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Chorionic villus sampling: Quality control - A continuous improvement model
Key words: Chorionic villus sampling, quality control
Although many medical centers in this country perform chorionic villus sampling for early prenatal testing of genetic diseases and although the literature on the subject is expanding rapidly, in many areas of this country chorionic villus sampling is either unavailable or a considerable distance from the patient's home. The Food and Drug Administration has approved a chorionic villus sampling catheter (Trophocan, Concord/Portex, Keene, N.H.) for general use; therefore it is likely that many institutions not currently using this new, informative, safe, and popular procedure will soon be embarking on setting up a process whereby chorionic villus sampling will be offered. This report is offered as a description of our experience establishing a chorionic villus sampling clinic in September 1987, with emphasis on our multidisciplinary team approach and quality assurance process along with the results and outcome of our first 1000 cases. Using a continuous improvement model from the onset of the project allowed for numerous changes, From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center. Presented at the Sixtieth Annual Meeting of The Central Association of Obstetricians and Gynecologists, Chicago, Illinois, October 15-17, 1992. Reprint requests: Frank H. Boehm, MD, Department of Obstetrics and Gynecology, Vanderbilt University, 1211 22nd Ave., S., Nashville, TN 38163. Copyright © 1993 by Mosby-Year Book, Inc. 0002-9378/93 $1.00 + .20 6/6/46193
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which resulted in an improved process and outcome for patients, personnel, and referring health care providers.
Methods History. Sampling offetal tissue in the first trimester was first proposed by Mohr' in 1968. The first chorionic villus sampling of pregnancies that were allowed to go to term were performed in China and reported in 1983. 2 Since that report there have been a large number of reports on the technique's safety and on acceptance of chorionic villus sampling.'·'2 In 1989 the national collaborators' study on chorionic villus sampling was reported. I. That long-awaited randomized study on the safety of chorionic villus sampling compared with amniocentesis concluded that chorionic villus sampling was a safe and effective technique for the early prenatal diagnosis of cytogenetic abnormalities, but that it probably entailed a slightly higher risk of procedure failure and fetal loss than did amniocentesis. In 1991 Young et a1. 14 reported a single center comparison of results of 1000 patients undergoing chorionic villus sampling with 1000 patients undergoing amniocentesis. Analysis of their data also revealed that chorionic villus sampling is a safe and accurate alternative to amniocentesis. Several of the early investigators using this new technique urged that before centers began offering chorionic villus sampling to their patients personnel should become experienced with sampling techniques and culturing villus material in the laboratory and that the
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obstetricians and ultrasonographers should draw samples from at least 50 women who have elected to terminate their pregnancy.3. 15 The Vanderbilt group therefore began its program of offering chorionic villus sampling in September 1987 after having practiced the procedure on 50 patients in a nearby abortion center. The group consisted of obstetricians (2), ultrasonographers (2), and an ultrasonologist (1), a geneticist (1), genetic technologists (2), genetic counselors (3), nurses (2), and secretaries (2). A chorionic villus sampling catheter under investigation by the Food and Drug Administration was used for the first 1000 cases (Angiomed, Los Angeles). Procedure of quality control. Each 3 months the entire team including medical, nursing, technical, and secretarial support reviewed the experience of our chorionic villus sampling clinic in the preceding 3 months. Each aspect of the patient's experience, from the initial phone call for appointment to a follow-up phone call by the research nurse to the patient's home within 1 month of the procedure was reviewed in this continuous process until 1000 patients had been completed. In addition, the patient's physician was asked to fill out a form noting any complications or complaints after the procedure and giving maternal and fetal follow-up after completion of the pregnancy. On the basis of the information reported certain specific and general changes were initiated. Statistical methods. R x C tables were analyzed with Fisher's exact test (StatXact software). Factors influencing the spontaneous abortion rate were analyzed with logistic regression analysis (SAS version 6.01). Continuous improvement: the information period. The first 100 procedures spanned an 8-month period, from September 1987 through April 1988, and the second 100 cases were performed within a 6-month period. Thus it took 14 months to complete the first 200 cases. However, because it became known that this procedure was being offered and performed at our institution, the number of appointments increased. The next 200 cases took 8 months to complete and the last 200 only 4 months. Overall, it took 26 months to complete the first 500 cases and 13 months to perform the next 500. The entire 1000 cases occurred from Sept. 10, 1987, to Jan. 15, 1991. A total of 243 physicians referred the first 1000 patients to the program for chorionic villus sampling. Because of this increasing volume, our group identified the need for a more focused and detailed intake interview by a single secretary dedicated to this process. The appointment was made by a referring physician, and the patient was then notified by mail of the time and place of the procedure and received a brochure explaining chorionic villus sampling testing at our institution. In addition, the patient was encouraged to
