i.e. timing of delivery), by attempting to determine the optimal balance between the opposing risks of stillbirth and prematurity.19 Late-onset FGR is more common than early-onset FGR with a prevalence of 5%–10%. In contrast to early-onset FGR, it is usually milder, is less likely to be associated with pre-eclampsia, and is usually associated with normal umbilical artery Doppler. Therefore, the main challenge with regard to late-onset FGR is diagnosis, while management (i.e. delivery) is relatively simple given that the diagnosis is commonly made during the late-preterm or term periods, where the risks associated with delivery are relatively small. The diagnosis of late-onset FGR mainly relies on adaptive changes in the cerebral circulation ("redistribution" or "brain-sparing effect"), which is reflected by low resistance to flow in the middle cerebral artery thereby generating a low cerebroplacental ratio, as described in section 8.1.7. Given that the umbilical artery and ductus venosus Doppler studies are usually normal in cases of late-onset FGR, the natural history in these cases is less predictable and there is a risk of sudden decompensation and stillbirth.16, 19 FGR is often the result of one or more maternal, placental, or fetal disorders that interfere with the normal mechanisms regulating fetal growth.20, 21 The most common etiologies of FGR are listed in Box 2. It is important to note that there is often confusion in the literature between "etiologies" (or pathogenetic pathways) and "risk factors" for FGR. For example, although maternal conditions such as chronic hypertension, kidney disease, systemic lupus erythematosus, and long-standing diabetes are often listed as "maternal etiologies" for FGR, these conditions should probably be viewed instead as maternal risk factors for abnormal placentation that may result in placenta-mediated FGR. Given that maternal nutrition and fetal growth are closely related,22, 23 maternal undernutrition is an important cause of FGR worldwide.24-26 The impact of maternal undernutrition on fetal growth depends on its timing and severity.20 To date, maternal interventions in dietary advice and modifications have lacked significant success in preventing FGR. While the mechanisms by which maternal anemia contribute to FGR are unclear, both impaired nutrient transport to the fetus 27 and abnormal placental adaptation to low maternal hemoglobin 28 have been suggested as potential mechanisms. Abnormal placentation is a common cause of FGR, 29 which is often diagnosed by ultrasound Doppler studies 30 and typical histopathological placental findings.31-33 Chromosomal abnormalities have been suggested to contribute to up to 5% of FGR cases; triploidy and trisomy 13 and 18 are important considerations in early-onset FGR and the risk of many aneuploidies is higher in the presence of structural fetal anomalies.34-36 In 1%–6% of cases of FGR with normal karyotype, submicroscopic (micro) duplications/deletions can be found using chromosomal microarray analysis,35 even when FGR is an apparently isolated finding.37 FGR is also more prevalent in fetuses with structural malformations, and the risk increases when multiple anomalies are present.38 FGR is related to intrauterine infection in up to 5% of cases.20, 39 Viral agents such as rubella, cytomegalovirus, HIV, and Zika are common causes of infection-related FGR.40-44 Protozoan infections like toxoplasmosis and malaria are another important cause, especially in endemic areas.45, 46 The main mechanism involved in the pathogenesis of FGR in these cases is a decline in cell population.20 Finally, maternal exposure to teratogens such as radiation,47 illicit drugs,48, 49 and alcohol50 is another important etiology for FGR. The main short- and long-term risks associated with FGR are listed in Box 3. It is associated with both fetal and obstetric complications. The most devastating complication is stillbirth,51-53 and there is a well-established inverse relationship between weight percentile and the risk of stillbirth,54-57 which is more pronounced in the early preterm period than at term.58 FGR is an important cause of iatrogenic preterm birth,59 as early delivery remains the main and perhaps only strategy for the prevention of stillbirth in cases of severe FGR.16, 60 FGR is also an independent risk factor for spontaneous preterm birth.61 Other obstetric complications associated with FGR include pre-eclampsia and placental abruption, as the pathophysiology of these conditions is often closely related.29, 30, 62-66 Despite ongoing improvements in neonatal care, FGR is associated with increased neonatal mortality and short-term morbidity. The risk of perinatal mortality in term FGR is reported to be five- to 10-fold higher than in appropriately grown neonates.57, 61, 67 The severity of FGR, Doppler abnormalities, and associated prematurity are independent predictors of neonatal complications.68 Among preterm infants, the co-presence of FGR further increases the risk of certain prematurity-related complications such as respiratory morbidity, intraventricular hemorrhage, necrotizing enterocolitis, and metabolic disorders.57 Among term infants, FGR increases the risks of low cord artery pH,69 low Apgar score,69 and neonatal complications such as hypoglycemia, hypothermia, and jaundice.70-72 Growth-restricted infants are also at risk of long-term complications including neurodevelopmental impairment 11, 73-78 and noncommunicable diseases.15, 79-82 This is discussed in greater detail in section 9.1 (Infant follow-up). Early prediction of FGR is important as it can identify women at high risk of FGR who may benefit from preventive interventions and close monitoring during pregnancy. Box 4 lists the most common risk factors for FGR. While the predictive value of individual risk factors is low, clinical prediction models that are based on combinations of the risk factors outlined below can considerably improve the prediction of FGR. One important limitation of most of the studies on early prediction of FGR is the lack of a gold standard for the antenatal or postnatal diagnosis of FGR. As such, there is wide variation among studies regarding the outcomes being predicted, including either SGA (birth weight below the 10th or 3rd percentile) or adverse perinatal outcomes that are associated with (but are not specific to) FGR. As many SGA infants are constitutionally