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• W2003178103 abstract "ObjectiveWe sought to review indications, technical aspects, risks, and recommendations for fetal blood sampling (FBS).MethodsA systematic review was performed using MEDLINE, PubMed, EMBASE, and Cochrane Library using the terms “fetal blood sampling,” “percutaneous umbilical blood sampling,” and “cordocentesis.” The search was restricted to English-language articles published from 1966 through July 2012. Priority was given to articles reporting original research, in particular randomized controlled trials, although review articles and commentaries also were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion in this document. Evidence reports and guidelines published by organizations or institutions such as the National Institutes of Health, Agency for Health Research and Quality, American Congress of Obstetricians and Gynecologists, and Society for Maternal-Fetal Medicine were also reviewed, and additional studies were located by reviewing bibliographies of identified articles. Grade (Grading of Recommendations Assessment, Development, and Evaluation) methodology was employed for defining strength of recommendations and rating quality of evidence. Consistent with US Preventive Task Force guidelines, references were evaluated for quality based on the highest level of evidence.Results and RecommendationsUltrasound-guided FBS is the only procedure that provides direct access to the fetal circulation. When invasive testing is planned for suspected severe fetal anemia or thrombocytopenia, we recommend FBS as the procedure of choice, with availability of immediate transfusion if confirmed. We recommend against the use of FBS for indications in which other less invasive, and therefore lower risk, alternatives are available. The overall success rate of FBS is high, and blood samples can be obtained in >98% of patients. We suggest that counseling for FBS include discussion about the potential risk of FBS that may include, but may not be limited to: bleeding from puncture site (20-30%); fetal bradycardia (5-10%); pregnancy loss (≥1.3%, depending on indication, gestational age, and placental penetration); and vertical transmission of hepatitis or human immunodeficiency virus. We recommend that FBS be performed by experienced operators at centers with expertise in invasive fetal procedures when feasible. We sought to review indications, technical aspects, risks, and recommendations for fetal blood sampling (FBS). A systematic review was performed using MEDLINE, PubMed, EMBASE, and Cochrane Library using the terms “fetal blood sampling,” “percutaneous umbilical blood sampling,” and “cordocentesis.” The search was restricted to English-language articles published from 1966 through July 2012. Priority was given to articles reporting original research, in particular randomized controlled trials, although review articles and commentaries also were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion in this document. Evidence reports and guidelines published by organizations or institutions such as the National Institutes of Health, Agency for Health Research and Quality, American Congress of Obstetricians and Gynecologists, and Society for Maternal-Fetal Medicine were also reviewed, and additional studies were located by reviewing bibliographies of identified articles. Grade (Grading of Recommendations Assessment, Development, and Evaluation) methodology was employed for defining strength of recommendations and rating quality of evidence. Consistent with US Preventive Task Force guidelines, references were evaluated for quality based on the highest level of evidence. Ultrasound-guided FBS is the only procedure that provides direct access to the fetal circulation. When invasive testing is planned for suspected severe fetal anemia or thrombocytopenia, we recommend FBS as the procedure of choice, with availability of immediate transfusion if confirmed. We recommend against the use of FBS for indications in which other less invasive, and therefore lower risk, alternatives are available. The overall success rate of FBS is high, and blood