Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #8: The fetus at risk for anemia–diagnosis and management
2015; Elsevier BV; Volume: 212; Issue: 6 Linguagem: Inglês
10.1016/j.ajog.2015.01.059
ISSN1097-6868
AutoresGiancarlo Mari, Mary E. Norton, Joanne Stone, Vincenzo Berghella, Anthony Sciscione, Danielle Tate, Mauro Schenone,
Tópico(s)Fetal and Pediatric Neurological Disorders
ResumoObjectiveWe sought to provide evidence-based guidelines for the diagnosis and management of fetal anemia.MethodsA systematic literature review was performed using MEDLINE, PubMed, EMBASE, and the Cochrane Library. The search was restricted to English-language articles published from 1966 through May 2014. Priority was given to articles reporting original research, in particular randomized controlled trials, although review articles and commentaries were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion. Evidence reports and published guidelines were also reviewed, and additional studies were located by reviewing bibliographies of identified articles. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology was used for defining the strength of recommendations and rating the quality of evidence. Consistent with US Preventive Task Force guidelines, references were evaluated for quality based on the highest level of evidence.Results and RecommendationsWe recommend the following: (1) middle cerebral artery peak systolic velocity (MCA-PSV) measured by ultrasound Doppler interrogation be used as the primary technique to detect fetal anemia; (2) amniotic fluid delta OD450 not be used to diagnosis fetal anemia; (3) MCA-PSV assessment be reserved for those patients who are at risk of having an anemic fetus (proper technique for MCA-PSV evaluation includes assessment of the middle cerebral artery close to its origin, ideally at a zero degree angle without angle correction); (4) if a fetus is deemed at significant risk for severe fetal anemia (MCA greater than 1.5 multiples of the median or hydropic), fetal blood sampling be performed with preparation for an intrauterine transfusion, unless the pregnancy is at a gestational age when the risks associated with delivery are considered to be less than those associated with the procedure; (5) if a fetus is deemed at significant risk for severe fetal anemia, the patient be referred to a center with expertise in invasive fetal therapy; (6) MCA-PSV be considered to determine the timing of a second transfusion in fetuses with anemia, and, alternatively, a predicted decline in fetal hemoglobin may be used for timing the second procedure; and (7) pregnancies with a fetus at significant risk for fetal anemia be delivered at 37-38 weeks of gestation unless indications develop prior to this time. We sought to provide evidence-based guidelines for the diagnosis and management of fetal anemia. A systematic literature review was performed using MEDLINE, PubMed, EMBASE, and the Cochrane Library. The search was restricted to English-language articles published from 1966 through May 2014. Priority was given to articles reporting original research, in particular randomized controlled trials, although review articles and commentaries were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion. Evidence reports and published guidelines were also reviewed, and additional studies were located by reviewing bibliographies of identified articles. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology was used for defining the strength of recommendations and rating the quality of evidence. Consistent with US Preventive Task Force guidelines, references were evaluated for quality based on the highest level of evidence. We recommend the following: (1) middle cerebral artery peak systolic velocity (MCA-PSV) measured by ultrasound Doppler interrogation be used as the primary technique to detect fetal anemia; (2) amniotic fluid delta OD450 not be used to diagnosis fetal anemia; (3) MCA-PSV assessment be reserved for those patients who are at risk of having an anemic fetus (proper technique for MCA-PSV evaluation includes assessment of the middle cerebral artery close to its origin, ideally