Produção Nacional
Revisado por pares
The International Federation of Gynecology and Obstetrics ( FIGO ) initiative on pre‐eclampsia: A pragmatic guide for first‐trimester screening and prevention
2019; Elsevier BV; Volume: 145; Issue: S1 Linguagem: Inglês
10.1002/ijgo.12802
ISSN1879-3479
AutoresLiona C. Poon, Andrew Shennan, Jonathan Hyett, Anil Kapur, Eran Hadar, Hema Divakar, Fionnuala M. McAuliffe, Fabrício da Silva Costa, Peter von Dadelszen, David McIntyre, Anne‐Beatrice Kihara, Gian Carlo Di Renzo, Roberto Romero, Mary E. D’Alton, Vincenzo Berghella, K. H. Nicolaides, Moshe Hod,
Tópico(s)Maternal and fetal healthcare
ResumoPre-eclampsia (PE) is a multisystem disorder that typically affects 2%–5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset. Globally, 76 000 women and 500 000 babies die each year from this disorder. Furthermore, women in low-resource countries are at a higher risk of developing PE compared with those in high-resource countries. Although a complete understanding of the pathogenesis of PE remains unclear, the current theory suggests a two-stage process. The first stage is caused by shallow invasion of the trophoblast, resulting in inadequate remodeling of the spiral arteries. This is presumed to lead to the second stage, which involves the maternal response to endothelial dysfunction and imbalance between angiogenic and antiangiogenic factors, resulting in the clinical features of the disorder. Accurate prediction and uniform prevention continue to elude us. The quest to effectively predict PE in the first trimester of pregnancy is fueled by the desire to identify women who are at high risk of developing PE, so that necessary measures can be initiated early enough to improve placentation and thus prevent or at least reduce the frequency of its occurrence. Furthermore, identification of an “at risk” group will allow tailored prenatal surveillance to anticipate and recognize the onset of the clinical syndrome and manage it promptly. PE has been previously defined as the onset of hypertension accompanied by significant proteinuria after 20 weeks of gestation. Recently, the definition of PE has been broadened. Now the internationally agreed definition of PE is the one proposed by the International Society for the Study of Hypertension in Pregnancy (ISSHP). It is well established that a number of maternal risk factors are associated with the development of PE: advanced maternal age; nulliparity; previous history of PE; short and long interpregnancy interval; use of assisted reproductive technologies; family history of PE; obesity; Afro-Caribbean and South Asian racial origin; co-morbid medical conditions including hyperglycemia in pregnancy; pre-existing chronic hypertension; renal disease; and autoimmune diseases, such as systemic lupus erythematosus and antiphospholipid syndrome. These risk factors have been described by various professional organizations for the identification of women at risk of PE; however, this approach to screening is inadequate for effective prediction of PE. These subclassifications are not mutually exclusive. Early-onset PE is associated with a much higher risk of short- and long-term maternal and perinatal morbidity and mortality. Obstetricians managing women with preterm PE are faced with the challenge of balancing the need to achieve fetal maturation in utero with the risks to the mother and fetus of continuing the pregnancy longer. These risks include progression to eclampsia, development of placental abruption and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. On the other hand, preterm delivery is associated with higher infant mortality rates and increased morbidity resulting from small for gestational age (SGA), thrombocytopenia, bronchopulmonary dysplasia, cerebral palsy, and an increased risk of various chronic diseases in adult life, particularly type 2 diabetes, cardiovascular disease, and obesity. Women who have experienced PE may also face additional health problems in later life, as the condition is associated with an increased risk of death from future cardiovascular disease, hypertension, stroke, renal impairment, metabolic syndrome, and diabetes. The life expectancy of women who developed preterm PE is reduced on average by 10 years. There is also significant impact on the infants in the long term, such as increased risks of insulin resistance, diabetes mellitus, coronary artery disease, and hypertension in infants born to pre-eclamptic women. The International Federation of Gynecology and Obstetrics (FIGO) brought together international experts to discuss and evaluate current knowledge on PE and develop a document to frame the issues and suggest key actions to address the health burden posed by PE. FIGO's objectives, as outlined in this document, are: (1) To raise awareness of the links between PE and poor maternal and perinatal outcomes, as well as to the future health risks to mother and offspring, and demand a clearly defined global health agenda to tackle this issue; and (2) To create a consensus document that provides guidance for the first-trimester