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Fetal blood sampling

      Objective

      We sought to review indications, technical aspects, risks, and recommendations for fetal blood sampling (FBS).

      Methods

      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.

      Results and Recommendations

      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.

      Key words

      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.
      • Bang J.
      • Bock J.E.
      • Trolle D.
      Ultrasound-guided fetal intravenous transfusion for severe rhesus hemolytic disease.
      • Daffos F.
      • Capella-Pavlovsky M.
      • Forestier F.
      A new procedure for fetal blood sampling in utero: preliminary results of fifty-three cases.
      In 1963, Liley
      • Liley A.W.
      Intrauterine transfusion of fetus in hemolytic disease.
      was the first to treat fetal anemia by intraperitoneal transfusion of blood. In 1979, Rodeck and Campbell
      • Rodeck C.H.
      • Campbell S.
      Umbilical-cord insertion as source of pure fetal blood for prenatal diagnosis.
      described the ability to perform FBS utilizing a fetoscopic approach, while 4 years later, Daffos et al
      • Daffos F.
      • Capella-Pavlovsky M.
      • Forestier F.
      A new procedure for fetal blood sampling in utero: preliminary results of fifty-three cases.
      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 medication
      • Hansmann M.
      • Gembruch U.
      • Bald R.
      • Manz M.
      • Redel D.A.
      Fetal tachyarrhythmias: transplacental and direct treatment of the fetus-a report of 60 cases.
      • Blanch G.
      • Walkinshaw S.A.
      • Walsh K.
      Cardioversion of fetal tachyarrhythmia with adenosine.
      or other substances, such as contrast media,
      • Denbow M.L.
      • Blomley M.J.
      • Cosgrove D.O.
      • Fisk N.M.
      Ultrasound microbubble contrast angiography in monochorionic twin fetuses.
      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,
      • Berry 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.
      microproteins,
      • Berry S.M.
      • Lecolier B.
      • Smith R.S.
      • et al.
      Predictive value of fetal serum beta 2-microglobulin for neonatal renal function.
      • Tassis B.M.
      • Trespidi L.
      • Tirelli A.S.
      • Pace E.
      • Boschetto C.
      • Nicolini U.
      Serum beta 2-microglobulin in fetuses with urinary tract anomalies.
      blood gas analysis, and thyroid hormone levels.
      • Thorpe-Beeston J.G.
      • Nicolaides K.H.
      Fetal thyroid function.
      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.
      • Geaghan S.M.
      Fetal laboratory medicine: on the frontier of maternal-fetal medicine.
      In addition, use of fetal blood can allow rapid karyotyping when indicated for prenatal genetic diagnosis.
      • Gosden C.
      • Rodeck C.H.
      • Nicolaides K.H.
      • Campbell S.
      • Eason P.
      • Sharp J.C.
      Fetal blood chromosome analysis: some new indications for prenatal karyotyping.
      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.

      What are the current possible indications 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 sampling
      IndicationsComment
      Current 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 cases
      Especially 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
       Others
      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.
      a Especially if middle-cerebral artery peak systolic velocity is elevated; See text for details.
      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.
      • Mari 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.
      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.
      • Freda V.J.
      • Gorman J.G.
      • Pollack W.
      Rh factor: prevention of isoimmunization and clinical trial on mothers.
      • Crowther C.A.
      • Keirse M.J.
      Anti-D administration in pregnancy for preventing rhesus alloimmunization.
      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.
      • Chilcott 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.
      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%).
      • Johnstone-Ayliffe C.
      • Prior T.
      • Ong C.
      • Regan F.
      • Kumar S.
      Early procedure-related complications of fetal blood sampling and intrauterine transfusion for fetal anemia.
      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.
      • Mari 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.
      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,
      • Mari 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.
      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%).
      • Nicolaides K.H.
      • Thilaganathan B.
      • Rodeck C.H.
      • Mibashan R.S.
      Erythroblastosis and reticulocytosis in anemic fetuses.
      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.
      • Bussel J.B.
      • Berkowitz R.L.
      • Hung C.
      • et al.
      Intracranial hemorrhage in alloimmune thrombocytopenia: stratified management to prevent recurrence in the subsequent affected fetus.
      • McQuilten 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.
      Fetal hydrops can also be evaluated by FBS. The differential diagnosis of fetal hydrops is extensive,
      • Bellini C.
      • Hennekam R.C.
      • Fulcheri E.
      • et al.
      Etiology of nonimmune hydrops fetalis: a systematic review.
      • Santo S.
      • Mansour S.
      • Thilaganathan B.
      • et al.
      Prenatal diagnosis of non-immune hydrops fetalis: what do we tell the parents?.
      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.

      What are some historical or less common indications for FBS?

      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.
      • Hsu L.Y.
      • Benn P.A.
      Revised guidelines for the diagnosis of mosaicism in amniocytes.
      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.
      • Fisk 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.
      PCR analysis of amniocytes can also determine platelet antigen type,
      • Simsek 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.
      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.
      • Muller 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.
      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.
      • Finning 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.
      • Wright C.F.
      • Burton H.
      The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis.
      • van der Schoot C.E.
      • Hahn S.
      • Chitty L.S.
      Non-invasive prenatal diagnosis and determination of fetal Rh status.
      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.
      • Leung T.Y.
      • Lao T.T.
      Thalassemia in pregnancy.
      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.
      • Dwinnell 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.
      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.
      • Boupaijit K.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      • Tongsong T.
      Effect of placenta penetration during cordocentesis at mid-pregnancy on fetal outcomes.
      Other past indications for FBS include measurement of biochemical or other serum markers for fetal infections and diseases (eg, thyroid, renal).
      • Corbacioglu Esmer A.
      • Gul A.
      • Dagdeviren H.
      • Turan Bakirci I.
      • Sahin O.
      Intrauterine diagnosis and treatment of fetal goitrous hypothyroidism.
      • Bliddal 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.
      • Freedman 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.
      • Haddad M.R.
      • Macri C.J.
      • Holmes C.S.
      • et al.
      In utero copper treatment for Menkes disease associated with a severe ATP7A mutation.
      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.
      • Sanchez 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.
      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.
      • Tomek V.
      • Marek J.
      • Spalova I.
      • et al.
      Intraumbilical therapy of fetal supraventricular tachycardia.
      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.
      • Hansmann M.
      • Gembruch U.
      • Bald R.
      • Manz M.
      • Redel D.A.
      Fetal tachyarrhythmias: transplacental and direct treatment of the fetus-a report of 60 cases.
      • Blanch G.
      • Walkinshaw S.A.
      • Walsh K.
      Cardioversion of fetal tachyarrhythmia with adenosine.
      • Dangel J.H.
      • Roszkowski T.
      • Bieganowska K.
      • Kubicka K.
      • Ganowicz J.
      Adenosine triphosphate for cardioversion of supraventricular tachycardia in two hydropic fetuses.
      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,
      • Tchirikov 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.
      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.
      • Fisk 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 needling.
      Again, no evidence of fetal benefit from this treatment was demonstrated. In general, FBS has rarely been used for medical therapies other than transfusions or refractory arrhythmias, and evidence for benefits from these other therapies is lacking.