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complete and return a family and medical history form before her appointment, to allow the genetic counselors to review literature, obtain additional records when appropriate, and also facilitate making advance preparations for specialized testing such as for cystic fibrosis or hemophilia. Because counseling each patient became time consuming, our group introduced the use of a slide presentation, whcih was viewed by several patients simultaneously before the couple's individual counseling session with the genetic counselor. This insured uniformity in presentation of material and provided information to the patient and spouse. Included in the slide presentation was information on both chorionic villus sampling and amniocentesis, thus informing the patient of all options. Because the slide program was designed after implementation of the chorionic villus sampling program, the presentation addressed the typical questions asked by patients previously, thus reducing the time required during the individual counseling session that followed the slide presentation. Because some patients were noted on the initial ultrasonographic examination to have a fetal death, an additional counseling room needed to be made available, because after the ultrasonographic study a special area was needed to further counsel these often extremely distraught patients, and to allow the patient and her partner time and privacy for initiating grief counseling. By reviewing the chorionic villus sampling experience on a regular basis, the genetic counselors were able to expand their data base on the risks of chorionic villus sampling that were quoted to patients on the basis of actual, continuing experience at our own institution in addition to data reported from other studies in the literature. Because most patients were very interested in the incidence of spontaneous abortions in our chorionic villus sampling population, it was and is paramount to have this information updated on a regular basis. In addition, this continuing evaluation of our patients gave us information on what symptoms may be expected after the procedure. The first 1000 procedures were performed on 910 (91 %) patients for maternal age risk factors and on 90 (9%) patients for carrier or previous pregnancy problems. A computerized data base (DBase III) was used for continuing analysis of complications (i.e., abortion) and for allowing facile access to pertinent information. The procedure. After counseling and signing of a consent form, patients with a full bladder underwent a complete ultrasonic examination including verification of fetal life, biometry measurement, and location of placenta. As a general rule, patients who were 9 weeks to 11 weeks, 6 days gestational age were accepted for the procedure. A support person (usually the husband)
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Table I. Spontaneous abortion rates before and after transabdominal chorionic villus sampling was offered Placental site
Before transabdominal chorionic villus sampling
Anterior Posterior Fundal Other
6/156 5/180 11/63 1/15
6/209 11/278 2/47 0/10
(2.87%) (3.96%) (4.26%) (0.00%)
23/414
19/544
p = 0.0008
NS
TOTAL
Test of significant difference among sites within each time period
(3.85%) (2.78%) (17.5%) (6.7%)
After transabdominal chorionic villus sampling
Test of diffirence within site NS NS P = 0.04 NS
NS, Not significant. Forty-two of 958 are not reported: 28 abnormal, eight no site, and six elective abortion.
Table II. Cytogenetic results Normal 46,XY 46,XX No results Abnormal 47,XXX 47,XXY 48,XXXY 5pTrisomy 21 Trisomy 18 46,XX 10/14 Cystic fibrosis Congenital adrenal hyperplasia ~X
Ornithine transcarbamylase deficiency Gaucher disease Hemophilia TOTAL
945 480 465 27 28 3 1 1 2 9 4 1 1 1
2 1 1 1
1000
was encouraged to be with the patient during the entire procedure. Mter verification of dates and fetal viability, the physician viewed the placental site to determine feasibility of the chorionic villus sampling procedure. This information was discussed with the couple and they were kept informed throughout the procedure. A cytogenetic technologist waited behind a screen in the room where the chorionic villus sampling procedure was performed and took the sample immediately from the operator, viewed the sample under a dissecting microscope to verify adequate sampling, and thereby assured the patient and operator that sufficient material has been removed for diagnosis. Results
Transabdominal chorionic villus sampling was not offered to our first 400 patients and only transcervical procedures were performed during this period. Review of our spontaneous abortion rate in patients undergoing transcervical chorionic villus sampling with a fundal
placenta, however, resulted in our changing our policy and procedure to include the transabdominal route for selected patients. Spontaneous abortions were noted to occur in six of 156 (3.85%) of patients with anterior placentas, in five of 180 (2.78%) of patients with a posterior placenta, and in 11 of 63 (17.5%) of patients with a fundal placenta. Table I lists the spontaneous abortion rates both before and after transabdominal chorionic villus sampling was offered. In the first 400 patients, when only transcervical chorionic villus sampling with a fundal placenta was offered, the spontaneous abortion rates differed significantly by site (p = 0.0008) with spontaneous abortion rates being higher with the fundal placenta site. Mter transabdominal chorionic villus sampling was offered, there was no significant difference in the spontaneous abortion rates among the sites. The rate of unsuccessful sampling was reduced by the addition of transabdominal chorionic villus sampling and by the increased experience of the two (F.H.B., S.J.L.) operators. No villi were obtained for genetic study in 16 (4%) of the first 400 patients, and only three (0.75%) patients of the next 400 underwent the procedure without villi being obtained (p = 0.004). Of the first 1000 procedures 945 were noted to have normal karyotypes, whereas 28 were reported as abnormal (Table II). Although 22 of the 28 patients with abnormal karyotypes underwent an elective abortion, three spontaneously aborted and three chose to continue their pregnancies. Six patients with normal karyotypes chose nonetheless to terminate their pregnancies, therefore leaving 966 patients available to study the effect of chorionic villus sampling on the spontaneous abortion rate. A spontaneous abortion was defined as an abortion occurring in a genetically normal conception after chorionic villus sampling up to 24 weeks' gestation. A total of 42 patients had a spontaneous abortion. A spontaneous abortion rate on the total 966 patients,
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Table III. Spontaneous abortion rate 42 Total First 300 Last 700
4.3% 7.0% 3.0%
Table V. No. of days after procedure until spontaneous abortion, range 2 to 96 days No. of days
No. of cases
2-14 15-28 29-42 42-96
6 13 10 13
TOTAL
42
Table IV. Spontaneous abortion rate by gestational age at time of test Gestational age (wk)
Spontaneous abortion
No spontaneous abortions (%)
<9 9-9.9 10-10.9 11-11.9 12-12.9
3(14 14/264 7/387 15/257 3/37
21.4 5.3 1.8 5.8 8.1
For seven patients no gestational age was listed, 28 underwent elective abortion (abnonnal), and six undeIWent elective abortion (normal).