screening and prevention of preterm PE, and to disseminate and encourage its use. Based on high-quality evidence, the document outlines current global standards for the first-trimester screening and prevention of preterm PE, which is in line with FIGO good clinical practice advice on first trimester screening and prevention of pre-eclampsia in singleton pregnancy.1 It provides both the best and the most pragmatic recommendations according to the level of acceptability, feasibility, and ease of implementation that have the potential to produce the most significant impact in different resource settings. Suggestions are provided for a variety of different regional and resource settings based on their financial, human, and infrastructure resources, as well as for research priorities to bridge the current knowledge and evidence gap. To deal with the issue of PE, FIGO recommends the following: Public health focus: There should be greater international attention given to PE and to the links between maternal health and noncommunicable diseases (NCDs) on the Sustainable Developmental Goals agenda. Public health measures to increase awareness, access, affordability, and acceptance of preconception counselling, and prenatal and postnatal services for women of reproductive age should be prioritized. Greater efforts are required to raise awareness of the benefits of early prenatal visits targeted at reproductive-aged women, particularly in low-resource countries. Universal screening: All pregnant women should be screened for preterm PE during early pregnancy by the first-trimester combined test with maternal risk factors and biomarkers as a one-step procedure. The risk calculator is available free of charge at https://fetalmedicine.org/research/assess/preeclampsia. FIGO encourages all countries and its member associations to adopt and promote strategies to ensure this. The best combined test is one that includes maternal risk factors, measurements of mean arterial pressure (MAP), serum placental growth factor (PLGF), and uterine artery pulsatility index (UTPI). Where it is not possible to measure PLGF and/or UTPI, the baseline screening test should be a combination of maternal risk factors with MAP, and not maternal risk factors alone. If maternal serum pregnancy-associated plasma protein A (PAPP-A) is measured for routine first-trimester screening for fetal aneuploidies, the result can be included for PE risk assessment. Variations to the full combined test would lead to a reduction in the performance screening. A woman is considered high risk when the risk is 1 in 100 or more based on the first-trimester combined test with maternal risk factors, MAP, PLGF, and UTPI. Contingent screening: Where resources are limited, routine screening for preterm PE by maternal factors and MAP in all pregnancies and reserving measurements of PLGF and UTPI for a subgroup of the population (selected on the basis of the risk derived from screening by maternal factors and MAP) can be considered. Prophylactic measures: Following first-trimester screening for preterm PE, women identified at high risk should receive aspirin prophylaxis commencing at 11–14+6 weeks of gestation at a dose of ~150 mg to be taken every night until 36 weeks of gestation, when delivery occurs, or when PE is diagnosed. Low-dose aspirin should not be prescribed to all pregnant women. In women with low calcium intake (<800 mg/d), either calcium replacement (≤1 g elemental calcium/d) or calcium supplementation (1.5–2 g elemental calcium/d) may reduce the burden of both early- and late-onset PE. This document is directed at multiple stakeholders with the intention of bringing attention to PE, which is a preventable but common and potentially life-threatening complication of pregnancy with grave consequences for both the mothers and the offspring. This document proposes to create a global framework for action for early screening and prevention of PE. In assessing the quality of evidence and grading of strength of recommendations, the document follows the terminology proposed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group (http://www.gradeworkinggroup.org/). This system uses consistent language and graphical descriptions for the strength and quality of the recommendations and the evidence on which they are based. Strong recommendations are numbered as 1 and conditional (weak) recommendations are numbered 2. For the quality of evidence, cross-filled circles are used: ⊕OOO denotes very low-quality evidence; ⊕⊕OO low quality; ⊕⊕⊕O moderate quality; and ⊕⊕⊕⊕ high-quality evidence (Tables 1 and 2). High ⊕⊕⊕⊕ Moderate ⊕⊕⊕O Low ⊕⊕OO Very low ⊕OOO Pre-eclampsia (PE) is a multisystem disorder of pregnancy previously defined by the onset of hypertension accompanied by significant proteinuria after 20 weeks of gestation. Recently, the definition of PE has been broadened.2-5 PE typically affects 2%–5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset.6, 7 Globally, 76 000 women and 500 000 babies die each year from this disorder.8 Furthermore, women in low-resource countries are at a higher risk of