Using ultrasound to guide needle placement into the umbilical cord to withdraw pure fetal blood, Fernand Daffos and his team introduced a new technique that was safer than fetoscopy and allowed for rapid prenatal diagnosis of disease in the fetus.
The team of Fernand Daffos, Martine Capella-Pavlovsky, and François Forestier developed a new and improved technique for collection of fetal blood samples in 1982, which they reported after numerous successes in 1983. Pure samples of fetal blood were obtained from the large vein in the umbilical cord, using a long, twenty-gauge spinal needle that was guided by real-time ultrasound imaging. The transducer of the ultrasound apparatus was held immobile at the point of needle entry on the mother’s abdomen, and it showed the location of the needle with respect to the placenta, fetus, and umbilical cord. Blood was collected from a point on the cord about 2.5 centimeters from its connection to the placenta, into a syringe attached to the needle. Between 1 and 2 milliliters of blood was collected in each case. The new procedure was a dramatic improvement in fetal blood collection compared with other methods in use at the time for prenatal diagnosis of disease in the fetus.
Prenatal diagnosis of numerous genetic defects can be done by various means, including laboratory examination of blood, skin, or amniotic fluid cells from the fetus. For different suspected disorders, different methods and tissues work better. A common diagnostic procedure in use since the 1950’s is amniocentesis, in which a sample of amniotic fluid surrounding the fetus is withdrawn by a needle. Cells from the fluid are grown for several weeks in the laboratory, and then karyotypes are prepared from the cells or other diagnostic tests are performed. There is a specific time span in which collection must occur, with best results at about sixteen to eighteen weeks of gestation. Repeat sampling for karyotyping is not possible later if the first cells fail to grow, and results are not available until weeks after the amniocentesis.
Direct examination of the fetus by a process called fetoscopy
The fetoscopic procedure depends on ultrasound to visualize the location of the fetoscope, the collection device, and various parts of the fetus. Ultrasound, or sonography, uses directed high-frequency sound waves that are bounced off tissues and collected. Reflected sound collected by the transducer device is interpreted as light and dark areas on a computer screen, and moving internal tissues can be visualized. As technology has improved the resolution of these systems, it has become possible to see very small features of fetal tissues within the uterus.
One drawback to fetoscopy for fetal blood collection in the early 1980’s was that the fetoscope was either rigid with a narrow diameter or flexible with a wide diameter. An optimal fetoscope would have both flexibility and a small diameter; this has since been developed. In addition, fetoscopy is an invasive procedure, requiring surgery. A cut must be made in the mother’s abdomen and uterine wall to allow the admission of the fetoscope, and a larger cut will increase the risk of inducing labor.
Another means of obtaining blood from the fetus still in use in the early 1980’s was placentesis, puncture of the placenta to remove fluid. This older procedure generally was being replaced by fetoscopy. Although not requiring use of the fetoscope, placentesis involved ultrasound. Sonography was used to locate the placenta, where maternal and fetal blood accumulate for the exchange processes. This less invasive procedure involved passing a long needle into the placenta to withdraw blood from it. Unfortunately, samples containing from 2 percent fetal blood to 100 percent fetal blood have been reported using this technique, and maternal blood contamination occurred in a reported 76 percent of the samples. Although the maternal blood cells can be removed selectively from the sample, the procedure was considered seriously flawed in this respect. The risk of miscarriage following placentesis was also higher than that for fetoscopy, because tissue was disrupted in the placenta as the blood was withdrawn.
Daffos and his colleagues’ new technique removed many of the problems associated with prenatal diagnosis by amniocentesis, placentesis, and fetoscopy. The narrow 10- or 13-centimeter needle used in this method could be placed into the vein either through the uterine wall or through the placenta, thereby allowing greater adaptability for use with different placenta placements. The procedure was easier to perform than fetoscopy; in sixty-two of the early cases reported, the first blood collection attempt was successful, and another four cases were successful at the second attempt twenty-four hours after the first. Blood could not be obtained in only two pregnancies out of the first sixty-eight sampled, giving an early failure rate of only 3.1 percent.
Dilution of the blood sample occurred in two cases, but maternal blood contamination was not seen. In three cases, the fetus was sampled a second time after an interval of a few days, and the hematocrit and hemoglobin levels showed no significant loss of blood from the first sampling. In all the procedures, only one abdominal wall puncture was needed to enter the amniotic cavity, and in most cases, the procedure was completed within ten minutes with a single puncture of the umbilical cord. In some cases, the cord slipped away from the needle, causing a longer procedure time, and in two cases, it was necessary to penetrate the cord two or three times to obtain a sample.
Because this procedure is less invasive, requiring only entry of the needle instead of a surgical incision, the risks to mother and fetus were reduced drastically compared with fetoscopy, and pregnancy loss was not observed. The gestational age range for the procedure was much greater than that for fetoscopy: between seventeen and thirty-two weeks in reports of the first sixty-six successful cases, as compared to eighteen to twenty-one weeks for fetoscopy. During development of this procedure, blood was drawn from fetuses that were scheduled for elective abortion or for prenatal diagnosis of toxoplasmosis, rubella, or Duehenne muscular dystrophy. Other uses were added later.
This new fetal blood sampling procedure combined the simplicity of placentesis with even better results than fetoscopy. Multiple samples could be taken over a period of several days with no apparent harm to the fetus, which could not be done with fetoscopy. Fetal blood cells were evaluated more easily than cells collected in a similar noninvasive way through amniocentesis. In contrast to the fibroblast cells obtained by amniocentesis, blood cells are grown in culture for only two or three days rather than for several weeks before being karyotyped to show chromosomal structure.