at a zero degree angle without angle correction); (4) if a fetus is deemed at significant risk for severe fetal anemia (MCA greater than 1.5 multiples of the median or hydropic), fetal blood sampling be performed with preparation for an intrauterine transfusion, unless the pregnancy is at a gestational age when the risks associated with delivery are considered to be less than those associated with the procedure; (5) if a fetus is deemed at significant risk for severe fetal anemia, the patient be referred to a center with expertise in invasive fetal therapy; (6) MCA-PSV be considered to determine the timing of a second transfusion in fetuses with anemia, and, alternatively, a predicted decline in fetal hemoglobin may be used for timing the second procedure; and (7) pregnancies with a fetus at significant risk for fetal anemia be delivered at 37-38 weeks of gestation unless indications develop prior to this time. Click Supplementary Content under the article title in the online Table of Contents Anemia continues to be an uncommon but life-threatening condition for the developing fetus. Red cell alloimmunization has historically been the most common cause of fetal anemia in the United States and in many other parts of the world. Other causes of fetal anemia include parvovirus infection and other less common conditions. This review describes the causes, surveillance options, and management strategies for the pregnancy at risk for fetal anemia. Fetal anemia can be defined using either hemoglobin or hematocrit values. A hemoglobin value that is more than 2 SD below the mean is diagnostic of fetal anemia. Normally, fetal hemoglobin concentration increases with advancing gestation (Figure 1).1Mari G. Deter R.L. Carpenter R.L. et al.Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses (Level II-1).N Engl J Med. 2000; 342: 9-14Crossref PubMed Scopus (926) Google Scholar Reference ranges for fetal hemoglobin concentrations as a function of gestational age (from 18 to 40 weeks of gestation) have been established using fetal blood sampling (Table 1).1Mari G. Deter R.L. Carpenter R.L. et al.Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses (Level II-1).N Engl J Med. 2000; 342: 9-14Crossref PubMed Scopus (926) Google ScholarTable 1Reference ranges for fetal hemoglobin concentrations (grams per deciliter) as a function of gestational ageAdapted from Mari et al.1Mari G. Deter R.L. Carpenter R.L. et al.Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses (Level II-1).N Engl J Med. 2000; 342: 9-14Crossref PubMed Scopus (926) Google ScholarGestational age, wks1.0 MoM, median0.55 MoM0.65 MoM0.84 MoM1810.65.86.98.91910.96.07.19.12011.16.17.29.32111.46.27.49.52211.66.47.59.72311.86.57.69.92412.06.67.810.02512.16.77.910.22612.36.88.010.32712.46.88.110.42812.66.98.210.62912.77.08.310.73012.87.18.310.83113.07.18.410.93213.17.28.511.03313.27.28.611.13413.37.38.611.13513.47.48.711.23613.57.48.711.33713.57.58.811.43813.67.58.911.43913.77.58.911.54013.87.69.011.6Normal hemoglobin values were 0.84 MoM or greater; mild anemia: Hgb values were between 0.65 and 0.84 MoM; moderate anemia: Hgb values were between 0.55 and 0.64 MoM; and severe anemia: Hgb values were 0.55 MoM or less.Hgb, hemoglobin; MoM, multiples of the median.SMFM. The fetus at risk for anemia. Am J Obstet Gynecol 2015. Open table in a new tab Normal hemoglobin values were 0.84 MoM or greater; mild anemia: Hgb values were between 0.65 and 0.84 MoM; moderate anemia: Hgb values were between 0.55 and 0.64 MoM; and severe anemia: Hgb values were 0.55 MoM or less. Hgb, hemoglobin; MoM, multiples of the median. SMFM. The fetus at risk for anemia. Am J Obstet Gynecol 2015. The severity of fetal anemia can be categorized based on hemoglobin concentrations expressed as multiples of the median (MoM) for gestational age as mild (MoM 0.83–0.65), moderate (MoM 0.64–0.55), and severe (MoM <0.55).1Mari G. Deter R.L. Carpenter R.L. et al.Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses (Level II-1).N Engl J Med. 2000; 342: 9-14Crossref PubMed Scopus (926) Google Scholar Severe anemia can lead to hydrops fetalis and fetal death. Hydrops related to anemia is rare in fetuses with hemoglobin concentrations greater than 5 g/dL,2Nicolaides K.H. Soothill P.W. Clewell W.H. Rodeck C.H. Mibashan R.S. Campbell S. Fetal haemoglobin measurement in the assessment of red cell isoimmunisation (Level II-3).Lancet. 1988; 1: 1073-1075Abstract PubMed Scopus (206) Google Scholar a value corresponding to 0.47 MoM at 18 weeks of gestation and 0.36 MoM at 37 weeks of gestation. Using a fetal hematocrit of less than 30% as a cutoff for fetal anemia appears equally reliable as using hemoglobin levels and is often used in routine clinical care.3Moise Jr., K.J. Management of rhesus alloimmunization in pregnancy (Level III).Obstet Gynecol. 2008; 112: 164-176Crossref PubMed Scopus (148) Google Scholar Fetal anemia can result from a large number of pathologic processes (Table 2). The most common causes in the United States are maternal alloimmunization and parvovirus infection. Other causes include inherited conditions such as alpha-thalassemia and genetic metabolic disorders as well as acquired conditions, such as fetal blood loss and infection. Fetal anemia can occur in association with Down syndrome, because of transient abnormal myelopoeisis, a leukemic condition that occurs in approximately 10% of infants with Down syndrome.4Smrcek J.M. Baschat A.A. Germer U. Gloeckner-Hofmann K. Gembruch U. Fetal hydrops and hepatosplenomegaly in the second half of pregnancy: a sign of myeloproliferative disorder in fetuses with trisomy 21 (Level III).Ultrasound Obstet Gynecol. 2001; 17: 403-409Crossref PubMed Scopus (57) Google Scholar, 5Hendricks S.K. Sorensen T.K. Baker E.R. Trisomy 21, fetal hydrops, and anemia: prenatal diagnosis of transient myeloproliferative disorder (Level III)?.Obstet Gynecol. 1993; 82: 703-705PubMed Google Scholar Vascular tumors and arteriovenous malformations of the fetus or placenta are also rare causes of fetal anemia.6Okada T. Sasaki F. Cho K. et al.Management and outcome in prenatally diagnosed sacrococcygeal teratomas (Level III).Pediatr Int. 2008; 50: 576-580Crossref PubMed Scopus (27) Google Scholar, 7Wu T.J. Teng R.J. Diffuse neonatal haemangiomatosis with intra-uterine haemorrhage and hydrops fetalis: a case report (Level III).Eur J Pediatr. 1994; 153: 759-761Crossref PubMed Scopus (10) Google ScholarTable 2Potential causes of fetal anemiaCategoriesCauseImmuneRed blood cell alloimmunizationRhAtypical antigensInfectiousParvovirusCMVToxoplasmosisSyphilisInheritedLysosomal storage diseases (eg, mucopolysaccharidosis type VII, Niemann-Pick disease, Gaucher disease)Blackfan-Diamond anemiaFanconi anemiaAlpha-thalassemiaaAlpha-thalassemia is a common cause of hydrops in regions where this inherited disorder is common, such as Southeast Asia.Pyruvate kinase deficiencyG-6-PD deficiencyOtherAneuploidyTTTS; twin anemia-polycythemia sequenceFetomaternal hemorrhageMaternal acquired red cell aplasiaCMV, cytomegalovirus; G-6-PD, glucose-6-phosphate dehydrogenase; TTTS, twin-to-twin transfusion syndrome.SMFM. The fetus at risk for anemia. Am J Obstet Gynecol 2015.a Alpha-thalassemia is a common cause of hydrops in regions where this inherited disorder is common, such as Southeast Asia. Open table in a new tab CMV, cytomegalovirus; G-6-PD, glucose-6-phosphate dehydrogenase; TTTS, twin-to-twin transfusion syndrome. SMFM. The fetus at risk for anemia. Am J Obstet Gynecol 2015. Maternal red blood cell alloimmunization occurs when the immune system is sensitized to foreign erythrocyte surface antigens, stimulating the production of immunoglobulin G (IgG) antibodies. These IgG antibodies can cross the placenta and lead to hemolysis if the fetus is positive for the specific erythrocyte surface antigens. This process, known as hemolytic disease of the fetus and newborn, can result in extramedullary hematopoiesis, reticuloendothelial clearance of fetal erythrocytes, fetal anemia, hydrops fetalis, and fetal death. The most common routes of maternal alloimmunization are blood transfusion or fetomaternal hemorrhage associated with delivery, trauma, spontaneous or induced abortion, ectopic pregnancy, or invasive obstetric procedures. The introduction of Rh (D) immune globulin in 1968 has greatly decreased the incidence of fetal anemia caused by Rh (D) alloimmunization in North America. As a result, other alloantibodies have increased in relative importance. These include antibodies to other antigens of the Rh blood group system (c, C, e, E) and other atypical antibodies also known to cause severe fetal anemia, such as anti-Kell (K, k), anti-Duffy (Fya), and anti-Kidd (Jka, Jkb) (Table 3).Table 3Non–Rh (D) antibodies and associated hemolytic disease newborn and fetusAntigen systemSpecific antigenAntigen systemSpecific antigenAntigen systemSpecific antigenFrequently associated with severe disease Kell-K (K1) Rhesus-cInfrequently associated with severe disease Colton-CoaMNS-MtaRhesus-HOFM-Co3-MUT-LOCR Diego-ELO-Mur-Riv-Dia-Mv-Rh29-Dib-s-Rh32-Wra-sD-Rh42-Wrb-S-Rh46 Duffy-Fya-U-STEM Kell-Jsa-Vw-Tar-JsbRhesus-BeaOther antigens-HJK-k (K2)-C-JFV-Kpa-Ce-JONES-Kpb-Cw-Kg-K11-Cx-MAM-K22-ce-REIT-Ku-Dw-Rd-Ula-E Kidd-Jka-Ew MNS-Ena-Evans-Far-e-Hil-G-Hut-Goa7-M-Hr-Mia-Hro-Mit-JALAssociated with mild disease Dombrock-DoaGerbich-Ge2Scianna-Sc2-Gya-Ge3Other-Vel-Hy-Ge4-Lan-Joa-Lsa-Ata Duffy-FybKidd-Jkb-Jra-Fy3-Jk3Reproduced, with permission, from Moise.69Moise K.J. Fetal anemia due to non-Rhesus-D red-cell alloimmunization (Level III).Semin Fetal Neonatal Med. 2008; 13: 207-214Abstract Full Text Full Text PDF PubMed Scopus (126) Google ScholarSMFM. The fetus at risk for anemia. Am J Obstet Gynecol 2015. Open table in a new tab Reproduced, with permission, from Moise.69Moise K.J. Fetal anemia due to non-Rhesus-D red-cell alloimmunization (Level III).Semin Fetal Neonatal Med. 2008; 13: 207-214Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar SMFM. The fetus at risk for anemia. Am J Obstet Gynecol 2015. Parvovirus is the most commonly reported infectious cause of fetal anemia.8Crane J. Society of Obstetricians and Gynaecologists of Canada. Parvovirus B19 infection in pregnancy (Level III).Obstet Gynaecol Can. 2002; 24 (quiz 44-6): 727-743PubMed Google Scholar, 9van Gessel P.H. Gaytant M.A. Vossen A.C. et al.Incidence of parvovirus B19 infection among an unselected population of pregnant women in The Netherlands: a prospective study (Level II-1).Eur J Obstet Gynecol Reprod Biol. 2006; 128: 46-49Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 10Miller E. Fairley C.K. Cohen B.J. Seng C. Immediate and long term outcome of human parvovirus B19 infection in pregnancy (Level II-2).Br J Obstet Gynaecol. 1998; 105: 174-178Crossref PubMed Scopus (249) Google Scholar, 11Rodis J.F. Quinn D.L. Gary Jr., G.W. et al.Management and outcomes of pregnancies complicated by human B19 parvovirus infection: a prospective study (Level II-2).Am J Obstet Gynecol. 1990; 163: 1168-1171Abstract Full Text PDF PubMed Scopus (140) Google Scholar In the fetus, the virus has a predilection for erythroid progenitor cells, leading to inhibition of erythropoiesis and resultant anemia. The risk of a poor outcome for the fetus is greatest when the congenital infection occurs before 20 weeks of gestation. The risk of fetal death has been reported to be 15% at 13–20 weeks of gestation, and 6% after 20 weeks of gestation.12Centers for Disease Control (CDC)Risks associated with human parvovirus B19 infection (Level III).MMWR Morb Mortal Wkly Rep. 1989; 38 (93-7): 81-88PubMed Google Scholar In most cases, the anemia is transient, but in severe cases, fetal intravascular transfusion may be needed to support the fetus through this aplastic crisis. A number of viral, bacterial, and parasitic infectious diseases, including toxoplasmosis, cytomegalovirus (CMV), coxsackie virus, and syphilis, have in rare cases been associated with fetal anemia and hydrops.13Wong A. Tan K.H. Tee C.S. Yeo G.S. Seroprevalence of cytomegalovirus, toxoplasma and parvovirus in pregnancy (Level II-2).Singapore Med J. 2000; 41: 151-155PubMed Google Scholar, 14Feldman D.M. Timms D. Borgida A.F. Toxoplasmosis, parvovirus, and cytomegalovirus in pregnancy (Level III).Clin Lab Med. 2010; 30: 709-720Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Fetal anemia can occur as a complication of monochorionic twin pregnancies, a condition referred to as twin anemia-polycythemia sequence.15Slaghekke F. Kist W.J. Oepkes D. et al.TAPS and TOPS: two distinct forms of feto-fetal transfusion in monochorionic twins (Level III).Z Geburtshilfe Neonatol. 