developing PE compared with those in high-resource countries. These subclassifications are not mutually exclusive. Early-onset PE is associated with a substantial risk of both short- and long-term maternal and perinatal morbidity and mortality.9, 10 Although a complete understanding of the pathogenesis remains unclear, the current theory suggests a two-stage process. The first stage is caused by shallow invasion of the trophoblast resulting in inadequate remodeling of the spiral arteries.11-13 This is presumed to lead to the second stage, which involves the maternal response to endothelial dysfunction and imbalance between angiogenic and antiangiogenic factors, resulting in the clinical features of the disorder.11-13 In late-onset disease, placentation is usually normal; however, feto-placental demands exceed supply, resulting in a placental response that triggers the clinical phenotype. Whilst the placenta certainly plays an essential role in the development of PE, there is a growing body of evidence that the maternal cardiovascular system may have a significant contribution to the disorder.14 While knowledge of the complex pathophysiology of PE is improving, accurate prediction and uniform prevention continue to elude us. The quest to effectively predict PE in the first trimester of pregnancy is fueled by the desire to identify women who are at high risk of developing PE, so that necessary measures can be initiated early to improve placentation and reduce the prevalence of the disease. Furthermore, identification of an “at risk” group will facilitate tailored prenatal surveillance to anticipate and recognize the onset of the clinical syndrome and manage it promptly. PE is broadly defined as development of hypertension and proteinuria in a previously normotensive woman. The difficulty in interpreting epidemiological studies of PE is due to the wide variation in the definitions of the disease. There are several definitions for the diagnosis of PE that have been reported in published literature and proposed by various professional bodies. Consequently, this has resulted in several different guidelines produced by professional bodies worldwide for the diagnosis and management of PE.2, 15-17 However, an internationally agreed definition of PE is that of the International Society for the Study of Hypertension in Pregnancy (ISSHP)5 (Box 1), which is endorsed by FIGO. Gestational hypertension PE de novo Gestational hypertension is defined as systolic blood pressure (sBP) at ≥140 mm Hg and/or diastolic blood pressure (dBP) at ≥90 mm Hg on at least two occasions measured 4 hours apart developing after 20 weeks of gestation in previously normotensive women. FIGO adopts the definition of PE as provided by the International Society for the Study of Hypertension in Pregnancy (ISSHP). It is well established that a number of maternal risk factors are associated with the development of PE. These risk factors have been described by various professional organizations for the identification of women at risk of PE.3, 4, 16, 18, 19 Advanced maternal age, defined as age greater than or equal to 35 years at the time of delivery, is associated with 1.2 to 3-fold increased risk of developing PE.19-22 Predictive probability of PE increases when maternal age is greater than 35 years and the probability further increases rapidly when maternal age is greater than 40 years.19 One study has evaluated the maternal age associated risk according to the severity of PE. Using multivariate logistic regression analysis, adjusting for confounders, the risk for late-onset PE has been shown to increase by 4% with every 1-year increase in maternal age above 32 years.23 However, maternal age is not associated with increased risk of early-onset PE.23 In nulliparous women, the increased risk of developing PE has been widely reported. One systematic review reported that the risk of PE is increased three-fold in nulliparous women.24 Another systematic review that included 26 studies reported that this increased risk for PE persists even after adjusting for other risk factors, such as maternal age, race, and body mass index (BMI) and the summary adjusted odds ratio (OR) was 2.71 (95% CI, 1.96–3.74).25 Parous women without prior history of PE have reduced risk of PE; however, this protective effect is lost when the conception partner is different.26 A large population-based study including 763 795 nulliparous women with a first delivery between 1987 and 2004 showed that the risk of PE was 4.1% in the first pregnancy and 1.7% in later pregnancies overall. However, the risk was 14.7% in the second pregnancy for women with a history of PE in their first pregnancy and 31.9% for women who had PE in the previous two pregnancies. The risk of PE for parous women without a history of PE was 1.1%. These observations suggest that the risk of PE is greater in nulliparous than parous women without a prior history of PE. Among parous women, the risk of PE in subsequent pregnancies depends on a prior history of PE.27 This relative risk for subsequent PE ranges from 7 to 10 times higher in a second