samples can be obtained in >98% of patients. We suggest that counseling for FBS include discussion about the potential risk of FBS that may include, but may not be limited to: bleeding from puncture site (20-30%); fetal bradycardia (5-10%); pregnancy loss (≥1.3%, depending on indication, gestational age, and placental penetration); and vertical transmission of hepatitis or human immunodeficiency virus. We recommend that FBS be performed by experienced operators at centers with expertise in invasive fetal procedures when feasible. See related editorial, page 163 Ultrasound-guided fetal blood sampling (FBS), also known as cordocentesis, or percutaneous umbilical cord blood sampling, was first described in the early 1980s.1Bang J. Bock J.E. Trolle D. Ultrasound-guided fetal intravenous transfusion for severe rhesus hemolytic disease.Br Med J (Clin Res Ed). 1982; 284 (Level III): 373-374Crossref PubMed Scopus (127) Google Scholar, 2Daffos F. Capella-Pavlovsky M. Forestier F. A new procedure for fetal blood sampling in utero: preliminary results of fifty-three cases.Am J Obstet Gynecol. 1983; 146 (Level II-3): 985-987Abstract Full Text PDF PubMed Scopus (150) Google Scholar In 1963, Liley3Liley A.W. Intrauterine transfusion of fetus in hemolytic disease.Br Med J. 1963; 2 (Level III): 1107-1109Crossref PubMed Scopus (408) Google Scholar was the first to treat fetal anemia by intraperitoneal transfusion of blood. In 1979, Rodeck and Campbell4Rodeck C.H. Campbell S. Umbilical-cord insertion as source of pure fetal blood for prenatal diagnosis.Lancet. 1979; 1 (Level III): 1244-1245Abstract PubMed Scopus (43) Google Scholar described the ability to perform FBS utilizing a fetoscopic approach, while 4 years later, Daffos et al2Daffos F. Capella-Pavlovsky M. Forestier F. A new procedure for fetal blood sampling in utero: preliminary results of fifty-three cases.Am J Obstet Gynecol. 1983; 146 (Level II-3): 985-987Abstract Full Text PDF PubMed Scopus (150) Google Scholar introduced the technique of ultrasound-guided FBS. Inserting a needle to gain access into the fetal circulation allows the operator to sample or transfuse blood, or other blood products such as platelets. FBS also allows medication5Hansmann M. Gembruch U. Bald R. Manz M. Redel D.A. Fetal tachyarrhythmias: transplacental and direct treatment of the fetus-a report of 60 cases.Ultrasound Obstet Gynecol. 1991; 1 (Level II-3): 162-168Crossref PubMed Scopus (138) Google Scholar, 6Blanch G. Walkinshaw S.A. Walsh K. Cardioversion of fetal tachyarrhythmia with adenosine.Lancet. 1994; 344 (Level III): 1646Abstract PubMed Scopus (14) Google Scholar or other substances, such as contrast media,7Denbow M.L. Blomley M.J. Cosgrove D.O. Fisk N.M. Ultrasound microbubble contrast angiography in monochorionic twin fetuses.Lancet. 1997; 349 (Level III): 773Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar to be injected directly into the fetal circulation. Fetal blood can also be collected and specimens analyzed for laboratory markers of fetal health or disease. These include, but are not limited to, red cell indices, white blood cell and differential counts, lymphocyte subset counts,8Berry S.M. Fine N. Bichalski J.A. Cotton D.B. Dombrowski M.P. Kaplan J. Circulating lymphocyte subsets in second- and third-trimester fetuses: comparison with newborns and adults.Am J Obstet Gynecol. 1992; 167 (Level II-3): 895-900Abstract Full Text PDF PubMed Scopus (42) Google Scholar microproteins,9Berry S.M. Lecolier B. Smith R.S. et al.Predictive value of fetal serum beta 2-microglobulin for neonatal renal function.Lancet. 1995; 345 (Level II-2): 1277-1278Abstract PubMed Scopus (43) Google Scholar, 10Tassis B.M. Trespidi L. Tirelli A.S. Pace E. Boschetto C. Nicolini U. Serum beta 2-microglobulin in fetuses with urinary tract anomalies.Am J Obstet Gynecol. 