      What are the technical aspects of FBS?

      Techniques to obtain samples of fetal blood for prenatal diagnosis, and to access the fetal circulation for the purpose of IUT have evolved over the last 50 years
      • Bang J.
      • Bock J.E.
      • Trolle D.
      Ultrasound-guided fetal intravenous transfusion for severe rhesus hemolytic disease.
      • Daffos F.
      • Capella-Pavlovsky M.
      • Forestier F.
      A new procedure for fetal blood sampling in utero: preliminary results of fifty-three cases.
      • Rodeck C.H.
      • Campbell S.
      Umbilical-cord insertion as source of pure fetal blood for prenatal diagnosis.
      (Table 2).
      • Johnstone-Ayliffe C.
      • Prior T.
      • Ong C.
      • Regan F.
      • Kumar S.
      Early procedure-related complications of fetal blood sampling and intrauterine transfusion for fetal anemia.
      • Tangshewinsirikul C.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      • Tongsong T.
      Effect of cord puncture site in cordocentesis at mid-pregnancy on pregnancy outcomes.
      • Tongsong T.
      • Wanapirak C.
      • Kunavikatikul C.
      • Sirirchotiyakul S.
      • Piyamongkol W.
      • Chanprapaph P.
      Cordocentesis at 16-24 weeks of gestation: experience of 1,320 cases.
      • Aina-Mumuney A.J.
      • Holcroft C.J.
      • Blakemore K.J.
      • et al.
      Intrahepatic vein for fetal blood sampling: one center's experience.
      • Nicolini U.
      • Nicolaidis P.
      • Fisk N.M.
      • Tannirandorn Y.
      • Rodeck C.H.
      Fetal blood sampling from the intrahepatic vein: analysis of safety and clinical experience with 214 procedures.
      • Somerset D.A.
      • Moore A.
      • Whittle M.J.
      • Martin W.
      • Kilby M.D.
      An audit of outcome in intravascular transfusions using the intrahepatic portion of the fetal umbilical vein compared to cordocentesis.
      • Sikovanyecz J.
      • Horvath E.
      • Sallay E.
      • Gellen J.
      • Pal A.
      • Szabo J.
      Fetomaternal transfusion and pregnancy outcome after cordocentesis.
      • Liao C.
      • Wei J.
      • Li Q.
      • Li L.
      • Li J.
      • Li D.
      Efficacy and safety of cordocentesis for prenatal diagnosis.
      • Boulot P.
      • Deschamps F.
      • Lefort G.
      • et al.
      Pure fetal blood samples obtained by cordocentesis: technical aspects of 322 cases.
      Currently, there are several ways to accomplish ultrasound-guided placement of a needle into the fetal circulation: directly into the umbilical cord (either at the placental cord insertion [PCI] or abdominal cord insertion [ACI] or into a free loop); into the intrahepatic portion of the umbilical vein (also called the intrahepatic vein [IHV]); or into the fetal heart (cardiocentesis). Besides differences in sampling sites, there are variations in other technical aspects of the procedure, such as use of prophylactic antibiotics, anesthesia, paralytic agents, ultrasound techniques, placental penetration, and other considerations. Table 2 summarizes technical aspects as reported by some of the largest series, while Table 3 provides a summary of suggestions.
      Table 2Summary of studies regarding fetal blood sampling technique
      StudyNo. of proceduresMaternal sedationLocal anesthesiaUltrasound techniquePuncture siteConfirmation of fetal blood
      Tangshewinsirikul et al,
      • Tangshewinsirikul C.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      • Tongsong T.
      Effect of cord puncture site in cordocentesis at mid-pregnancy on pregnancy outcomes.
      2011
      2214NoYesFreehandPCI or free loopn/a
      Tongsong et al,
      • Tongsong T.
      • Wanapirak C.
      • Kunavikatikul C.
      • Sirirchotiyakul S.
      • Piyamongkol W.
      • Chanprapaph P.
      Cordocentesis at 16-24 weeks of gestation: experience of 1,320 cases.
      2000
      1320NoYesFreehandPCI or free loopYes
      Aina-Mumuney et al,
      • Aina-Mumuney A.J.
      • Holcroft C.J.
      • Blakemore K.J.
      • et al.
      Intrahepatic vein for fetal blood sampling: one center's experience.
      2008
      210YesYesn/aIHV, PCI, or bothMCV
      Nicolini et al,
      • Nicolini U.
      • Nicolaidis P.
      • Fisk N.M.
      • Tannirandorn Y.
      • Rodeck C.H.
      Fetal blood sampling from the intrahepatic vein: analysis of safety and clinical experience with 214 procedures.
      1990
      214Only 1 y, not last 2 yn/aFreehandIHVn/a
      Somerset et al,
      • Somerset D.A.
      • Moore A.
      • Whittle M.J.
      • Martin W.
      • Kilby M.D.
      An audit of outcome in intravascular transfusions using the intrahepatic portion of the fetal umbilical vein compared to cordocentesis.
      2006
      221n/an/an/aIHV, PCI, or intracardiacn/a
      Sikovanyecz et al,
      • Sikovanyecz J.
      • Horvath E.
      • Sallay E.
      • Gellen J.
      • Pal A.
      • Szabo J.
      Fetomaternal transfusion and pregnancy outcome after cordocentesis.
      2001
      268n/aNoFreehandPCI or free loopn/a
      Liao et al,
      • Liao C.
      • Wei J.
      • Li Q.
      • Li L.
      • Li J.
      • Li D.
      Efficacy and safety of cordocentesis for prenatal diagnosis.
      2006
      2010n/aNoFixed needle guide97% free loop, 3% PCIKHB
      Boulot et al,
      • Boulot P.
      • Deschamps F.
      • Lefort G.
      • et al.
      Pure fetal blood samples obtained by cordocentesis: technical aspects of 322 cases.
      1990
      322NoYesn/aPCI (majority) or free loopKHB or MCV
      Johnstone-Ayliffe et al,
      • Johnstone-Ayliffe C.
      • Prior T.
      • Ong C.
      • Regan F.
      • Kumar S.
      Early procedure-related complications of fetal blood sampling and intrauterine transfusion for fetal anemia.
      2012
      114n/an/aFreehandPCI, IHV, or free loopn/a
      IHV, intrahepatic vein; KHB, Kleihauer-Betke test; MCV, mean corpuscular volume; n/a, not available; PCI, placental cord insertion.
      SMFM. Fetal blood sampling. Am J Obstet Gynecol 2013.
      Table 3Technical aspects of fetal blood sampling?
      See text for details.
      Technical aspectComments
      Prophylactic antibioticsInsufficient evidence to recommend
      Maternal sedationUsed infrequently
      Local anesthesiaUsed by some centers
      Skin preparationPreprocedural antibacterial skin preparation and aseptic technique are recommended
      Needle guidanceBoth needle guide instrument and freehand techniques have been reported and are acceptable; direct needle into target (eg, umbilical vein) under continuous ultrasound guidance; avoid umbilical arteries if feasible
      Needle gauge and length20- or 22-gauge; gauge and length depend on indication, suspicion of thrombocytopenia, gestational age, maternal body habitus, and distance from skin to target
      Sampling site
      • Umbilical vein usually preferred, either at PCI or ACI, or into free loop;
      • IHV
      • Fetal heart (cardiocentesis)
      Paralytic agent for transfusionPancuronium, atracurium, or vecuronium
      ACI, abdominal cord insertion; IHV, intrahepatic vein; PCI, placental cord insertion.
      SMFM. Fetal blood sampling. Am J Obstet Gynecol 2013.
      a See text for details.