2009; 213: 248-254Crossref PubMed Scopus (23) Google Scholar, 16Lopriore E. Deprest J. Slaghekke F. et al.Placental characteristics in monochorionic twins with and without twin anemia-polycythemia sequence (Level II-2).Obstet Gynecol. 2008; 112: 753-758Crossref PubMed Scopus (97) Google Scholar This condition has been reported to occur spontaneously in 3–5% of monochorionic twins or after laser therapy for twin-twin transfusion syndrome (TTTS) in 13% of cases.17Herway C. Johnson A. Moise K. Moise Jr., K.J. Fetal intraperitoneal transfusion for iatrogenic twin anemia-polycythemia sequence after laser therapy (Level III).Ultrasound Obstet Gynecol. 2009; 33: 592-594Crossref PubMed Scopus (41) Google Scholar Twin anemia-polycythemia sequence is distinct from TTTS because it occurs in the absence of amniotic fluid abnormalities characteristic of classical TTTS. Fetal anemia can also result from fetomaternal hemorrhage, which may occur as an isolated acute event or as a chronic, ongoing hemorrhage.18Sebring E.S. Polesky H.F. Fetomaternal hemorrhage: incidence, risk factors, time of occurrence, and clinical effects (Level III).Transfusion. 1990; 30: 344-357Crossref PubMed Scopus (207) Google Scholar, 19Sinha B. Giles R.W. Pathak S. Idiopathic, asymptomatic fetomaternal haemorrhage causing fetal death (Level III).J Obstet Gynaecol. 2012; 32: 95-96Crossref PubMed Scopus (3) Google Scholar, 20Thomas A. Mathew M. Unciano Moral E. Vaclavinkova V. Acute massive fetomaternal hemorrhage: case reports and review of the literature (Level III).Acta Obstet Gynecol Scand. 2003; 82: 479-480Crossref PubMed Scopus (17) Google Scholar, 21Lipitz S. Achiron R. Horoshovski D. Rotstein Z. Sherman D. Schiff E. Fetomaternal haemorrhage discovered after trauma and treated by fetal intravascular transfusion (Level III).Eur J Obstet Gynecol Reprod Biol. 1997; 71: 21-22Abstract Full Text PDF PubMed Scopus (13) Google Scholar Several inherited disorders are associated with fetal anemia.22Karnpean R. Fetal blood sampling in prenatal diagnosis of thalassemia at late pregnancy (Level III).J Med Assoc Thai. 2014; 97: S49-S55PubMed Google Scholar, 23Karnpean R. Fucharoen G. Fucharoen S. Ratanasiri T. Fetal red blood cell parameters in thalassemia and hemoglobinopathies (Level III).Fetal Diagn Ther. 2013; 34: 166-171Crossref PubMed Scopus (5) Google Scholar Alpha-thalassemia is the most common of these and occurs primarily in individuals of Southeast Asian descent. The severe hemolytic anemia associated with alpha-thalassemia typically leads to hydrops fetalis and fetal demise. Less common causes of fetal anemia and hydrops include erythrocyte enzymopathies such as glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and maternal acquired red cell aplasia.24Beutler E. Kuhl W. Fox M. Tabsh K. Crandall B.F. Prenatal diagnosis of glucose-6-phosphate-dehydrogenase deficiency (Level III).Acta Haematol. 1992; 87: 103-104Crossref PubMed Scopus (14) Google Scholar, 25Roberts D.J. Nadel A. Lage J. Rutherford C.J. An unusual variant of congenital dyserythropoietic anaemia with mild maternal and lethal fetal disease (Level III).Br J Haematol. 1993; 84: 549-551Crossref PubMed Scopus (21) Google Scholar Genetic conditions associated with aplastic anemia that may present in fetal life include Fanconi anemia and Diamond Blackfan anemia.26Dunbar 3rd, A.E. Moore S.L. Hinson R.M. Fetal Diamond-Blackfan anemia associated with hydrops fetalis (Level III).Am J Perinatol. 2003; 20: 391-394Crossref PubMed Scopus (11) Google Scholar, 27McLennan A.C. Chitty L.S. Rissik J. Maxwell D.J. Prenatal diagnosis of Blackfan-Diamond syndrome: case report and review of the literature (Level III).Prenat Diagn. 1996; 16: 349-353Crossref PubMed Scopus (17) Google Scholar Inherited metabolic disorders, particularly lysosomal storage diseases such as various mucopolysaccaridoses, Gaucher disease, and Niemann-Pick disease have also been reported to cause fetal anemia and hydrops.28Norton M.E. Chauhan S.P. Dashe J.S. Society for Maternal-Fetal Medicine (SMFM)clinical guideling #7: non-immune hydrops fetalis (Level III).Am J Obstet Gynecol. 