therefore, was 4.3%. When spontaneous abortion rates by number of procedures performed by our team were compared, it was noted that although 21 patients spontaneously aborted in the first 300 procedures, only 21 did so in the next 700 patients (Table III). Spontaneous abortion rates were also influenced by the gestational age at the time of the procedure (Table IV). The lowest abortion rate occurred at 10 weeks. In spite of a small sample size, an abortion rate of 21 % before 9 weeks resulted in an abandonment of chorionic villus sampling before this gestational age. Of the 42 patients spontaneously aborting, six aborted within 14 days, 13 aborted between 15 and 28 days, 10 between 29 and 42 days, and 13 beyond 42 days, with a range of 2 to 96 days (Table V). The number of passes per procedure was reviewed to assess learning curves of the operators. During the first 100 procedures, 67 samples were obtained with a single pass, whereas two passes were required in 31 patients and three passes in two patients. The reduction in the number of times two passes were needed to obtain an adequate sample was noted in the second 100 patients, in that a second attempt was required only 16 times (Table VI). The number of catheter passes was reviewed to ascertain any relationship to spontaneous abortion (Table VII). As can be noted, there was no significant difference between one and two passes. Follow-up on patients undergoing chorionic villus sampling for initial symptoms after sampling was obtained on 98.5% of our patients. Patients were subjectively questioned for presence and level of pain, cramps, and bleeding. Patients were also questioned about temperature elevations of 100° F or higher (Fig.
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Table VI. No. of chorionic villus sampling catheter passes to obtain adequate sample No. of passes
First 100 Second 100
1
2
3
67 83
31 (31.6%) 16 (16.2%)
2 1
p = 0.012. Table VII. Spontaneous abortion rate and number of catheter passes Spontaneous abortions per No. of chorionic villus samplings
%
2
3
33/811 8(150 1/5
4.0 5.3 20.0
TOTAL
42/966
No. of catheter passes
1
1). Most patients experienced few of these symptoms; however, as can be noted 150 (15.2%) did complain of moderate vaginal bleeding. Pregnancy follow-up including birthing data on 899 patients (93%) was obtained from referring physician questionnaires returned after birth or spontaneous abortion. Fifteen clinical markers were considered to be possibly influenced by a first-trimester chorionic villus sampling procedure (Table VIII). As can be noted, preterm labor, premature rupture of the membranes, subchorionic hemorrhage, and amnionitis occurred more frequently than other complications, although the incidence was not significantly higher than the expected rates. Because of reports of a possible causal relationship between chorionic villus sampling and fetal limb deformities,16, 17 all referring physicians were contacted by a second questionnaire or personal telephone call to ascertain if any had delivered a child with such limb deformities after a chorionic villus sampling procedure performed at our institution. Of the 243 referring physicians, 241 were contacted. The remaining two patient outcomes not obtained by the referring physi-
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1000 800 600 400 200
o
Pain
Cramping
rn None
•
Bleeding
Mild
•
Fever Moderate
15 patients: No information Fig. 1. Immediate responses.
Table VIII. Pregnancy outcome complications, 899 patients No. Subchorionic hematoma Elevated maternal serum a-fetoprotein Incompetent cervix Oligohydramnios Premature rupture of membranes Preterm labor Abruptio placentae Third-trimester bleeding Placenta previa Placenta accreta Intrauterine growth retardation Amnionitis Infection or sepsis Endometritis Uterine atony or hysterectomy
19 3 5 5 30 59
8 7
6
2
6 13 3 4 3
%
Table IX. Spontaneous abortion rate and transcervical chorionic villus sampling with fundal placenta
Transcervical I I.foruln,l placenta. All other
2.3
0.4 0.6 0.6 3.6 7.1 1.0 0.8 0.7
Spontaneous abortion No spontaneous abortion
11 (17.4%) 52
31 (3.5%) 864
p < 0.0001. No sites were noted for eight patients.
0.2
0.7 1.6 0.4 0.5 0.4
cians were determined by personal contacted by telephone to obtain 100% follow-up on pregnancy outcomes relating to fetal limb abnormalities after chorionic villus sampling. No patient in the first 1000 procedures was noted to have a child with limb deformities. None of our referring physicians had noted any such deformities even beyond the first 1000 cases. To consider the factors influencing the rate of spontaneous abortions a logistic regression model was used. With this method we are able to look at the significance of one factor once the spontaneous abortion rate has been adjusted for other significant factors. The four main factors that are significantly related to an increase in the rate of spontaneous abortions are transcervical chorionic villus sampling with a fundal placenta
the immediate follow-up period
0.1) were number of passes (one or more than one), maternal age at time of chorionic villus sampling, indication of pain during immediate followup period, and indication of cramps during immediate follow-up period. Cytogenetic information. The genetic learning curve began with a series of 50 samples obtained before a first-trimester elective abortion. Diagnostic samples were first received in September 1987, and of the first 35 samples processed in 1987 three failed to yield a direct harvest and eight did not yield a long-term culture result. Of the 27 long-term cultures obtained, four had maternal cell contamination with one specimen yielding only maternal cells. During 1988 only four of 191 samples failed to yield a direct harvest. Improvement in the direct harvest was obtained through modification of mitotic arresting time, hypotonic solution, and chromosome spreading technique. Exposure of villi to colchicine (Colcemid) (10 mg/ml) overnight has increased the mitotic index in the direct harvest. AI: 1 mixture of 0.5% potassium chloride and 1% sodium citrate solution has been found to be the optimal
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PERCENTAGE BY GROUP
80 60 40 20
o
o
100 200 300 400 500 600 700 800 900 1000 PATIENT COMMENTS BY GROUPS OF 100
+
Positive
• Negative
Fig. 2. Immediate patient comment, positive and negative responses.