      Prophylactic antibiotics

      There are no randomized trials on the efficacy of prophylactic antibiotic for FBS. Boulot et al
      • Boulot P.
      • Deschamps F.
      • Lefort G.
      • et al.
      Pure fetal blood samples obtained by cordocentesis: technical aspects of 322 cases.
      based their recommendation to use prophylactic antibiotics on the fact that 2 of the 6 fetal deaths in their series were attributed to amnionitis. However, most large series of FBS do not report use of prophylactic antibiotics for this sterile procedure.
      • Johnstone-Ayliffe C.
      • Prior T.
      • Ong C.
      • Regan F.
      • Kumar S.
      Early procedure-related complications of fetal blood sampling and intrauterine transfusion for fetal anemia.
      • Tangshewinsirikul C.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      • Tongsong T.
      Effect of cord puncture site in cordocentesis at mid-pregnancy on pregnancy outcomes.
      • Tongsong T.
      • Wanapirak C.
      • Kunavikatikul C.
      • Sirirchotiyakul S.
      • Piyamongkol W.
      • Chanprapaph P.
      Cordocentesis at 16-24 weeks of gestation: experience of 1,320 cases.
      • Aina-Mumuney A.J.
      • Holcroft C.J.
      • Blakemore K.J.
      • et al.
      Intrahepatic vein for fetal blood sampling: one center's experience.
      • Nicolini U.
      • Nicolaidis P.
      • Fisk N.M.
      • Tannirandorn Y.
      • Rodeck C.H.
      Fetal blood sampling from the intrahepatic vein: analysis of safety and clinical experience with 214 procedures.
      • Somerset D.A.
      • Moore A.
      • Whittle M.J.
      • Martin W.
      • Kilby M.D.
      An audit of outcome in intravascular transfusions using the intrahepatic portion of the fetal umbilical vein compared to cordocentesis.
      • Sikovanyecz J.
      • Horvath E.
      • Sallay E.
      • Gellen J.
      • Pal A.
      • Szabo J.
      Fetomaternal transfusion and pregnancy outcome after cordocentesis.
      • Liao C.
      • Wei J.
      • Li Q.
      • Li L.
      • Li J.
      • Li D.
      Efficacy and safety of cordocentesis for prenatal diagnosis.
      • Boulot P.
      • Deschamps F.
      • Lefort G.
      • et al.
      Pure fetal blood samples obtained by cordocentesis: technical aspects of 322 cases.
      In the American Congress of Obstetricians and Gynecologists Practice Bulletin on invasive testing for aneuploidy, there is no recommendation for the use of antibiotics to prevent intrauterine infection prior to invasive procedures.
      American College of Obstetricians and Gynecologists
      ACOG practice bulletin no. 88, December 2007: invasive prenatal testing for aneuploidy.

      Maternal sedation

      Use of maternal sedation is variable, although many centers no longer administer intravenous sedation (Table 2).