pregnancy.28-30 A study focusing on PE according to severity of disease showed that a history of PE doubled the risk of developing early-onset PE (<32 weeks) in a subsequent pregnancy as opposed to late-onset PE.31 Other studies have reported a 5% to 17% recurrence risk of early-onset PE (<34 weeks) in the index pregnancy for those with a prior history of early-onset PE.32, 33 A systematic review of 11 studies including 2377 women showed that the pooled recurrence risk of early-onset PE is approximately 8% in women who require delivery at less than 34 weeks following the development of early-onset PE in the first pregnancy.33 Both short and long interpregnancy intervals are associated with an increased risk of PE.34-36 A recent large multicentric retrospective study of 894 479 women reported that interpregnancy intervals of less than 12 months or greater than 72 months are associated with higher risk of PE development compared with interpregnancy intervals of 12–23 months.37 It has been observed that the longer the interval, the higher the risk of developing PE. The reasons for the association between short interpregnancy interval and PE are unclear, but several hypotheses have been proposed, including factors related to socioeconomic status, postpartum stress, malnutrition, and inadequate access to healthcare services. Meanwhile, the increased PE risk in women with long interpregnancy intervals might be attributed to advanced maternal age, infertility, and underlying maternal medical conditions.38, 39 Several studies have reported that the use of assisted reproductive technologies (ART) doubles the risk of PE.40-43 In a cohort study of more than 1 million pregnant women, the risk of having PE was increased in women exposed to hyperestrogenic ovarian stimulation medications regardless of ART type compared with those with spontaneous conception (ORs ranging from 1.32 to 1.83).44 In contrast, the use of nonhyperestrogenic ovarian stimulation drugs was not associated with an increased risk of PE.44 High estrogen levels during implantation may lead to impaired placentation and reduced uteroplacental circulation as well as decreased number of uterine spiral arteries with vascular invasion.44-46 Women conceiving by intrauterine insemination, in particular by donor sperm, are at a greater risk of developing PE.47-51 Those who have undergone donor ovum in vitro fertilization (IVF) appear to have a higher risk of PE than those who have had autologous ovum IVF.52 Evidence from IVF pregnancies with ovum donation suggests that there are altered extravillous trophoblast and immunological changes in decidua basalis, which may impede the modification of the spiral arteries.53 Although most cases of PE are sporadic, a familial susceptibility to PE has been documented. Daughters or sisters of women with PE are 3–4 times more likely to develop the condition than women without a family history.54-56 The mode of inheritance seems to be complex, including numerous variants, which individually have small effects, but collectively contribute to an individual's susceptibility to the disorder. Genome-wide association studies (GWAS) using sib-pair analysis have identified plausible, yet conflicting, positional candidate maternal susceptibility genes for PE. GWAS of PE affected families have demonstrated significant linkage to chromosomes 2p, 2q, 4p, 7p, 9p, 10q, 11q, and 22q.57 However, no other study has reproduced these significant or suggestive loci. There is substantial evidence to show that obesity (BMI ≥30 kg/m2) confers a 2 to 4-fold higher risk for PE.58-64 The exact mechanisms linking overweight/obesity and PE remain unclear. Obesity is known as a state of chronic, low-grade inflammation, also called “meta-inflammation”.65, 66 Low-grade inflammation can induce endothelial dysfunction and placental ischemia by immune mediated mechanisms, which in turn lead to production of inflammatory mediators resulting in an exaggerated maternal inflammatory response and development of PE.67 There is extensive evidence in the literature demonstrating the association between race and ethnicity and PE. Large population studies suggest that the risk of PE in Afro-Caribbean women is increased by 20%–50%.68-72 The risk of PE is also higher in women of South Asian origin than in those of non-Hispanic white women (adjusted OR 1.3; 95% CI, 1.2–1.4).73 Increased risk of PE reflects the metabolic profiles of nonpregnant women associated with an increased susceptibility to cardiovascular disease.74-76 Both Afro-Caribbean and South Asian women are more susceptible to developing chronic hypertension, diabetes mellitus, and cardiovascular disease. In a large prospective observational cohort study of more than 79 000 singleton pregnancies recruited in London, UK, the risk of PE was significantly higher in women of Afro-Caribbean and South Asian racial origin compared with white women.77 The increased risk remains significant even after adjusting for other confounding risk factors for PE. There are certain medical conditions that predispose women to developing PE. These include