Table XI. Spontaneous abortion rates for indication of fever in follow-up
Table X. Spontaneous abortion rates for gestational age < 9 weeks Gestational age 2!9 wk
Spontaneous abortion No spontaneous abortion
p
3 (2l.4%) 11
39 (4.1%) 906
Spontaneous abortion No spontaneous abortion
p
Fever
No fever
5 (22.7%) 17
37 (4.0%) 895
= 0.002. No information was available on 12 patients.
= 0.02. Of the 959 total procedures 28 were abnormal,
seven had no gestational age and six patients underwent elective abortions.
hypotonic solution. From July 1990 to the present a success rate of 99.8% has been achieved. The success rate of culture significantly improved by experimenting with different tissue dissociation enzymes and by physical dispersion. IS Recognition and isolation of villi from maternal decidua has improved with experience, thus reducing maternal cell contamination. Addition of growth factors to the medium and a reduction of the oxygen tension of the growth chamber have augmented cell growth. 19 A turnaround time of 18 to 21 days until the final report during 1989 and 1990 has been reduced to lO to 12 days. An accuracy of 100% has been reached through chromosomal analysis from direct harvest, from long-term culture, and by appropriate amniocentesis follow-up in cases of mosaicism. By the seven-hundredth procedure our chorionic villus sampling team noted incorrect sex reporting. In-depth analysis noted these cases to be associated with instances in which, because of small sample size, a direct harvest was not performed and only a long-term culture was performed and reported. Forty-four of these small-sized, long-term, culture-only specimens were noted by the research nurse to be associated with 25 normal female and 19 normal male infants at birth. Of the 25 normal female chorionic villus sampling results, six infants were in fact normal males (24% error rate). Extensive review of the procedure was under-
Table XII. Spontaneous abortion rates for indicatioh of bleeding in follow-up
Spontaneous abortion No spontaneous abortion
p
=
Bleeding
No bleeding
23 (6.3%) 344
19 (3.2%) 568
0.03. No information was available on 12 patients.
taken of this sub population of patients undergoing only long-term culture. Wrong sex reporting was found to be associated 100% of the time with a sample size of < 3 mg, thereby resulting in only long-term culture reporting. Since this discovery the operator makes every attempt to obtain at least 5 mg of villi. If unable to obtain at least 5 mg, the referring physician is notified of a 24% error rate and the need for follow-up amniocentesis if the long-term culture report is normal female. Patient responses. Patient responses were tabulated by the research nurse as either positive, negative, or neutral. As can be seen in Fig. 2, positive and negative comments remained at an equal level until after 200 procedures, when positive comments increased and negative comments decreased. Comment
This report clearly indicates the value of using a continuous improvement model for proper quality con-
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trol with a new procedure. Experience gained was helpful to the team and changes made on a continuing basis improved overall results. With the entire quality control team meeting every 3 months and reviewing the process from patient appointment to follow-up, numerous changes were made to allow for a well organized and informative process for both patient and health care provider. By reviewing patient comments as noted by the research nurse's call to each patient, certain deficiencies and negative aspects were corrected in a timely fashion. Mter reviewing only 100 patient comments, the team quickly realized that one of the most uncomfortable aspects of the test was the full bladder required for the procedure. Coordinating appointment times and performing the procedure in a timely fashion with attention to patients' bladder content became a major focus. In addition, the team also learned that this procedure was an extremely emotional one for patients and their significant others and that many were very apprehensive. Because of this, the health care providers who had contact with the patient needed to have heightened awareness to these patient concerns. The quality control process initiated by the Vanderbilt team allowed for the early discovery that transabdominal chorionic villus sampling needed to be offered to certain patients, in particular those with fundal placentas. By offering and performing the transabdominal procedure for these patients, the spontaneous abortion rate in those patients subsequent to offering transabdominal chorionic villus sampling was significantly reduced. It is not completely clear why transcervical chorionic villus sampling with a fundal placenta carries an increased risk of a spontaneous abortion. In addition, by offering and performing the transabdominal procedure in selected patients with fundal placentas, the number of patients who were unsuccessfully sampled was also reduced. Transabdominal chorionic villus sampling has been reported in the literature as an acceptable alternative to the transcervical route!O.23 Copeland et aJ.2 4 reported on the integration of the transabdominal technique into a continuing chorionic villus sampling program and noted that the transabdominal procedure could be rapidly and effectively incorporated by an operator already experienced with the transcervical procedure. Because conditions such as herpes genitalia, inaccessible cervical canal or placenta, and pronounced angle of uterine corpus on the cervix are contraindications to transcervical chorionic villus sampling,25 it becomes mandatory for those embarking on this procedure to become experienced with transcervical and transabdominal chorionic villus sampling. Brambati et al.!6 reporting on a comparison of 1501 procedures by the transcervical route and 910 by the transabdominal route, noted that there was a > 99% success rate for