      Local anesthesia

      Use of local anesthesia varies depending on the preference of the operator, as well as type of procedure (diagnostic sampling or IUT). Of 9 studies cited, 4 of them
      • Tangshewinsirikul C.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      • Tongsong T.
      Effect of cord puncture site in cordocentesis at mid-pregnancy on pregnancy outcomes.
      • Tongsong T.
      • Wanapirak C.
      • Kunavikatikul C.
      • Sirirchotiyakul S.
      • Piyamongkol W.
      • Chanprapaph P.
      Cordocentesis at 16-24 weeks of gestation: experience of 1,320 cases.
      • Aina-Mumuney A.J.
      • Holcroft C.J.
      • Blakemore K.J.
      • et al.
      Intrahepatic vein for fetal blood sampling: one center's experience.
      • Boulot P.
      • Deschamps F.
      • Lefort G.
      • et al.
      Pure fetal blood samples obtained by cordocentesis: technical aspects of 322 cases.
      reported use of local anesthesia, although not all studies reported on this aspect (Table 2). While some centers use regional anesthesia after a viable gestational age and depending on the clinical circumstances, there are no data or clinical reports to support this practice.

      Skin preparation

      The majority of studies endorse using an aseptic technique, including a preprocedural antibacterial skin preparation to reduce the risk of infection.
      • Johnstone-Ayliffe C.
      • Prior T.
      • Ong C.
      • Regan F.
      • Kumar S.
      Early procedure-related complications of fetal blood sampling and intrauterine transfusion for fetal anemia.
      • Tangshewinsirikul C.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      • Tongsong T.
      Effect of cord puncture site in cordocentesis at mid-pregnancy on pregnancy outcomes.
      • Tongsong T.
      • Wanapirak C.
      • Kunavikatikul C.
      • Sirirchotiyakul S.
      • Piyamongkol W.
      • Chanprapaph P.
      Cordocentesis at 16-24 weeks of gestation: experience of 1,320 cases.
      • Aina-Mumuney A.J.
      • Holcroft C.J.
      • Blakemore K.J.
      • et al.
      Intrahepatic vein for fetal blood sampling: one center's experience.
      • Nicolini U.
      • Nicolaidis P.
      • Fisk N.M.
      • Tannirandorn Y.
      • Rodeck C.H.
      Fetal blood sampling from the intrahepatic vein: analysis of safety and clinical experience with 214 procedures.
      • Somerset D.A.
      • Moore A.
      • Whittle M.J.
      • Martin W.
      • Kilby M.D.
      An audit of outcome in intravascular transfusions using the intrahepatic portion of the fetal umbilical vein compared to cordocentesis.
      • Sikovanyecz J.
      • Horvath E.
      • Sallay E.
      • Gellen J.
      • Pal A.
      • Szabo J.
      Fetomaternal transfusion and pregnancy outcome after cordocentesis.
      • Liao C.
      • Wei J.
      • Li Q.
      • Li L.
      • Li J.
      • Li D.
      Efficacy and safety of cordocentesis for prenatal diagnosis.
      • Boulot P.
      • Deschamps F.
      • Lefort G.
      • et al.
      Pure fetal blood samples obtained by cordocentesis: technical aspects of 322 cases.

      Needle guidance

      The insertion of the needle into the fetal circulation can be accomplished either with a needle guide instrument that attaches to the end of the ultrasound transducer, or by using an ultrasound-guided freehand technique. With either method, the operator can control the transducer with one hand and the needle with the other, or an assistant can control the transducer and find the appropriate place for a needle insertion attempt. The majority of studies seemed to describe the freehand technique, which may allow for greater flexibility (Table 2), although no trials exist comparing the 2 methods. With either technique, the operator follows the tip of the needle under continuous ultrasound guidance from soon after percutaneous entry point to placement into the fetal circulation. When the fetal umbilical cord is accessed, effort is made to insert the needle into the umbilical vein without puncturing one of the arteries as these may vasoconstrict when punctured, leading to fetal bradycardia and a subsequent emergency delivery.

      Needle gauge and length

      Most centers use a 20- or 22-gauge spinal needle, depending on the indication for procedure (diagnostic vs therapeutic IUT), and suspicion for thrombocytopenia.
      • Pacheco L.D.
      • Berkowitz R.L.
      • Moise Jr., K.J.
      • Bussel J.B.
      • McFarland J.G.
      • Saade G.R.
      Fetal and neonatal alloimmune thrombocytopenia: a management algorithm based on risk stratification.
      Other important considerations when choosing the appropriate needle are gestational age, maternal body habitus, and distance from skin to target. For example, at an earlier gestational age (eg, <24 weeks), it might be preferable to use a 22- (instead of 20-) gauge needle given the smaller umbilical cord vessels. In women with a thick panniculus, a larger-bore 20-gauge needle may be useful to prevent bending of the needle and to improve visualization. The distance from skin to target is also important to measure to determine if the standard 9-cm spinal needle length is appropriate, or if a longer needle is needed. Finally, some operators prefer to run heparin through the needle prior to sampling to prevent the formation of a blood clot within the needle.