hyperglycemia in pregnancy (pre-pregnancy type 1 and type 2 diabetes mellitus, overt diabetes in pregnancy, and gestational diabetes requiring insulin treatment), pre-existing chronic hypertension, renal disease, and autoimmune diseases such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Recently, a systematic review and meta-analysis evaluated clinical risk factors at less than or equal to 16 weeks of gestation in 25 356 655 pregnant women in 27 countries.78 Patients with a history of chronic hypertension have a higher risk of developing PE than those without this condition (relative risk [RR] 5.4; 95% CI, 4.0–6.5). Pre-existing diabetes mellitus, APS, SLE, and chronic kidney disease are also associated with an increased risk of developing PE (RR 3.7; 95% CI, 3.1–4.3; RR 2.8; 95% CI, 1.8–4.3; RR 2.5; 95% CI, 1.0–6.3; and RR 1.8; 95% CI, 1.5–2.1, respectively).78 FIGO acknowledges the many maternal risk factors that are associated with the development of pre-eclampsia, which must be taken into consideration for screening practices. The most common cause of death in women with PE is intracranial hemorrhage.101 Other serious complications include placental abruption, HELLP syndrome, acute pulmonary edema, respiratory distress syndrome, and acute renal failure.102 Chesley et al.103 were the first to propose the concept that pregnancy is a stress test, based on the observation that pregnant women who have never developed PE have a lower risk of cardiovascular disease than the general female population; whereas women with eclampsia have a similar risk of cardiovascular disease in later life as appropriately matched women with unknown pregnancy history. Therefore, while PE may not directly cause cardiovascular disease in later life, pregnancy itself acts as a challenge test to reveal underlying metabolic risk factors for atherosclerosis and cardiovascular disease.103 Evidence in support of this hypothesis is that PE and cardiovascular disease share many risks factors, including obesity, insulin resistance, diabetes mellitus, underlying hypertension, and dyslipidemia.103-106 A recent meta-analysis demonstrated that women with previous PE have a RR of 3.13 (95% CI, 2.51–3.89) for future development of chronic hypertension, an OR of 2.28 (95% CI, 1.87–2.78) for future cardiovascular disease, and an OR of 1.8 (95% CI, 1.43–2.21) for cardiovascular accident.107 It has been observed that the earlier the onset of PE, the more severe the condition and the higher the risk of developing subsequent cardiovascular disease.108 Compared with normotensive women, women with PE are also more likely to have microalbuminuria (a marker of renal damage) at 3–5 years after delivery.109 PE may adversely impact future kidney function since glomerular endotheliosis—a typical renal lesion in PE that was previously thought to resolve soon after delivery—can be observed long after pregnancy in some women who had PE.110 A prospective cohort study reported an association between PE and subsequent end-stage renal disease (RR 4.7; 95% CI, 3.6–6.1).111 Patients with a history of PE should be aware of the increased risk of future cardiovascular disease,107, 108 metabolic syndrome,112, 113 and chronic or end-stage renal disease.111 It remains to be determined whether lifestyle modifications as well as close monitoring for signs and symptoms of metabolic syndromes after delivery among patients with PE can reduce these risks.114 PE is associated with a number of short- and long-term perinatal and neonatal complications, including death (Table 3). These are mostly related to birth weight and gestational age at delivery and are therefore mainly attributed to early-onset PE. PE is commonly associated with placental lesions. The underlying vascular manifestations and the presence of oxidative stress and endothelial damage can lead to fetal growth restriction (FGR) with underlying hypoxia and acidosis. A multicenter prospective study of 30 639 unselected women with singleton pregnancies demonstrated that in 614 (2%) women who developed PE there was an inverse significant association between the gestational age at delivery and prevalence of small for gestational age (SGA) (r=−0.99, P 10 years).16 In the USA, the American College of Obstetricians and Gynecologists (ACOG) issued the Hypertension in Pregnancy Task Force Report recommending daily low-dose aspirin beginning in the late first trimester for women with a history of early-onset PE and preterm delivery at less than 34 weeks of gestation, or for women with more than one prior pregnancy complicated by PE.128 The US Preventive Services Task Force published a similar guideline, although the list of indications for low-dose aspirin use was more expansive.129 An updated version of the US Preventive Services Task Force guideline has now been endorsed by ACOG, the Society for Maternal-Fetal Medicine, and the American Diabetes Association.130 Low-dose aspirin prophylaxis at 81 mg/d from 12 and 28 weeks of gestation (optimally at <16 weeks of gestation), continued daily until de
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