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both sampling procedures. They noted that the transcervical method was more difficult to learn. This has been our experience as well. Silver et al. 27 used placental localization to determine the choice of the transcervical or transabdominal approach when initiating their program and found that this approach was feasible and associated with a lower failure rate when compared with reliance on only one technique. The authors preferred the transcervical approach on only posterior placentas and the transabdominal when the placenta was anterior or fundal. Review of our spontaneous abortion rate also convinced our team that the learning curve of the operators exceeded what had been published in the literature. Review of our data indicates that not until each operator had performed at least 150 sampling procedures did spontaneous abortion rates drop from 7% to 3%. The spontaneous abortion rate since the first 300 procedures has been approximately 3% on a continuing basis. In addition, the team noted that those few patients who had chorionic villus sampling performed before 9 weeks had a higher spontaneous abortion rate, and therefore no patient was subsequently sampled who was not demonstrated by dates and ultrasonography to be 2: 9 weeks. Hogge et al. 5 also noted this important fact, reporting a 12.9% spontaneous abortion rate at < 9 weeks and 17.1 % at 2: 12 weeks compared with 3.8% in those pregnancies at 9 weeks to 11 weeks, 6 days. Many of our patients were concerned about spontaneously aborting and wanted to know when they would reach a point in gestation at which they could consider themselves safe. Our data enabled us to inform our patients that as many as 12 patients aborted beyond 42 days and that the range of abortion was between 2 and 96 days. Our data convinced the operators that no more than two passes should generally be performed. There was no significant difference between the first and second pass; however, in spite of small numbers when a third pass was performed one of five spontaneously aborted. Young et al. 14 also noted that the number of catheter passes was related to spontaneous abortion rates, with 12.8% aborting with three passes and only 3.1% and 5.7% with one and two passes, respectively. As has been noted by others,' the geneticists and genetic technologists clearly increased their success rate of culture and decreased the time for completion of the long-term culture reporting with increasing experience. The turnaround time of 18 to 21 days until the final report during 1989 and 1990 has been reduced to a current 10 to 12 days, with an accuracy of 100% having been reached by chromosomal analysis through direct and long-term culture techniques and by appropriate amniocentesis follow-up in cases of mosaicism. 28 • 29
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One important change noted by the quality control team was that incorrect sex reporting was noted to be associated with those patients in whom a small sample was obtained « 3 mg) and long-term culture only being reported from this small specimen. In doing so, a 24% error rate was noted. This fact made the operators go back for a second pass if a small sample was obtained with the initial catheter placement, and if unsuccessful with a second pass to inform patients that if the small sample long-term culture resulted in a normal female an amniocentesis would be required for verification. Since that correction no wrong sex reporting has been noted by the quality control team. Maternal cell contamination and incorrect identification of villi are considered responsible for this observation. 30 Importantly, in view of patient responses that were tabulated by our research nurse, it is clear that as the team performed more procedures, more positive and fewer negative comments were made by our patients (Fig. 1). The break seemed to occur after 200 patients had undergone chorionic villus sampling. It is concluded therefore that it takes up to 200 procedures performed by an entire team before many of the negative aspects of the testing process can be eliminated. Several reports on patient attitudes toward chorionic villus sampling compared with amniocentesis revealed that prenatal testing by means of chorionic villus sampling results in earlier and sustained anxiety reduction. 31 -33 Other studies have noted significantly greater attachment to the pregnancy during the second trimester than in women undergoing amniocentesis, giving evidence to the premise that attachment suppression exists among women receiving amniocentesis for prenatal testing." In a study on the acceptability of chorionic villus sampling for prenatal diagnosis, McGovern et al. 35 studied 520 women of advanced maternal age concerning their attitudes toward the two procedures after undergoing a sampling procedure during that pregnancy and amniocentesis in another gestation. The m£tiority of responding individuals indicated that the time at which chorionic villus sampling was performed (76%), the rapid availability of diagnostic results (72%) and the type of abortion procedure available (68%) would make them choose this method over amniocentesis. In contrast, the factors that influenced women to choose amniocentesis included a lower risk of spontaneous abortion (76%) and the confidence of the skill of the obstetrician who would perform the chorionic villus sampling procedure (56%). When all the factors were considered, 68% of those responding chose amniocentesis on the basis of the known low risk of spontaneous abortion. Therefore this study indicated that if the fetal loss rate was demonstrably low and approaching that of amniocentesis most women of advanced maternal age would prefer chorionic villus sampling.
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It is imperative therefore to be able to discuss abortion risks with couples contemplating chorionic villus sampling, because in most instances this is the couple's m£tior concern. Because it is difficult to compare abortion rates between chorionic villus sampling and amniocentesis, there is some debate as to the actual risk difference between these two prenatal testing modalities. The 1989 Collaborative Study noted that after adjustments for slight differences in gestation and maternal age, the total loss rate for women in the chorionic villus sampling group exceeded that of the amniocentesis group by only 0.8%.'3 Young et al.,14 reporting on 1000 chorionic villus sampling procedures, noted a 3.9% spontaneous abortion rate up to 26 weeks' gestation, whereas Hogge et al:' reported a 3.8% total spontaneous abortion rate on their 1000 cases and Green et al.,7 reporting on 940 procedures, noted a total fetal loss rate of 2.4%. Wade and Young'O reported an unintended abortion rate of 4.1 % by 20 weeks' gestation. These figures are in line with our 3% spontaneous abortion rate on the last 700 patients of the first 1000 chorionic villus sampling procedures. Because patients at this gestational age have an inherent spontaneous abortion rate without undergoing a procedure, it is obvious therefore that this 3% is not totally procedure related. Simpson et al. 36 noted that when ultrasonographic confirmation of fetal viability at 8 weeks was noted seven (3.2%) of 220 women with a mean age of 30.09 years aborted, and Christiaens and Stoutenbeck" noted a 3.3% fetal loss rate in 274 women with proved fetal viability at 10 weeks. In addition, there is evidence that older women not undergoing prenatal testing have even higher spontaneous abortion rates. Wilson et al. 38 found a total fetal loss rate, after proving fetal viability by first-trimester ultrasonography, of 1.4% in women < 30 years old, 2.6% between 30 and 34 years old, and 4.3% in women ~ 35 years old. A chorionic villus sampling loss rate of 3% therefore is balanced by a spontaneous loss rate of approximately 3%. In spite of this, however, we are counseling our patients that a ~ 1% abortion rate secondary to the procedure should be considered in making a decision of whether to undergo chorionic villus sampling. Pregnancy loss related to amniocentesis in experienced hands is 0.2% to 0.5% over and above the spontaneous pregnancy loss rate at 16 weeks' gestation. 39 Concern for a possible relationship between chorionic villus sampling and fetal limb deformities '6. '7 resulted in our quality control process initiating a second questionnaire to establish if any patient undergoing the procedure in our institution had delivered a child with a limb deformity. None were reported. When comparing the limb deformity incidence of over 80,000 patients listed in the CVS Registry to the incidence of spontaneous limb deformities noted in the