1997; 176 (Level II-1): 54-57Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar blood gas analysis, and thyroid hormone levels.11Thorpe-Beeston J.G. Nicolaides K.H. Fetal thyroid function.Fetal Diagn Ther. 1993; 8 (Level III): 60-72Crossref PubMed Scopus (28) Google Scholar It is important to assure that values obtained are compared with appropriate gestational age–matched normal values, as these may differ significantly from newborn levels.12Geaghan S.M. Fetal laboratory medicine: on the frontier of maternal-fetal medicine.Clin Chem. 2012; 58 (Level III): 337-352Crossref PubMed Scopus (11) Google Scholar In addition, use of fetal blood can allow rapid karyotyping when indicated for prenatal genetic diagnosis.13Gosden C. Rodeck C.H. Nicolaides K.H. Campbell S. Eason P. Sharp J.C. Fetal blood chromosome analysis: some new indications for prenatal karyotyping.Br J Obstet Gynaecol. 1985; 92 (Level II-2): 915-920Crossref PubMed Scopus (29) Google Scholar Since its introduction into clinical practice in the mid-1980s, the indications for FBS have evolved. The emergence of newer, less invasive testing modalities and development of molecular genetic techniques have greatly decreased the need for FBS, although there is a paucity of national data published on changing rates and indications for FBS. From 2006 through 2011, the 21 member centers of the North American Fetal Therapy Network performed an average of 13 FBS procedures per center per year (unpublished data, courtesy of Francois I. Luks, MD, PhD, North American Fetal Therapy Network; written communication, Nov. 30, 2012). The purpose of this guideline is to review the indications, technical aspects, risks, and current recommended clinical use for FBS. FBS has been described for a large number of indications (Table 1), although many are now obsolete or represent isolated case reports. For many indications, FBS has been replaced by technologic advances such as molecular testing for genetic disorders or polymerase chain reaction (PCR) for viral infections that allow testing of chorionic villi or amniotic fluid samples, resulting in earlier, more accurate, and safer access to the same, and in some cases superior, diagnostic results.Table 1Indications for fetal blood samplingIndicationsCommentCurrent common indications Diagnose and treat fetal severe anemiaMost common indication for FBS Diagnose and evaluate therapeutic response in NAIT Evaluate nonimmune fetal hydropsOnly in selected casesaEspecially if middle-cerebral artery peak systolic velocity is elevated; See text for details.Historical and less common indications Fetal aneuploidy for karyotypingRarely used in current practice; largely replaced by CVS or amniocentesis with FISH, or by NIPT Determine fetal blood type and platelet antigen statusLargely replaced by other tests, eg, NIPT, CVS, or amniocentesis, and molecular testing Diagnose genetic disorders (eg, hemophilia, thalassemia)Largely replaced by CVS or amniocentesis for molecular genetic diagnosis Measurement of biochemical or other serum markers for fetal disease (eg, fetal infection, thyroid function)Largely replaced by amniocentesis and PCR (eg, infection); rarely needed (eg, thyroid function) Direct intravascular therapyReported rarely, most commonly for failed maternal systemic treatment of fetal supraventricular tachycardia OthersCVS, chorionic villus sampling; FBS, fetal blood sampling; FISH, fluorescence in-situ hybridization; NAIT, neonatal alloimmune thrombocytopenia; NIPT, noninvasive prenatal testing; PCR, polymerase chain reaction.SMFM. Fetal blood sampling. Am J Obstet Gynecol 2013.a Especially if middle-cerebral artery peak systolic velocity is elevated; See text for details. Open table in a new tab CVS, chorionic villus sampling; FBS, fetal blood sampling; FISH, fluorescence in-situ hybridization; NAIT, neonatal alloimmune thrombocytopenia; NIPT, noninvasive prenatal testing; PCR, polymerase chain reaction. SMFM. Fetal blood sampling. Am J Obstet Gynecol 2013. Suspected severe fetal anemia is the most common current indication for FBS in the United States. Direct measurement of fetal hemoglobin, and therefore accurate diagnosis of fetal anemia, can only be made by FBS. Anemia may be suspected due to the presence of maternal alloantibodies, maternal parvovirus exposure or infection, other viral infections, or due to ultrasound findings such as fetal hydrops or elevated peak systolic velocity (PSV) of the fetal middle cerebral artery (MCA) by Doppler studies.14Mari 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.N Engl J Med. 2000; 342 (Level II-3): 9-14Crossref PubMed Scopus (926) Google Scholar Maternal anti-D alloimmunization remains the most common cause of fetal anemia, although this incidence has significantly decreased since the development and routine use of maternal anti-D prophylaxis with Rh immune globulin.15Freda V.J. Gorman J.G. Pollack W. Rh factor: prevention of isoimmunization and clinical trial on mothers.Science. 