      Sampling site

      FBS is most commonly performed via the umbilical vein close to the PCI. It is less commonly performed at the fetal ACI, through penetration of a free loop of cord, via cannulation of the IHV, and is rarely performed by fetal cardiocentesis. There are currently no published randomized control trials comparing the efficacy and safety of these techniques.
      • Sarno Jr., A.P.
      • Wilson R.D.
      Fetal cardiocentesis: a review of indications, risks, applications and technique.
      Advantages of sampling at the PCI are the relative stability of the cord for easier insertion and shorter procedure time.
      • Tangshewinsirikul C.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      • Tongsong T.
      Effect of cord puncture site in cordocentesis at mid-pregnancy on pregnancy outcomes.
      A disadvantage is the possibility of contamination by maternal blood, and need to confirm that the sample obtained is indeed of fetal origin. FBS performed from a free loop of cord may result in more bleeding and longer bleeding time due to piercing of the wall of the vessel, although it has the advantage of avoiding placental penetration, and avoiding the need for confirmation of fetal origin.
      • Sikovanyecz J.
      • Horvath E.
      • Sallay E.
      • Gellen J.
      • Pal A.
      • Szabo J.
      Fetomaternal transfusion and pregnancy outcome after cordocentesis.
      Indeed in one large study comparing outcomes for PCI (n = 559) vs free loop (n = 1655), the mean duration of the procedure was significantly shorter in the PCI group (4.5 vs 6.7 minutes, P = .001), while the rate of maternal blood contamination was significantly lower in the free loop group (0.6% vs 2.3%, P = .001). There were no differences in success rates, fetal bradycardia, or fetal loss rates between groups.
      • Tangshewinsirikul C.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      • Tongsong T.
      Effect of cord puncture site in cordocentesis at mid-pregnancy on pregnancy outcomes.
      The first large series published on FBS via the IHV reported a 91% success rate for obtaining a sample, and a successful IUT in 90% of those attempted.
      • Nicolini U.
      • Nicolaidis P.
      • Fisk N.M.
      • Tannirandorn Y.
      • Rodeck C.H.
      Fetal blood sampling from the intrahepatic vein: analysis of safety and clinical experience with 214 procedures.
      In this series, a 20-gauge needle was introduced into the fetal abdominal wall and advanced through the liver parenchyma into the umbilical vein or left portal vein. The needle was left unheld, allowing it to move freely with fetal movement and to minimize dislodgment. The dislodgment rate was 8.7%, and all of the 2.3% of cases of intraperitoneal bleeding resolved.
      • Nicolini U.
      • Nicolaidis P.
      • Fisk N.M.
      • Tannirandorn Y.
      • Rodeck C.H.
      Fetal blood sampling from the intrahepatic vein: analysis of safety and clinical experience with 214 procedures.
      Potential advantages of the IHV approach are the lack of need to confirm fetal origin of the sample, less fetomaternal hemorrhage due to avoidance of the placenta, and less streaming.
      • Aina-Mumuney A.J.
      • Holcroft C.J.
      • Blakemore K.J.
      • et al.
      Intrahepatic vein for fetal blood sampling: one center's experience.
      In a retrospective study of outcomes of IHV sampling compared with cordocentesis, a total of 210 procedures were performed in 139 pregnancies. One hundred were by IHV only, 80 by cordocentesis only, 19 by IHV following failed cordocentesis, and 11 by cordocentesis following failed IHV. Success rates for IHV only, cordocentesis only, conversion of IHV to cordocentesis, and cordocentesis to IHV were 95%, 83%, 91%, and 84%, respectively. Postprocedure streaming was significantly less common with IHV (1% vs 31%); although there were no differences in nonreassuring fetal heart rate patterns, need for urgent delivery, or fetal/neonatal deaths.
      • Aina-Mumuney A.J.
      • Holcroft C.J.
      • Blakemore K.J.
      • et al.
      Intrahepatic vein for fetal blood sampling: one center's experience.
      In another series of 382 procedures, IHV sampling was performed in 76%, cordocentesis in 18%, and cardiocentesis in 5%.
      • Chinnaiya A.
      • Venkat A.
      • Dawn C.
      • et al.
      Intrahepatic vein fetal blood sampling: current role in prenatal diagnosis.
      Multivariable analysis demonstrated a statistically significant increased risk of fetal loss for the cardiocentesis group only. In general, success rates are high with all methods, and the particular sampling site should be individualized based on experience of operator, as well as placental, umbilical cord, and fetal position.

      Placental penetration

      Concerns for placental penetration during FBS involve the potential increased risk for fetomaternal hemorrhage, and potential for higher fetal death rates. Few data exist, although a recent study compared 615 cases of cordocentesis with placental penetration to 1560 cases without penetration.
      • Boupaijit K.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      • Tongsong T.
      Effect of placenta penetration during cordocentesis at mid-pregnancy on fetal outcomes.
      Not surprisingly, almost all cases with placental penetration had an anterior placenta. Cordocentesis with placental penetration was associated with a significantly higher rate of fetal loss (3.6% vs 1.3%, P = .01), low birthweight (14.5% vs 11.0%, P < .05), umbilical cord bleeding (32.0% vs 28.4%, P < .05), and lower gestational age at delivery. There were no differences in duration of procedure, success rate, or rates of fetal bradycardia. Significant placental bleeding was observed in a third of cases with placental penetration, and no cases without penetration.

      Fetal blood specimen

      Once the needle has been successfully placed, blood is aspirated into a previously heparinized syringe. Many centers send an initial sample to determine if the blood obtained is fetal in origin.
      • Tongsong T.
      • Wanapirak C.
      • Kunavikatikul C.
      • Sirirchotiyakul S.
      • Piyamongkol W.
      • Chanprapaph P.
      Cordocentesis at 16-24 weeks of gestation: experience of 1,320 cases.
      • Liao C.
      • Wei J.
      • Li Q.
      • Li L.
      • Li J.
      • Li D.
      Efficacy and safety of cordocentesis for prenatal diagnosis.
      • Boulot P.
      • Deschamps F.
      • Lefort G.
      • et al.
      Pure fetal blood samples obtained by cordocentesis: technical aspects of 322 cases.
      Techniques such as measuring mean corpuscular volume (MCV) and the Kleihauer-Betke test have been successful in determining fetal origin. Additionally some centers draw and evaluate a maternal sample drawn prior to the procedure, for comparison of MCV and hemoglobin/hematocrit, since the fetal MCV is usually larger, and fetal hemoglobin/hematocrit values are typically different than corresponding maternal values. When the IHV, a free umbilical cord loop, or ACI are accessed, or if fetal cardiocentesis is performed, there is no need for verification of fetal blood since these sites assure a lack of maternal blood contamination.
      • Aina-Mumuney A.J.
      • Holcroft C.J.
      • Blakemore K.J.
      • et al.
      Intrahepatic vein for fetal blood sampling: one center's experience.
      In the case of suspected fetal anemia, the blood is sent for immediate analysis of hemoglobin/hematocrit to determine the amount of blood needed for IUT. Once IUT or sampling is complete, the needle is withdrawn. There is insufficient evidence to assess if monitoring the puncture site for bleeding (“streaming”) is necessary. During IUT, the fetal heart can be intermittently observed directly by ultrasound, and/or (with same view focused on umbilical insertion site) by using Doppler color flow or blood velocity waveforms by pulse Doppler.
      • Weiner C.P.
      • Wenstrom K.D.
      • Sipes S.L.
      • Williamson R.A.
      Risk factors for cordocentesis and fetal intravascular transfusion.