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1,213,913 live births followed in the British Columbia Registry (1952 through 1984):° there was no statistically significant difference (6.00/10,000 vs 5.42110,000).41 In addition, one of the reports implicating chorionic villus sampling as a possible cause of limb deformities reported on a cluster of four cases of fetal limb deformities out of 260 chorionic villus sampling procedures. 16 Three limb deformity cases followed transcervical chorionic villus sampling with a catheter (Cook OB/GYN catheter) 25% larger than the Food and Drug Administration-approved Trophocan catheter (1.9 mm vs 1.45 mm). The fourth case occurred after transabdominal chorionic villus sampling. In addition, the spontaneous abortion rate with the Cook OB/GYN catheter was 10.9% (20/183), a rate considered far higher than reported from other centers. The conclusion made by the participants in the May 1992 World Health Organization European Regional Office Meeting on Early Prenatal Diagnosis of Genetic Diseases was that, "There is no evidence to suggest any increased risk of congenital malformation when CVS is performed after the eighth completed week."'1 Although our series is relatively small, in the absence of finding any fetal limb deformities in patients undergoing chorionic villus sampling at our institution delivered of liveborn infants, we agree with that conclusion. It is hoped that this quality control initiated by the Vanderbilt team to continuously improve the chorionic villus sampling procedure will be helpful to other institutions beginning the process of setting up a chorionic villus sampling program. It is imperative that the operators performing the procedure have considerable experience in placement of the catheter; this can best be done in a formal training program with observation of 50 procedures followed by close hands-on supervision of another 100 cases. Our initial team has now successfully trained four maternal-fetal medicine fellows with this approach. In addition, it is advisable for other members of the team, such as ultrasonographers, nurses, and counselors, to visit centers performing this procedure to obtain as much information as possible on the various aspects of the entire process. Setting up a genetic laboratory for this process is highly technical and the reader is referred to other articles in the genetic literature that will be useful"; however, genetic technologists will need to have additional training on the process of handling of the chorionic villus sampling material. At least two technologists should be dedicated to the program. Each one should have practiced on 100 samples to become independent. The training should include evaluation of the sample at the site of operation, separation of villi from decidua at the laboratory, direct harvesting, culturing and harvesting, chromosome analysis, and karyotyping. Technologists should also be
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knowledgable III placental mosaICism, pseudomosaicism, and procedures required to follow up cases with abnormal results. Health care providers interested in setting up a chorionic villus sampling program should (1) set up a multidisciplinary core group of individuals participating in the various aspects of the procedure and plan periodic scheduled meetings to impart information on follow-up data and to implement changes as needs are identified; (2) establish a computerized data base for following outcome and complications, thus allowing for rapid and continuous access to patient information; (3) include both transcervical and transabdominal routes to obtain sample material; and (4) only individuals who have had extensive education, observation of 50 cases, and supervised hands-on experience of 100 patients should perform chorionic villus sampling. We thank Salvatore J. Lombardi, MD, Arthur C. Fleischer, MD, Robin Johns, RDMS, Melinda Cohen, Janet Ulm, Vicki Hannig, Jean Pfotenhauer, Laura Hobbs, Jessie Gore, Periclis Roussis, MD, Richard Rosemond, MD, Donna Kepple, John Phillips, MD, and Stephen Entman, MD. REFERENCES 1. Mohr J. Foetal genetic diagnosis: development of techniques for early sampling of foetal cells. Acta Pathol Microbiol Scandinav 1968;73:73-7. 2. Rodeck CH, Morsman ]M. Indications of chorionic villus sampling according to the technology used. Br Med Bull 1983;39:338. 3. Elias S, Simpson ]L, Martin AO, Sabbagha RE, Gerbie AB, Keith LG. Chorionic villus sampling for first-trimester prenatal diagnosis: Northwestern University program. AM ] OBSTET GYNECOL 1985;152:204-13. 4. Elias S, Simpson JL, Martin AO, Sabbagh a RE, et al. Chorionic villus sampling in continuing pregnancies. AM] OBSTET GYNECOL 1986;154:1349-52. 5. Hogge WA, Schonberg SA, Golbus MS. Chorionic villus sampling: experience of the first 1000 cases. AM ] OSSTET GYNECOL 1986; 154: 1249-52. 6. Leschot N], Wolf H, Verjaal M, et al. Chorionic villus sampling: cytogenetic and clinical findings in 500 pregnancies. BM] 1987;295:407-10. 7. Green ]E, Dorfmann A, Jones SL, Bender S, Patton L, Schulman ]D. Chorionic villus sampling: experience with an initial 940 cases. Obstet Gynecol 1988; 71 :208. 8. Wilson D, McGillivray B, Kalousek D, et al. Multicentre randomised clinical trial of chorionic villus sampling and amniocentesis. Lancet 1989; 1: 1-6. 9. ]ahoda MG], Pupers L, Reuss A, Los F], Wladimiroff ]W, Sachs ES. Evaluation of transcervical chorionic villus sampling with a completed follow-up of 1550 consecutive pregnancies. Prenat Diagn 1989;9:621-8. 10. Wade RV, Young SR. Analysis of fetal loss after transcervical chorionic villus sampling - a review of 719 patients. AM] OBSTET GYNECOL 1989;161:513-9. 11. Clark BA, Bissonnette ]M, Olson SB, Magenis RE. Pregnancy loss in a small chorionic villus sampling series. AM] OSSTET GYNECOL 1989;161:301-2. 12. Doran TA. Chorionic villus sampling as the primary diagnostic tool in prenatal diagnosis. J Reprod Med 1990;35: 935-40. 13. Rhoads GG, Jackson LG, Schlesselman SE, et al. The safety and efficacy of chorionic villus sampling for early
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15. 16. 17. 18.