small and healthy, differentiating between healthy small fetuses and those that are small due to FGR is critically important. As a rule, the prediction of early-onset severe FGR is better than of late-onset FGR. Abbreviations: FGR, fetal growth restriction; PlGF, placental growth factor; PAPP-A, pregnancy-associated plasma protein-A; AFP, alpha-fetoprotein. aRefers to placental dimension (short-based thick placenta) and texture (calcifications, echogenic cystic lesions). Several maternal factors influence fetal growth and the risk of FGR: advanced maternal age, racial/ethnic origin (e.g. South Asian), consanguinity, low body mass index, nulliparity, use of recreational drugs and alcohol, assisted reproductive technology, and medical disorders such as chronic hypertension, diabetes mellitus, and autoimmune conditions (Box 4).83-89 Cigarette smoking is a common risk factor for FGR and reduces birth weight by an average of 200 g in a dose–response manner.90 In a cohort of 33 602 pregnancies, maternal characteristics predicted 37% of women who subsequently delivered SGA neonates (birth weight 2 cm from placental disc margin), marginal (within 2 cm of margin), or velamentous (inserting into the surrounding membranes).114 In a cohort of 60 high-risk women with abnormal uterine artery Doppler, women with abnormal placental shape at 19–23 weeks had higher odds of FGR (OR 4.7) than women with normal placental shape.108 However, the use of 2D placental imaging has significant limitations, including difficulty in assessing nonanterior placentas and a wide variability in the morphology of normal placentas. Furthermore, there are no large-scale prospective studies validating the use of this modality for prediction of FGR.114 Improvements in ultrasonographic imaging provide a tool for estimating placental volume using three- and four-dimensional scanning techniques. Placental volume has been proposed as a marker for various obstetric complications related to defective placental function, including FGR.117, 118 A systematic review estimating the value of first-trimester 3D placental volume for the prediction of SGA found a detection rate of 24.7% at a 10% false-positive rate.119 Another parameter is the placental quotient, defined as the ratio of the placental volume to the fetal crown–rump length. The placental quotient was reported to have a high negative predictive value for perinatal complications but was not very useful when used for screening of SGA in a low-risk population, with a sensitivity of 27.1%.120 The discriminatory ability of placental volume alone for SGA appears to be modest, but may be integrated into a multivariable screening model. However, the use of 3D placental volume as a routine screening tool for FGR is limited by the need for proper equipment and training required to obtain these measurements in a reproducible manner. Currently there is no single screening test sufficiently predictive of FGR to recommend routine clinical use. Investigations are underway to combine various tests, but such prediction models have not been sufficiently validated in terms of outcomes studies and therefore must be considered investigative protocols at this time. In a prospective cohort of 4970 women, the combination of first-trimester maternal serum PAPP-A, beta hCG, maternal blood pressure, and uterine artery Doppler performed in the first trimester had a detection rate of 73% for early SGA (<34 weeks) but only 32% for late SGA (≥34 weeks).19 A different model that included maternal characteristics, first-trimester blood pressure, uterine artery pulsatility index, PlGF, and sFlt-1 was evaluated in a larger cohort of 9150 women and achieved a detection rate of 86% for early-onset FGR and 66% for late-onset FGR, both at a false-positive rate of 10%.19, 121 In the second trimester, the SCOPE consortium examined 5606 healthy nulliparous women with singleton pregnancies and found that the combination of clinical risk factors, 15-week biomarkers (53 biomarkers were used), and 20-week ultrasound (fetal biometry and Doppler studies of the umbilical and uterine arteries) had only a moderate detection rate for SGA below the 10th percentile, with a positive predictive value of 32% and a negative predictive value of 91%.122 Ideally, all women should plan their pregnancies, adopting a healthy lifestyle and optimizing any medical conditions and their body mass index. The preconception period provides an opportunity for health promotion with the aim of reducing accepted risk factors, including those associated with FGR.123 Insufficient gestational weight gain has been associated with an increased risk of FGR, especially in women with low body mass index (BMI, calculated as weight in kilograms divided by height in meters squared).124 Recognizing that these associations are only based on observational data, we still believe that it would be reasonable to recommend monitoring of weight gain and informing women of the target weight gain range, as recommended by the 2009 Institute of Medicine guidelines.125 These guidelines recommend a total gestational weight gain of 12.5–18 kg (28–40 lb) for underweight women (BMI <18.5); 11.5–16 kg (25–35 lb) for the normal weight group (BMI 18.5–24.9); 7–11.5 kg (15–25 lb) for overweight women (BMI 25.0–29.9); and 5–9 kg (11–20 lb) for obese women (BMI ≥30).126 Substance use, including smoking, alcohol, and illicit drugs, is associated with low birth weight and increased perinatal morbidity and mortality.90 Interventions to promote smoking cessation during pregnancy have been shown to result in a reduction in low birth weight (RR 0.81) and an increase in mean birth weight (+33 g).127 Women should be advised that smoking cessation at any point in gestation is of benefit, and that the greatest benefit is associated with cessation before 15 weeks of pregnancy.128 The risk of SGA with alcohol intake is increased with as little as one drink per day.129 Most studies on early prevention of placental complications have focused on pre-eclampsia, with the results often being extrapolated to FGR due to the common pathophysiology. However, to date, other than lifestyle modifications, no medical interventions to prevent FGR have been clearly established. Aspirin is recommended for women at increased risk of pre-eclampsia, but there is some evidence that it may a
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