      Use of paralytic agents

      In 1988, Copel et al
      • Copel J.A.
      • Grannum P.A.
      • Harrison D.
      • Hobbins J.C.
      The use of intravenous pancuronium bromide to produce fetal paralysis during intravascular transfusion.
      first reported the intravenous injection of a muscle relaxant, pancuronium bromide, to reduce fetal movement during intravascular IUT. Since then, many centers routinely use agents such as pancuronium, atracurium, or vecuronium.
      • Moise Jr., K.J.
      • Deter R.L.
      • Kirshon B.
      • Adam K.
      • Patton D.E.
      • Carpenter Jr., R.J.
      Intravenous pancuronium bromide for fetal neuromuscular blockade during intrauterine transfusion for red-cell alloimmunization.
      • Bernstein H.H.
      • Chitkara U.
      • Plosker H.
      • Gettes M.
      • Berkowitz R.L.
      Use of atracurium besylate to arrest fetal activity during intrauterine intravascular transfusions.
      • Leveque C.
      • Murat I.
      • Toubas F.
      • Poissonnier M.H.
      • Brossard Y.
      • Saint-Maurice C.
      Fetal neuromuscular blockade with vecuronium bromide: studies during intravascular intrauterine transfusion in isoimmunized pregnancies.
      These agents differ in several respects. Pancuronium is a long-acting agent, while atracurium and vecuronium are both short-acting. Atracurium may be beneficial in fetuses with hydrops because it is not eliminated by the liver, and has the added benefit that the breakdown products do not have significant cardiovascular and neuromuscular effects.
      • Bernstein H.H.
      • Chitkara U.
      • Plosker H.
      • Gettes M.
      • Berkowitz R.L.
      Use of atracurium besylate to arrest fetal activity during intrauterine intravascular transfusions.
      • Mouw R.J.
      • Klumper F.
      • Hermans J.
      • Brandenburg H.C.
      • Kanhai H.H.
      Effect of atracurium or pancuronium on the anemic fetus during and directly after intravascular intrauterine transfusion: a double blind randomized study.
      • Chapple D.J.
      • Clark J.S.
      Pharmacological action of breakdown products of atracurium and related substances.
      In one study that compared the effects of pancuronium (0.1 mg/kg) or atracurium (0.4 mg/kg) on the onset and duration of fetal paralysis, fetal movements, and fetal heart rate parameters, no differences were found in the median time needed to complete the procedure or differences in transfusion volume, although pancuronium produced a major reduction in fetal heart rate variability and fetal movements after the procedure. The authors concluded that, when the need for use of fetal paralysis during IUT is thought to be necessary, atracurium may be a better choice.
      • Mouw R.J.
      • Klumper F.
      • Hermans J.
      • Brandenburg H.C.
      • Kanhai H.H.
      Effect of atracurium or pancuronium on the anemic fetus during and directly after intravascular intrauterine transfusion: a double blind randomized study.
      Paralytic agents may be particularly useful when large transfusion volumes (and therefore longer operating times) are anticipated, or when vigorous fetal movements make the procedure more challenging. They are not usually necessary when FBS is performed for indications other than potential IUT, or when an anterior placenta and cord insertion are present.

      Other

      Several technical aspects of FBS are important, but not studied or well documented in the literature. For example, there is no reliable information about the efficacy or prevalence of regional anesthesia for FBS. Similarly, little information exists about the choice of physical location (eg, operating room, ultrasound suite, office) for the procedure. Once viability is reached, it is prudent to perform the procedure in close proximity to or within an available operating room should the need for emergency cesarean delivery arise. The decision to use prophylactic steroids for fetal lung maturity prior to FBS is also not well documented, but should be considered when FBS is performed around 23 0/7 to 33 6/7 weeks, given the increased risk of preterm birth.

      Operator experience

      A current dilemma with respect to the FBS procedure is the ongoing continuing need for FBS in certain clinical situations (Table 1), concomitant with a decrease in number of procedures performed annually in the United States, which affects the training of future physicians. Given the current paucity of widely accepted clinical indications for the procedure, the capability to train physicians to perform FBS and to maintain a reasonable level of skill in doing the procedure poses challenges. Several authors have described simulation models
      • Ville Y.
      • Cooper M.
      • Revel A.
      • Frydman R.
      • Nicolaides K.H.
      Development of a training model for ultrasound-guided invasive procedures in fetal medicine.
      • Tongprasert F.
      • Wanapirak C.
      • Sirichotiyakul S.
      • Piyamongkol W.
      • Tongsong T.
      Training in cordocentesis: the first 50 case experience with and without a cordocentesis training model.
      that appear to be effective for teaching, and aid in the maintenance of the skills needed to competently perform FBS.

      What are the procedure-related risks of FBS?