2015; 212: 127-139Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Women with pregnancies with the conditions listed in Table 2, most commonly red blood cell alloimmunization and parvovirus infection, are considered at risk for fetal anemia. The management of such patients is based on the suspected etiology. In women with red cell alloimmunization, parental assessment and testing are key initial steps to determine the potential fetal antigen status (Figure 2). This can be done through parental zygosity testing, direct genotyping of the fetus with amniocentesis, or noninvasive fetal genotyping from maternal blood using cell-free DNA. At this point in time, only cell-free DNA testing for Rh (D) is clinically available in the United States, whereas in Europe assays have been developed for c, E, and Kell antigens. Currently cell-free DNA testing is reported to detect the Rh (D) genotype with a sensitivity of 97.2% and a specificity of 96.8%.29Pirelli K.J. Pietz B.C. Johnson S.T. Pinder H.L. Bellissimo D.B. Molecular determination of RHD zygosity: predicting risk of hemolytic disease of the fetus and newborn related to anti-D (Level II-2).Prenat Diagn. 2010; 30: 1207-1212Crossref PubMed Scopus (29) Google Scholar, 30Lo Y.M. Hjelm N.M. Fidler C. et al.Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma (Level II-2).N Engl J Med. 1998; 339: 1734-1738Crossref PubMed Scopus (602) Google Scholar, 31Bombard A.T. Akolekar R. Farkas D.H. et al.Fetal RHD genotype detection from circulating cell-free fetal DNA in maternal plasma in non-sensitized RhD negative women (Level II-2).Prenat Diagn. 2011; 31: 802-808Crossref PubMed Scopus (54) Google Scholar Another recent study reported the accuracy for Rh (D) by trimester: 99.1% in the first trimester, 99.1% in the second trimester, and 98.1% in the third trimester.32Moise Jr., K.J. Boring N.H. O'Shaughnessy R. et al.Circulating cell-free fetal DNA for the detection of RHD status and sex using reflex fetal identifiers (Level II-1).Prenat Diagn. 2013; 33: 95-101Crossref PubMed Scopus (27) Google Scholar In alloimmunized women who do not undergo fetal or paternal testing and do not have a prior history of an affected pregnancy, serial antigen titers can be measured and followed up until they surpass a critical titer that places the fetus at risk for the development of severe anemia and hydrops.3Moise Jr., K.J. Management of rhesus alloimmunization in pregnancy (Level III).Obstet Gynecol. 2008; 112: 164-176Crossref PubMed Scopus (148) Google Scholar The critical titer is set by each laboratory and may be different for various red cell antigens. Titers should be repeated serially every 4 weeks and then more frequently if they are found to be rising or with advancing gestational age. Once the critical titer is reached, 2 options exist for subsequent evaluation: fetal antigen testing (cell-free fetal DNA testing for Rh [D] or amniocentesis for fetal Rh genotyping) or initiation of ultrasound surveillance with middle cerebral artery (MCA) Doppler assessment. The potential benefit of fetal antigen testing first is to avoid multiple serial MCA Doppler assessments (often weekly) in an antigen-negative fetus. However, cell-free DNA testing for fetal Rh (D) type is not 100% sensitive, particularly at earlier gestational ages, so a small number of at risk fetuses may be missed if this approach is chosen.33Chitty L.S. Finning K. Wade A. et al.Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: population based cohort study (Level II-2).BMJ. 2014; 349: g5243Crossref PubMed Scopus (75) Google Scholar Although uncommon, maternal titers can increase, even in antigen-negative fetuses. Given the approximately 10% false-positive rate of MCA Doppler for the detection of severe anemia, without confirmation of fetal antigen status, women are at risk for unnecessary procedures including invasive testing. Clinicians managing alloimmunized women should be aware of these potential issues. In women who are at risk for fetal anemia caused by parvovirus exposure, maternal antibody status (eg, immunoglobulin M positive status or IgG seroconversion) is useful to determine prior exposure and the presence of immunity. Although the peak risk for hydrops is 4–6 weeks after maternal infection, weekly evaluation of MCA Doppler studies and ultrasound surveillance for fetal hydrops are often continued for up to 10–12 weeks after exposure. An algorithm for the screening and diagnosis of fetal anemia is presented in Figure 2. The definitive diagnosis of fetal anemia is generally made by fetal blood sampling, whereas screening is performed with MCA Doppler. Fetal anemia can be directly diagnosed by fetal blood sampling in fetuses with hydrops or in cases that have surpassed the critical threshold for MCA Doppler values (Table 4) and are thereby at significant risk.34Daffos F. Capella-Pavlovsky M. Forestier F. Fetal blood sampling via the umbilical cord using a needle guided by ultrasound. Report of 66 cases (Level III).Prenat Diagn. 1983; 3: 271-277Crossref PubMed Scopus (144) Google Scholar, 35Berry S.M. Stone J. Norton M.E. Johnson D. Berghella V. Society for Maternal-Fetal Medicine (SMFM)Fetal blood sampling (Level III).Am J Obstet Gynecol. 2013; 209: 170-180Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar These procedures carry potential risk to the fetus and mother of infection, preterm premature rupture of membranes, abruption, premature labor, fetal or maternal bleeding, worsening alloimmunization, and fetal death. Although the risk of fetal loss because of fetal blood sampling is reported to be 1–2%, it is gestational age dependent, with earlier gestations at higher risk.36Oepkes D. Seaward P.G. Vandenbussche F.P. et al.DIAMOND Study Group. Doppler ultrasonography versus amniocentesis to predict fetal anemia (Level II-1).N Engl J Med. 2006; 355: 156-164Crossref PubMed Scopus (199) Google ScholarTable 4Expected peak velocity of systolic blood flow in the middle cerebral artery as a function of GAReproduced, with permission, from Mari et al.1Mari G. Deter R.L. Carpenter R.L. et al.Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses (Level II-1).N Engl J Med. 2000; 342: 9-14Crossref PubMed Scopus (926) Google ScholarGA, wksMultiples of the median, cm/s1.01.291.501.551823.229.934.836.02025.532.838.239.52227.936.041.943.32430.739.546.047.52633.643.350.452.12836.946.655.457.23040.552.260.762.83244.457.366.668.93448.762.973.175.63653.369.080.282.93858.775.788.091.04064.483.096.699.8GA, gestational age; MoM, multiples of the median.SMFM. The fetus at risk for anemia. Am J Obstet Gynecol 2015. Open table in a new tab GA, gestational age; MoM, multiples of the median. SMFM. The fetus at risk for anemia. Am J Obstet Gynecol 2015. The use of delta optical density 450 to detect fetal anemia is primarily of historic interest.37Nicolaides K.H. Rodeck C.H. Mibashan R.S. Kemp J.R. Have Liley charts outlived their usefulness (Level II-3)?.Am J Obstet Gynecol. 1986; 155: 90-94Abstract Full Text PDF PubMed Scopus (87) Google Scholar, 38Ananth U. Queenan J.T. Does midtrimester delta OD450 of amniotic fluid reflect severity of Rh disease (Level II-3)?.Am J Obstet Gynecol. 1989; 161: 47-49Abstract Full Text PDF PubMed Scopus (17) Google Scholar In the past, the diagnosis of fetal anemia in cases of red cell alloimmunization associated with hemolysis was based on spectrophotometric measurement of the amniotic fluid for increased bilirubin concentration.39Ananth U. Warsof S.L. Coulehan J.M. Wolf P.H. Queenan J.T. Midtrimester amniotic fluid delta optical density at 450 nm in normal pregnancies (Level III).Am J Obstet Gynecol. 1986; 155: 664-666Abstract Full Text PDF PubMed Scopus (10) Google Scholar, 40Queenan J.T. Eglinton G.S. Tomai T.P. Ural S.H. King J.C. Spong C.Y. Hemolytic disease of the fetus: a comparison of the Queenan and extended Liley methods (Level III).Obstet Gynecol. 1999; 93: 162-163Crossref PubMed Google Scholar In rare cases in which MCA Doppler studies cannot be performed, measuring the delta optical density 450 levels in amniotic fluid as a screening test for fetal
Referência(s)