1966; 151 (Level II-1): 828-830Crossref PubMed Scopus (53) Google Scholar, 16Crowther C.A. Keirse M.J. Anti-D administration in pregnancy for preventing rhesus alloimmunization.Cochrane Database Syst Rev. 2000; 2 (Level III): CD000020PubMed Google Scholar Most cases of anti-D alloimmunization in current practice result from failure of the mother to receive antenatal or postnatal prophylaxis, or to sensitization despite prophylaxis due to a high volume of fetomaternal red cell transfusion.17Chilcott J. Lloyd Jones M. Wight J. et al.A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus-negative.Health Technol Assess. 2003; 7 (Level III): iii-62Google Scholar Given the decrease in cases of anti-D alloimmunization, fetal anemia due to sensitization from other red cell antigens (C, c, E, e, or Kell) or from infectious causes (usually parvovirus) has increased in relative proportion. In a study from one tertiary referral center in the United Kingdom, 45 women underwent FBS due to fetal anemia from 2003 through 2010. The causes were anti-D in 21 (47%), anti-Kell in 7 (16%), anti-C or E alloimmunization in 6 (13%), parvovirus infection in 6 (13%), Down syndrome (with red cell dysplasia) in 1 (2%), and unknown etiology of anemia in 4 (9%).18Johnstone-Ayliffe C. Prior T. Ong C. Regan F. Kumar S. Early procedure-related complications of fetal blood sampling and intrauterine transfusion for fetal anemia.Acta Obstet Gynecol Scand. 2012; 91 (Level II-2): 458-462Crossref PubMed Scopus (24) Google Scholar Current management of the pregnancy at risk for fetal anemia typically involves assessment with Doppler velocimetry of the fetal MCA, which has widely supplanted amniocentesis as the primary means of assessment for fetal anemia in pregnancies complicated by red cell alloimmunization. Based on the principle that worsening anemia is associated with increases in blood flow velocity, fetal anemia can be predicted by Doppler MCA in most cases.14Mari 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.N Engl J Med. 2000; 342 (Level II-3): 9-14Crossref PubMed Scopus (926) Google Scholar MCA Doppler measurements of PSV vary by gestational age, and values are converted to multiples of the median. A MCA PSV of ≥1.5 multiples of the median is generally considered indicative of moderate or severe fetal anemia,14Mari 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.N Engl J Med. 2000; 342 (Level II-3): 9-14Crossref PubMed Scopus (926) Google Scholar and FBS is warranted to directly measure fetal hemoglobin (or hematocrit) levels and determine the need for intrauterine transfusion (IUT). IUT is generally performed if fetal anemia is confirmed. The degree of anemia that causes hydrops, and therefore increases the risk of fetal death, is unpredictable, but hydrops most commonly occurs when the fetal hemoglobin is <7 g/dL (equivalent to hematocrit of about <20%).19Nicolaides K.H. Thilaganathan B. Rodeck C.H. Mibashan R.S. Erythroblastosis and reticulocytosis in anemic fetuses.Am J Obstet Gynecol. 1988; 159 (Level II-2): 1063-1065Abstract PubMed Google Scholar Neonatal alloimmune thrombocytopenia (NAIT) is a disorder in which transplacental passage of maternal antiplatelet antibodies causes fetal (and neonatal) thrombocytopenia, at times severe and with devastating consequences such as intracranial hemorrhage. The diagnosis of fetal thrombocytopenia caused by NAIT in the current pregnancy can only be made with FBS. Historically, at-risk pregnancies have been managed with FBS to detect fetal thrombocytopenia, with platelets immediately available for fetal IUT. Currently, maternal intravenous immunoglobulin, sometimes in conjunction with corticosteroids, is administered to increase the fetal platelet count. While FBS is used in some circumstances to assess the response to this treatment, some experts believe that FBS may be unnecessary if maternal therapy is already being administered and vaginal delivery is not being considered, because FBS may not add enough additional information to justify the risks associated with the procedure.20Bussel J.B. Berkowitz R.L. Hung C. et al.Intracranial hemorrhage in alloimmune thrombocytopenia: stratified management to prevent recurrence in the subsequent affected fetus.Am J Obstet Gynecol. 