      The risks of FBS often vary depending on the condition of the fetus, but there are common features (Table 4). The most common procedure-related risk is bleeding from the umbilical cord puncture site. The incidence has been reported to be 20-30% and is usually self-limiting, unless thrombocytopenia is present. An abnormal fetal heart rate can also occur after the procedure. Bradycardia is more common than tachycardia, with a reported incidence of 5-10%.
      • Han J.Y.
      • Nava-Ocampo A.A.
      Fetal heart rate response to cordocentesis and pregnancy outcome: a prospective cohort.
      The majority of fetal bradycardias resolves within 5 minutes and usually requires no further intervention.
      Table 4Risks of fetal blood sampling
      See text for details.
      RiskComments
      Bleeding from puncture site (eg, umbilical cord)20-30%; usually self-limited
      Abnormal fetal heart rate5-10% bradycardia; majority resolve within 5 min
      Pregnancy loss1.3% if no structural anomalies or hydrops and no placental penetration
      Vertical transmission of maternal infection (eg, hepatitis B, hepatitis C, or HIV)Insufficient information to estimate risk
      HIV, human immunodeficiency virus.
      SMFM. Fetal blood sampling. Am J Obstet Gynecol 2013.
      a See text for details.
      FBS does carry risk of procedure-related pregnancy loss, usually defined as the risk of pregnancy loss/fetal demise within 2 weeks of the procedure.
      • Sarno Jr., A.P.
      • Wilson R.D.
      Fetal cardiocentesis: a review of indications, risks, applications and technique.
      For a fetus without structural abnormalities, the procedure-related loss rate is estimated to be about 1%.
      • Maxwell D.J.
      • Johnson P.
      • Hurley P.
      • Neales K.
      • Allan L.
      • Knott P.
      Fetal blood sampling and pregnancy loss in relation to indication.
      • Tongsong T.
      • Wanapirak C.
      • Kunavikatikul C.
      • Sirirchotiyakul S.
      • Piyamongkol W.
      • Chanprapaph P.
      Fetal loss rate associated with cordocentesis at midgestation.
      Higher loss rates have been reported for fetuses with structural malformations, severe growth restriction, or hydrops (7%, 14%, and 25%, respectively) indicating that the procedure-related loss is dependent on the indication for the procedure.
      • Maxwell D.J.
      • Johnson P.
      • Hurley P.
      • Neales K.
      • Allan L.
      • Knott P.
      Fetal blood sampling and pregnancy loss in relation to indication.
      Besides the procedure indication, placental penetration affects the procedure-related loss risk, as mentioned above.
      • Boupaijit K.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      • Tongsong T.
      Effect of placenta penetration during cordocentesis at mid-pregnancy on fetal outcomes.
      Early gestational age (eg, <24 weeks) at the time of the procedure may also be associated with increased loss rates.
      • Liao C.
      • Wei J.
      • Li Q.
      • Li L.
      • Li J.
      • Li D.
      Efficacy and safety of cordocentesis for prenatal diagnosis.
      Invasive prenatal diagnostic tests performed in women chronically infected with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) carry a theoretical risk of vertical transmission. Very limited information is available about the risk of vertical transmission during FBS. From small studies of amniocentesis, the procedure-related risks of vertical transmission of HIV, hepatitis B, and hepatitis C appear to be exceedingly low, and related to maternal viral load.
      • Ko T.M.
      • Tseng L.H.
      • Chang M.H.
      • et al.
      Amniocentesis in mothers who are hepatitis B virus carriers does not expose the infant to an increased risk of hepatitis B virus infection.
      • Alexander J.M.
      • Ramus R.
      • Jackson G.
      • Sercely B.
      • Wendel Jr., G.D.
      Risk of hepatitis B transmission after amniocentesis in chronic hepatitis B carriers.
      • Delamare C.
      • Carbonne B.
      • Heim N.
      • et al.
      Detection of hepatitis C virus RNA (HCV RNA) in amniotic fluid: a prospective study.
      • Somigliana E.
      • Bucceri A.M.
      • Tibaldi C.
      • et al.
      Early invasive diagnostic techniques in pregnant women who are infected with the HIV: a multicenter case series.
      • Towers C.V.
      • Asrat T.
      • Rumney P.
      The presence of hepatitis B surface antigen and deoxyribonucleic acid in amniotic fluid and cord blood.
      The risk of vertical HIV transmission is higher in women who are not taking antiretroviral therapy, compared with women who are being treated and have undetectable viral loads.

      Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. HIV infected women. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed Aug. 7, 2013. Level III.

      In patients for whom no alternative exists to FBS, eg, severe fetal hemolytic disease requiring IUT, the potential risks of FBS related to vertical transmission should be discussed prior to the procedure. Treatment aimed at decreasing the viral load for both HIV and hepatitis B virus in patients with these infections should be considered. When performing FBS in a patient with one of these infections, efforts should be made to avoid traversing the placenta with the needle, if possible.

      Recommendations

      Ultrasound-guided FBS is the only procedure that provides direct access to the fetal circulation. While the number of indications for FBS is decreasing because of newly available less invasive and accurate techniques, FBS can be both beneficial and lifesaving in some cases of fetal anemia, NAIT, and hydrops (Table 1). The overall success rate of FBS is high, and blood samples can be obtained in >98% of patients.
      • Liao C.
      • Wei J.
      • Li Q.
      • Li L.
      • Li J.
      • Li D.
      Efficacy and safety of cordocentesis for prenatal diagnosis.
      This access comes at the price of at least a 1% incidence of fetal loss (Table 4). Proper technique should be adhered to, in order to minimize complications (Table 3).
      The Society for Maternal-Fetal Medicine Publications Committee has adopted the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach in the development of its clinical recommendations (www.gradeworkinggroup.org).
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.
      • et al.
      for the GRADE Working Group
      Rating quality of evidence and strength of recommendations GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      Recommendations regarding FBS are presented in Table 5. The grading scheme classifies recommendations as either strong (grade 1) or weak (grade 2), and classifies the quality of evidence as high (grade A), moderate (grade B), or low (grade C).
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.
      • et al.
      for the GRADE Working Group
      Rating quality of evidence and strength of recommendations GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.

      UpToDate, grading guide. Available at: http://www.uptodate.com/home/grading-guide#GradingRecommendations. Accessed March 10, 2013. Level III.