Fetal blood sampling was an accepted procedure for prenatal diagnosis at the time of Daffos’s development of umbilical cord puncture. Clinical use of fetoscopy was replacing placentesis in treatment centers in England, Europe, and the United States. Of particular importance was the detection of hemoglobinopathies by this method, as done by D. V. I. Fairweather’s group in London. Although Daffos’s procedure was clearly superior to fetoscopy, Fairweather’s group continued to use their more familiar method through 1985. A paper published in 1985 stated that “fetoscopy is now regarded as the method of choice for diagnostic fetal blood sampling,” even though fetal loss was relatively high, particularly in cases where a repeat procedure was required. Daffos’s method was not discussed in Fairweather’s paper.
The procedure developed by Daffos, Capella-Pavlovsky, and Forestier was independently developed in Sweden in 1984. P. G. Lindgren and Bo S. Lindberg published a paper in 1985 describing their development of ultrasound-guided puncture of the umbilical cord in rhesus monkeys to collect fetal blood. The Daffos papers again were not referenced. Daffos and his group continued to use the procedure for numerous applications, showing its versatility. Small amounts of fetal blood were used to provide information about infection, genetic diseases caused by abnormal genes or chromosomes, and normal developmental processes of growth and blood production in the fetuses studied.
An interesting use of this fetal blood collection procedure was reported in 1985, in the prenatal diagnosis of genetically produced high cholesterol levels, called familial hypercholesterolemia. The standard means of prenatal diagnosis of this disease is through amniocentesis. A French couple had a previous child homozygous for familial hypercholesterolemia, with cholesterol levels about eight times normal. Prenatal testing by amniocentesis of the mother’s second pregnancy gave ambiguous results. It was not possible to repeat the amniocentesis, so Daffos’s group sampled for fetal blood, and the assay for cholesterol was performed on the blood. Diagnosis of a homozygous fetus enabled the parents to decide on elective abortion, and direct examination of the tissues showed that the fetus was indeed affected. The patient’s third pregnancy was tested in the same way by fetal blood sampling, and again a homozygous fetus was aborted.
Many genetic diseases can be determined from fetal blood sampling, and it may be expected that, as this technique becomes more widespread, the waiting period between fetal sampling and diagnosis will be greatly reduced. One effect of such prenatal diagnosis is that parents who might not want to risk having an affected child will have improved information to use in making the decision of whether or not to abort an affected fetus.
Daffos’s procedure may be used also in pharmacological studies of chemical or drug movement between the mother and fetus. Repeated fetal blood samples or intravenous injections can be obtained using ultrasound to guide the needle to the umbilical vein, as reported by Daffos’s group in 1984.
Daffos’s group conducted studies on fetal growth control processes using blood left over after collection to test for possible fetal infection by maternal transmission of disease. The researchers examined various growth factors through immunoassay, with results leading to the conclusion that fetal growth in midpregnancy does not appear to depend on the same hormonal mechanisms seen in later growth in infants and children. The large number of research and clinical reports from Daffos and his colleagues underscored the usefulness of this means of fetal blood collection. The technique makes it possible to produce diagnostic results more quickly and at less risk to mother and fetus than with previous methods.
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Daffos, Fernand, Martine Capella-Pavlovsky, and François Forestier. “Fetal Blood Sampling via the Umbilical Cord Using a Needle Guided by Ultrasound: Report of Sixty-Six Cases.” Prenatal Diagnosis 3 (1983): 271-277. A longer report that discusses the use of a needle visualized by ultrasound to enter the umbilical cord and collect fetal blood uncontaminated by maternal blood or amniotic fluid. Includes a discussion of the results of the blood evaluations. -
_______. “A New Procedure for Fetal Blood Sampling in Utero: Preliminary Results of Fifty-three Cases.” American Journal of Obstetrics and Gynecology 146 (August 15, 1983): 985-987. A short report that describes the procedure used by Daffos and his group to obtain fetal blood samples from the umbilical cord. A sonogram and drawing illustrate how it was performed. -
Forestier, François, et al. “Hematological Values of 163 Normal Fetuses Between Eighteen and Thirty Weeks of Gestation.” Pediatric Research 20 (1986): 342-346. Gives normal blood values for various cells and chemicals in fetuses of different gestational ages, as determined through the process of umbilical cord blood collection. Interesting as a research use of the method developed by Daffos and his colleagues. -
Harrison, Michael R., ed. The Unborn Patient: Prenatal Diagnosis and Treatment. 3d ed. Philadelphia: W. B. Saunders, 2001. Gives a general overview of the state of fetal diagnosis. Interesting discussions of amniocentesis, genetic counseling, and fetoscopy and fetal sampling. -
Kurjak, Asim, ed. The Fetus as a Patient. Amsterdam: Exerpta Medica, 1985. Contains the papers presented at an international symposium on the fetus as patient in June, 1984. Several topics are of interest in regard to prenatal diagnosis and the moral, ethical, and legal aspects of what can be done for or to the fetus. Covers genetic abnormalities. -
Tortora, Gerard J., and Nicholas P. Anagnostakos. Principles of Anatomy and Physiology. 11th ed. New York: John Wiley & Sons, 2006. College textbook on human anatomy and physiology is useful in helping readers to visualize the fetus and the umbilical connection to the placenta. Shows fetal circulation through the umbilical cord in the chapter on cardiovascular vessels and routes, and gives further information on the fetus in the chapter on development.
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