2010; 203 (Level II-2): 135.e1-135.e14Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 21McQuilten Z.K. Wood E.M. Savoia H. Cole S. A review of pathophysiology and current treatment for neonatal alloimmune thrombocytopenia (NAIT) and introducing the Australian NAIT registry.Aust N Z J Obstet Gynaecol. 2011; 51 (Level III): 191-198Crossref PubMed Scopus (34) Google Scholar Fetal hydrops can also be evaluated by FBS. The differential diagnosis of fetal hydrops is extensive,22Bellini C. Hennekam R.C. Fulcheri E. et al.Etiology of nonimmune hydrops fetalis: a systematic review.Am J Med Genet A. 2009; 149A (Level III): 844-851Crossref PubMed Scopus (149) Google Scholar, 23Santo S. Mansour S. Thilaganathan B. et al.Prenatal diagnosis of non-immune hydrops fetalis: what do we tell the parents?.Prenat Diagn. 2011; 31 (Level II-2): 186-195Crossref PubMed Scopus (79) Google Scholar but fetal anemia, aneuploidy, and infection are relatively common causes. Much of the evaluation for hydrops can be first accomplished with maternal serum analyses, detailed ultrasound evaluation, and amniocentesis. However, it is reasonable to offer FBS in the setting of nonimmune hydrops, especially if the rest of the workup is negative and the fetal MCA PSV is elevated. Otherwise, amniocentesis carries fewer risks than FBS, and can rapidly identify parvovirus and exclude causes of hydrops, such as aneuploidy, for which IUT would not alter the prognosis. Nonetheless, because fetal anemia is one of the most common causes of hydrops, FBS with the availability of blood for possible IUT is often part of the management of fetal hydrops. Several past indications for FBS have now been replaced by safer or more sophisticated tests, often available through noninvasive prenatal diagnosis, amniocentesis, or chorionic villus sampling (CVS) procedures. Rapid karyotyping to diagnose aneuploidy is no longer an indication for FBS. Because of the widespread availability of fluorescence in-situ hybridization for chromosomes 21, 18, 13, X, and Y, many couples now elect CVS or amniocentesis with fluorescence in-situ hybridization, followed by karyotyping or chromosomal microarray analysis, when rapid testing for aneuploidy is indicated. In this way, they can avoid the increased risks associated with FBS, detect the majority of fetuses with common aneuploidies within 24-48 hours, and obtain a complete karyotype or chromosomal microarray analysis result in 7-10 days. Noninvasive prenatal testing can also provide karyotype results for chromosomes 21, 18, 13, X, and Y in 7-10 days. Mosaicism–the presence of >1 cell line–on a karyotype from an amniocentesis or CVS can represent a laboratory artifact, an abnormality confined to the placenta or membranes, or a true fetal chromosomal abnormality. Historically, FBS was recommended in many cases in which mosaicism was identified by amniocentesis or CVS, but the limited prognostic utility of this approach has led to a decrease in procedures done for this indication.24Hsu L.Y. Benn P.A. Revised guidelines for the diagnosis of mosaicism in amniocytes.Prenat Diagn. 1999; 19 (Level III): 1081-1082Crossref PubMed Google Scholar Determination of fetal blood type and platelet antigen status is no longer an indication for FBS. Since the 1990s, fetal Rh status can be determined reliably by PCR analysis performed on amniocytes obtained from amniocentesis.25Fisk N.M. Bennett P. Warwick R.M. et al.Clinical utility of fetal RhD typing in alloimmunized pregnancies by means of polymerase chain reaction on amniocytes or chorionic villi.Am J Obstet Gynecol. 