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.
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. In 1963, Liley was the first to treat fetal anemia by intraperitoneal transfusion of blood. In 1979, Rodeck and Campbell described the ability to perform FBS utilizing a fetoscopic approach, while 4 years later, Daffos et al 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 or other substances, such as contrast media, 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, microproteins, blood gas analysis, and thyroid hormone levels. 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. In addition, use of fetal blood can allow rapid karyotyping when indicated for prenatal genetic diagnosis.
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.
| Indications | Comment |
|---|---|
| Current common indications | |
| Diagnose and treat fetal severe anemia | Most common indication for FBS |
| Diagnose and evaluate therapeutic response in NAIT | |
| Evaluate nonimmune fetal hydrops | Only in selected cases a |
| Historical and less common indications | |
| Fetal aneuploidy for karyotyping | Rarely used in current practice; largely replaced by CVS or amniocentesis with FISH, or by NIPT |
| Determine fetal blood type and platelet antigen status | Largely 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 therapy | Reported rarely, most commonly for failed maternal systemic treatment of fetal supraventricular tachycardia |
| Others |
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. 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. 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. 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%).
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. 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, 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%).
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.
Fetal hydrops can also be evaluated by FBS. The differential diagnosis of fetal hydrops is extensive, 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.
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. PCR analysis of amniocytes can also determine platelet antigen type, 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. 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.
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. 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. 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.
Other past indications for FBS include measurement of biochemical or other serum markers for fetal infections and diseases (eg, thyroid, renal). 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.
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. 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. 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, 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. 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 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.
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. PCR analysis of amniocytes can also determine platelet antigen type, 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. 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.
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. 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. 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.
Other past indications for FBS include measurement of biochemical or other serum markers for fetal infections and diseases (eg, thyroid, renal). 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.
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. 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. 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, 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. 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 ( Table 2 ). 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.
| Study | No. of procedures | Maternal sedation | Local anesthesia | Ultrasound technique | Puncture site | Confirmation of fetal blood |
|---|---|---|---|---|---|---|
| Tangshewinsirikul et al, 2011 | 2214 | No | Yes | Freehand | PCI or free loop | n/a |
| Tongsong et al, 2000 | 1320 | No | Yes | Freehand | PCI or free loop | Yes |
| Aina-Mumuney et al, 2008 | 210 | Yes | Yes | n/a | IHV, PCI, or both | MCV |
| Nicolini et al, 1990 | 214 | Only 1 y, not last 2 y | n/a | Freehand | IHV | n/a |
| Somerset et al, 2006 | 221 | n/a | n/a | n/a | IHV, PCI, or intracardiac | n/a |
| Sikovanyecz et al, 2001 | 268 | n/a | No | Freehand | PCI or free loop | n/a |
| Liao et al, 2006 | 2010 | n/a | No | Fixed needle guide | 97% free loop, 3% PCI | KHB |
| Boulot et al, 1990 | 322 | No | Yes | n/a | PCI (majority) or free loop | KHB or MCV |
| Johnstone-Ayliffe et al, 2012 | 114 | n/a | n/a | Freehand | PCI, IHV, or free loop | n/a |
| Technical aspect | Comments |
|---|---|
| Prophylactic antibiotics | Insufficient evidence to recommend |
| Maternal sedation | Used infrequently |
| Local anesthesia | Used by some centers |
| Skin preparation | Preprocedural antibacterial skin preparation and aseptic technique are recommended |
| Needle guidance | Both 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 length | 20- 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 |
|
| Paralytic agent for transfusion | Pancuronium, atracurium, or vecuronium |
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