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20. 21. 22. 23.
24.
25. 26. 27.
28. 29. 30.
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32. 33. 34.
prenatal diagnosis of cytogenetic abnormalities. N Engl J Med 1989;320:609-17. Young SR, Shipley CF, Wade RV, et al. Single-center comparison of results of 1000 prenatal diagnoses with chorionic villus sampling of 1000 diagnoses with amniocentesis. AM J OBSTET GVNECOL 1991;165:255-63. Hogge WA. Chorionic villus sampling: a new direction in prenatal diagnosis. Female Patient 1986;11:85-99. Firth HV, Chamberlain P, MacKenzie IZ, Lindenbaum RH, Huson SM. Severe limb abnormalities after chorionic villus sampling at 56-66 days' gestation. Lancet 1991 ;337 :762-3. Burton BK, Schulz CJ, Burd LI. Limb anomalies associated with chorionic villus sampling. Obstet Gynecol 1992; 79:726-30. Yu M, Yu C, Yu M, Maidman J, Warburton D. Improved methods of direct and cultured chromosome preparations from chorionic villus sampling. Am J Hum Genet 1986; 38:576-81. Brakertz M, Kubbies M, Feige A, Salk D. Decreased oxygen supply enhances growth in culture of human mid-trimester amniotic fluid cells. Hum Genet 1983;64: 334-8. Lilford RJ, Irving He, Linton G, Mason MK. Transabdominal chorion villus biopsy: 100 consecutive cases. Lancet 1987;1:1415-6. Bovicelli L, Rizzo N, Montacuti V, et al. Transabdominal chorionic villus sampling: analysis of 350 consecutive cases. Prenat Diagn 1988;8:495-500. Brambati B, Oldrini A, Lanzani A, Terzian E, Tognoni G. Transabdominal versus transcervical chorionic villus sampling: a randomized trial. Hum Reprod 1988;3:811-3. Elias S, Simpson JL, Shulman LP, Emerson D, Tharapel A, Seely L. Transabdominal chorionic villus sampling for first-trimester prenatal diagnosis. AM J OBSTET GVNECOL 1989;160:879-86. Copeland KL, Carpenter Rj, Fernolio KR, Ledbetter DH. Integration of the transabdominal technique into an ongoing chorionic villus sampling program. AM J OBSTET GVNECOL 1989;161:1289-94. Brambati B, 01drini A, Lanzani A. Transabdominal chorionic villus sampling: a freehand ultrasound-guided technique. AM J OBSTET GVNECOL 1987;157:134-7. Brambati B, Lanzani A, Tului L. Transabdominal and transcervical chorionic villus sampling: efficiency and risk evaluation of2,411 cases. AmJ Med Genet 1990;35: 160-4. Silver RK, MacGregor SN, Sholl JS, Elesh RH, Beaird JA, Waldee JK. Initiating a chorionic villus sampling program. Relying on placental location as the primary determinant of the sampling route. J Reprod Med 1990;35 :964-8. Kalousek DK, Dill FJ. Chromosomal mosaicism confined to the placenta in human conceptions. Science 1983;221: 665-7. Schwinger E, Seidl E, Klink F, Rehder H. Chromosome mosaicism of the placenta-a cause of developmental failure of the fetus? Prenat Diagn 1989;9:639-47. Roberts E, Duckett DP, Lang GD. Maternal cell contamination in chorionic villus samples assessed by direct preparations and three different culture methods. Prenat Diagn 1988;8:635-40. Robinson GE, Garner DM, Olmstead MP, ShimeJ, Hutton EM, Crawford BM. Anxiety reduction after chorionic villus sampling and genetic amniocentesis. AM J OBSTET GVNECOL 1988; 159:953-6. Sjogren B, Uddenberg N. Prenatal diagnosis and psychological distress: amniocentesis or chorionic villus biopsy? Prenat Diagn 1989;9:477-87. Spencer JW, Cox DN. Emotional responses of pregnant women to chorionic villus sampling or amniocentesis. AM J OBSTET GVNECOL 1987; 157: 1155-60. Spencer JW, Cox DN. A comparison of chorionic villus sampling and amniocentesis: acceptability of procedure and maternal attachment to pregnancy. Obstet Gynecol 1988;72:714-8.
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35. McGovern MM, GoldbergJD, Desnick RJ. Acceptability of chorionic villus sampling for prenatal diagnosis. AM J OBSTET GVNECOL 1986;155:25-9. 36. Simpson JL, Mills ML, Holmes LB, et al. Low fetal loss rates after ultrasound-proved viability in early pregnancy. JAMA 1987;258:2555-7. 37. Christiaens GC, Stoutenbeck MC. Spontaneous abortion in proven intact pregnancies. Lancet 1984;2:571-2. 38. Wilson RD, Kendrick V, Wittman BP, et al. Spontaneous abortion and pregnancy outcome after normal first-trimester ultrasound examination. Obstet Gynecol 1986;67: 352-5. 39. Eden R, Boehm FH, eds. Fetal assessment: physiologic, clinical, and medicolegal principles. Norwalk, Connecticut: Appleton & Lange, 1989:285. 40. Froster-Iskenius UG, Baird PA. Limb reduction defects in over one million consecutive livebirths. Teratology 1989; 39: 127-35. 41. Chorionic villus sampling (CVS): World Health Organization European Regional Office (WHO/EURO) meeting statement on the use of CVS in prenatal diagnosis. J Assist Reprod Gen 1992;9:299-303. 42. Priest JH. Prenatal chromosome diagnosis and cell culture. In: Barch M, ed. The ACT cytogenetics laboratory manual. New York: Raven Press, 1991:149-165.