1994; 171 (Level II-3): 50-54Abstract Full Text PDF PubMed Scopus (37) Google Scholar PCR analysis of amniocytes can also determine platelet antigen type,26Simsek S. Christiaens G.C. Kanhai H.H. et al.Human platelet antigen-1 (Zw) typing of fetuses by analysis of polymerase chain reaction-amplified genomic DNA from amniocytes.Transfus Med. 1994; 4 (Level III): 15-19Crossref PubMed Scopus (15) Google Scholar and this has been shown to be very useful in the clinical management of pregnancies at risk for NAIT. PCR performed using amniocyte-derived DNA can be done earlier in gestation than FBS, has been proven to be highly accurate, and is more widely available, easier, and safer than FBS. Since its introduction for Rh genotyping, this technology can now determine fetal red cell genotype for virtually all antigens capable of causing fetal hemolytic disease. Recently, cell-free DNA isolated from maternal plasma has also been used as a substrate for PCR testing to determine fetal Rh status. This noninvasive modality has been shown to be highly sensitive and specific.27Muller S.P. Bartels I. Stein W. et al.The determination of the fetal D status from maternal plasma for decision making on Rh prophylaxis is feasible.Transfusion. 2008; 48 (Level II-2): 2292-2301Crossref PubMed Scopus (99) Google Scholar Noninvasive fetal Rh typing with cell-free DNA is commonly used in many European countries as the procedure of choice for fetal blood type and platelet antigen status determination.28Finning K. Martin P. Summers J. Massey E. Poole G. Daniels G. Effect of high throughput RHD typing of fetal DNA in maternal plasma on use of anti-RhD immunoglobulin in RhD negative pregnant women: prospective feasibility study.BMJ. 2008; 336 (Level II-2): 816-818Crossref PubMed Scopus (194) Google Scholar, 29Wright C.F. Burton H. The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis.Hum Reprod Update. 2009; 15 (Level III): 139-151Crossref PubMed Scopus (191) Google Scholar, 30van der Schoot C.E. Hahn S. Chitty L.S. Non-invasive prenatal diagnosis and determination of fetal Rh status.Semin Fetal Neonatal Med. 2008; 13 (Level III): 63-68Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Inherited anemias or hemoglobinopathies have historically been a relatively common indication for FBS, with a sample of fetal blood traditionally required for hemoglobin electrophoresis to make a diagnosis of thalassemia. With the advent of modern molecular genetic techniques, fetal diagnosis can reliably be made using DNA obtained via CVS or amniocentesis.31Leung T.Y. Lao T.T. Thalassemia in pregnancy.Best Pract Res Clin Obstet Gynaecol. 2012; 26 (Level III): 37-51Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Cases of FBS and intrauterine exchange transfusions have been reported in the management of fetuses affected with alpha-thalassemia, a disorder that typically results in hydrops and fetal demise in utero. While such treatment has been successful in a handful of cases, it is dependent on availability of effective postnatal treatments, and long-term outcomes are unclear.32Dwinnell S.J. Coad S. Butler B. et al.In utero diagnosis and management of a fetus with homozygous alpha-thalassemia in the second trimester: a case report and literature review.J Pediatr Hematol Oncol. 2011; 33 (Level III): e358-e360Crossref PubMed Scopus (19) Google Scholar In some parts of the world, sophisticated molecular techniques may be unavailable and hemoglobinopathies relatively common, so FBS continues to be routinely used in the diagnosis of alpha- and beta-thalassemia. In 1 recent study reported from Thailand, for example, >2000 cordocenteses were performed from 1989 through 2010; >75% of these were done due to a risk of fetal thalassemia.33Boupaijit K. Wanapirak C. Piyamongkol W. Sirichotiyakul S. Tongsong T. Effect of placenta penetration during cordocentesis at mid-pregnancy on fetal outcomes.Prenat Diagn. 