      Thus, the recommendations can be 1 of the following 6 possibilities: 1A, 1B, 1C, 2A, 2B, 2C (Table 6).
      Tabled 1Quality of evidence
      The quality of evidence for each article was evaluated according to the method outlined by the US Preventative Services Task Force:
      IProperly powered and conducted randomized controlled trial (RCT); well-conducted systematic review or metaanalysis of homogeneous RCTs.
      II-1Well-designed controlled trial without randomization.
      II-2Well-designed cohort or case-control analytic study.
      II-3Multiple time series with or without the intervention; dramatic results from uncontrolled experiment.
      IIIOpinions of respected authorities, based on clinical experience; descriptive studies or case reports; reports of expert committees.
      Recommendations were graded in the following categories:
      Level A
      The recommendation is based on good and consistent scientific evidence.
      Level B
      The recommendation is based on limited or inconsistent scientific evidence.
      Level C
      The recommendation is based on expert opinion or consensus.
      Table 5Society for Maternal-Fetal Medicine recommendations for fetal blood sampling
      RecommendationsGrade of recommendations (Table 6)
      1When invasive testing is planned for suspected severe fetal anemia or thrombocytopenia, we recommend FBS as procedure of choice, with availability of immediate transfusion if confirmed1 C

      Strong recommendation, low-quality evidence
      2We recommend against use of FBS for indications in which other less invasive, and therefore lower risk, alternatives are available1 C

      Strong recommendation, low-quality evidence
      3We recommend counseling patients about potential risk of FBS that may include, but may not be limited to: bleeding from puncture site; fetal bradycardia; pregnancy loss; and potential vertical transmission of hepatitis or HIVBest practice
      4We recommend that FBS be performed by experienced operators at centers with expertise in invasive fetal procedures when feasibleBest practice
      FBS, fetal blood sampling; HIV, human immunodeficiency virus.
      SMFM. Fetal blood sampling. Am J Obstet Gynecol 2013.
      Table 6Grading of Recommendations Assessment, Development, and Evaluation (GRADE) recommendations
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.
      • et al.
      for the GRADE Working Group
      Rating quality of evidence and strength of recommendations GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.

      UpToDate, grading guide. Available at: http://www.uptodate.com/home/grading-guide#GradingRecommendations. Accessed March 10, 2013. Level III.

      Grade of recommendationClarity of risk/benefitQuality of supporting evidenceImplications
      1A

      Strong recommendation, high-quality evidence
      Benefits clearly outweigh risks and burdens, or vice versaConsistent evidence from well-performed randomized, controlled trials or overwhelming evidence of some other form; further research is unlikely to change our confidence in estimate of benefit and risksStrong recommendations, can apply to most patients in most circumstances without reservation; clinicians should follow strong recommendation unless clear and compelling rationale for alternative approach is present
      1B

      Strong recommendation, moderate-quality evidence
      Benefits clearly outweigh risks and burdens, or vice versaEvidence from randomized, controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence of some other research design; further research (if performed) is likely to have impact on our confidence in estimate of benefit and risks and may change estimateStrong recommendation and applies to most patients; clinicians should follow strong recommendation unless clear and compelling rationale for alternative approach is present
      1C

      Strong recommendation, low-quality evidence
      Benefits appear to outweigh risks and burdens, or vice versaEvidence from observational studies, unsystematic clinical experience, or randomized, controlled trials with serious flaws; any estimate of effect is uncertainStrong recommendation, and applies to most patients; some of evidence base supporting recommendation is, however, of low quality
      2A

      Weak recommendation, high-quality evidence
      Benefits closely balanced with risks and burdensConsistent evidence from well-performed randomized, controlled trials or overwhelming evidence of some other form; further research is unlikely to change our confidence in estimate of benefit and risksWeak recommendation, best action may differ depending on circumstances or patients or societal values
      2B

      Weak recommendation, moderate-quality evidence
      Benefits closely balanced with risks and burdens; some uncertainly in estimates of benefits, risks, and burdensEvidence from randomized, controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence of some other research design; further research (if performed) is likely to have impact on our confidence in estimate of benefits and risks and may change estimateWeak recommendation, alternative approaches likely to be better for some patients under some circumstances
      2C

      Weak recommendation, low-quality evidence
      Uncertainty in estimates of benefits, risks, and burdens; benefits may be closely balanced with risks and burdensEvidence from observational studies, unsystematic clinical experience, or randomized, controlled trials with serious flaws; any estimate of effect is uncertainVery weak recommendation; other alternatives may be equally reasonable
      Best practiceRecommendation in which either: (i) there is enormous amount of indirect evidence that clearly justifies strong recommendation–direct evidence would be challenging, and inefficient use of time and resources, to bring together and carefully summarize; or (ii) recommendation to contrary would be unethical
      SMFM. Fetal blood sampling. Am J Obstet Gynecol 2013.
      This opinion was developed by the Publications Committee of the Society for Maternal–Fetal Medicine with the assistance of Stanley M. Berry, MD, Joanne Stone, MD, Mary Norton, MD, Donna Johnson, MD, and Vincenzo Berghella, MD, and was approved by the executive committee of the society on March 11, 2012. Dr Berghella and each member of the publications committee (Vincenzo Berghella, MD [chair], Sean Blackwell, MD [vice-chair], Brenna Anderson, MD, Suneet P. Chauhan, MD, Jodi Dashe, MD, Cynthia Gyamfi-Bannerman, MD, Donna Johnson, MD, Sarah Little, MD, Kate Menard, MD, Mary Norton, MD, George Saade, MD, Neil Silverman, MD, Hyagriv Simhan, MD, Joanne Stone, MD, Alan Tita, MD, Michael Varner, MD) have submitted a conflict of interest disclosure delineating personal, professional, and/or business interests that might be perceived as a real or potential conflict of interest in relation to this publication.
      The practice of medicine continues to evolve, and individual circumstances will vary. This opinion reflects information available at the time of its submission for publication and is neither designed nor intended to establish an exclusive standard of perinatal care. This publication is not expected to reflect the opinions of all members of the Society for Maternal–Fetal Medicine.

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      Linked Article

      • Fetal blood sampling or follow up and postnatal treatment: a matter of time
        American Journal of Obstetrics & GynecologyVol. 210Issue 6
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          In recent years, indications for fetal blood sampling (FBS) have been reduced thanks to the introduction of advanced technologies that achieve the same or superior diagnostic results earlier and through less invasive procedures, such as fetal cell free DNA analysis, amniocentesis, or chorionic villi sampling. Indeed, FBS could result in serious complications such as bleeding from the umbilical cord access, fetal bradycardia, fetal loss, and maternal complications such as hemorrhage or maternal alloimmunization.
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