2012; 32 (Level II-2): 83-87Crossref PubMed Scopus (7) Google Scholar Other past indications for FBS include measurement of biochemical or other serum markers for fetal infections and diseases (eg, thyroid, renal).34Corbacioglu Esmer A. Gul A. Dagdeviren H. Turan Bakirci I. Sahin O. Intrauterine diagnosis and treatment of fetal goitrous hypothyroidism.J Obstet Gynaecol Res. 2013; 39 (Level III): 720-723Crossref PubMed Scopus (17) Google Scholar, 35Bliddal S. Rasmussen A.K. Sundberg K. Brocks V. Skovbo P. Feldt-Rasmussen U. Graves' disease in two pregnancies complicated by fetal goitrous hypothyroidism: successful in utero treatment with levothyroxine.Thyroid. 2011; 21 (Level III): 75-81Crossref PubMed Scopus (17) Google Scholar, 36Freedman A.L. Bukowski T.P. Smith C.A. et al.Use of urinary beta-2-microglobulin to predict severe renal damage in fetal obstructive uropathy.Fetal Diagn Ther. 1997; 12 (Level II-2): 1-6Crossref PubMed Scopus (34) Google Scholar, 37Haddad M.R. Macri C.J. Holmes C.S. et al.In utero copper treatment for Menkes disease associated with a severe ATP7A mutation.Mol Genet Metab. 2012; 107 (Level III): 222-228Crossref PubMed Scopus (18) Google Scholar FBS has been used to determine the presence and extent of fetal infection (eg, cytomegalovirus, toxoplasmosis, parvovirus), but amniotic fluid culture and/or PCR are currently the primary diagnostic modalities. In settings in which PCR is not readily available, FBS has been used for diagnosis, for example in rare cases of fetal varicella with measurement of varicella-zoster virus-specific IgM and viral culture.38Sanchez M.A. Bello-Munoz J.C. Cebrecos I. et al.The prevalence of congenital varicella syndrome after a maternal infection, but before 20 weeks of pregnancy: a prospective cohort study.J Matern Fetal Neonatal Med. 2011; 24 (Level II-2): 341-347Crossref PubMed Scopus (20) Google Scholar FBS allows direct intravascular therapy when indicated, although this has been reported relatively rarely. There are limited conditions for which a single dose of a medication is useful, and serial or chronic intravascular fetal therapy is impractical. In a number of cases and small series, direct intravascular administration of amiodarone or adenosine through the umbilical vein has been reported for treatment of fetal arrhythmias resistant to standard maternal systemic administration.39Tomek V. Marek J. Spalova I. et al.Intraumbilical therapy of fetal supraventricular tachycardia.Ceska Gynekol. 2002; 67 (Level III): 380-383PubMed Google Scholar This has been most commonly reported in fetal hydrops due to supraventricular tachycardia, where transplacental therapy is less effective and a single injection may resolve the arrhythmia.5Hansmann M. Gembruch U. Bald R. Manz M. Redel D.A. Fetal tachyarrhythmias: transplacental and direct treatment of the fetus-a report of 60 cases.Ultrasound Obstet Gynecol. 1991; 1 (Level II-3): 162-168Crossref PubMed Scopus (138) Google Scholar, 6Blanch G. Walkinshaw S.A. Walsh K. Cardioversion of fetal tachyarrhythmia with adenosine.Lancet. 1994; 344 (Level III): 1646Abstract PubMed Scopus (14) Google Scholar, 40Dangel J.H. Roszkowski T. Bieganowska K. Kubicka K. Ganowicz J. Adenosine triphosphate for cardioversion of supraventricular tachycardia in two hydropic fetuses.Fetal Diagn Ther. 2000; 15 (Level III): 326-330Crossref PubMed Scopus (9) Google Scholar While a single case of chronic fetal umbilical vein cannulation followed by daily infusion of nutrients has been reported for a fetus with severe intrauterine growth restriction,41Tchirikov M. Kharkevich O. Steetskamp J. Beluga M. Strohner M. Treatment of growth-restricted human fetuses with amino acids and glucose supplementation through a chronic fetal intravascular perinatal port system.Eur Surg Res. 2010; 45 (Level III): 45-49Crossref PubMed Scopus (11) Google Scholar evidence regarding the risks and benefits of this intervention are lacking and this approach is not recommended. In another report, 16 fetuses were treated with intravenous fentanyl in an attempt to ameliorate the fetal stress response to intrahepatic fetal transfusion.42Fisk N.M. Gitau R. Teixeira J.M. Giannakoulopoulos X. Cameron A.D. Glover V.A. Effect of direct fetal opioid analgesia on fetal hormonal and hemodynamic stress response to intrauterine nee" @default.
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