Discussion DR. NORMAN A. GINSBERG, Chicago, Illinois. This multidisciplinary team approach and a quality assurance process was clearly beneficial for chorionic villus sampling and would most likely be of benefit with other new procedures in the future. Emphasis was and should clearly be placed on the multidisciplinary nature of this procedure. The safety of this technique unquestionably rests on the ease of sampling and the infrequent need for an additional specimen. The first United States national collaborative study pointed out that the risk of loss increased with more than one attempt. I The second United States national collaborative study demonstrated that with additional experience and the application of transabdominal chorionic villus sampling (another way to make a difficult sampling easy) reduced the increased risk of chorionic villus sampling to that of amniocentesis. 2 Having dedicated ultrasonographers, in our experience, improves the easy flow of sampling and lessens the need for additional sampling attempts. Knowing the laboratory's limits in reliably processing small samples serves to control the number of sampling attempts. We believe that the use of a slide presentation is valuable for several reasons. This guarantees uniformity of information and relieves the genetic counselors from a tedious and monotonous task. With the slide presentation in place the genetic counselors can better direct their energies toward the patients' risk factors. From 9 to 12 completed weeks of gestation it appears that the tenth week is statistically the safest time to avoid a later spontaneous abortion. This is surprising, because one would expect the abortion rate to decrease as gestation advances. Less than 9 weeks is still a time of increased spontaneous abortion. One cannot make a linear regression below 9 weeks and necessarily state that there is an increased procedure-related loss at this time.
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The use of one's own experience in counseling on the risk of the procedure has both positive and negative aspects. On the one hand, providing patients with information that you are equal to or worse than the expected standard is important. However, it should be emphasized that with a small sample size it is impossible to scientifically state that one is truly doing better than expected. Standard literature-determined risk numbers should be used so as not to mislead patients about the risks. It needs to be pointed out that the 24% inaccuracy figure for samples < 3 mg needs to be doubled, because there would be an equal probability that maternal cells were analyzed in the presence of a female fetus. It would seem likely that these limits could easily be determine during the practice phase before continuing cases were started. It would be interesting to know if you found that you were less successful in getting an adequate sample with one attempt in your first 100 cases compared with the practice group. Certainly, when one goes from the laboratory examining cases in continuing pregnancies, circumstances are different. This kind of information might be helpful in determining how much additional practice might be required. I believe that today's standard for securing an adequate specimen in only one attempt should be ;::: 90%; this has been proposed by the World Health Organization.' I would agree with you that the learning curve far exceeds 50 cases, and even 150 cases is probably an underestimation. The fact that you had two separate samplers suggests that the individuals really only had experience with 25 cases before starting. You haven't discussed your rate of mosaicism or how these case were and are managed. This is probably one of the more difficult issues especially now that it has been recognized that the reduction to a normal number found at amniocentesis may reflect isodisomy in that chromosome group in rare circumstances. In your discussion about when is a patient out of the woods as far as a loss from the procedure, you found that losses occurred as late as 92 days after the procedure. This trend was also seen in the National Institutes of Health study!; however, a careful look at the data suggests that once 16 weeks was reached that the rate of abortion is similar to that of the background. In your table on complications it might be a little more valuable if some comparison of the results could be made to your own population at Vanderbilt. You should also include a statement about the presence or absence of congenital anomalies. This is particularly important because of the recent controversy on limb reduction abnormalities being associated with the procedure. It should be noted that a recent World Health Organization study that addressed this issue looked at over 80,000 children born after chorionic villus sampling; there was no increase in this abnormality over that of the expected background. 3 REFERENCES 1. Rhoads G, Jackson L, Schlesselman S, et al. The safety and
efficacy of chorionic villi sampling initial findings from the
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U.s. collaborative study. N Engl J Med 1989;320:609-17. 2. Jackson L, Zachary J, Fowler S, et al. National Institute of Child Health and Human Development Chorionic Villus Sampling and Amniocentesis Study Group. A randomized comparison of transcervical and transabdominal chorionicvillus sampling. N Engl J Med 1992;327:594-8. 3. Kuliev A, Modell B, Jackson L, et al. Chorionic villus sampling (CVS): World Health Organization European Regional Office (WHO/EURO) meeting statement on the use of CVS in prenatal diagnosis. J Assist Reprod Genet 1992; 9:299-302. DR. MARK I. EVANS, Detroit, Michigan. The development of new technologies follows a characteristic pattern. A small cadre of primary level investigators begins the formal process of development. Initial reports focus on basic techniques, an understanding of the risk of complications, and a first run at safety and efficacy. Traditionally, dramatically new procedures are reserved for patients considered at highest risk, and often patients must travel long distances to obtain such services. Examples in obstetrics have included amniocentesis, chorionic villus sampling, fetal blood sampling, fetal reduction, and selective termination. With increased awareness of a procedure and increasing technical expertise in a very limited number of centers, new investigators begin to enter the field. In reality, many of the second-generation investigators are responsible, conscientious physicians, who, although not needing to entirely reinvent the wheel, do jump through many of the preparatory hoops required to minimize complications. Sadly, there are sometimes other physicians who jump on the bandwagon at the finish line simply for financial or other professional gain. They often have not done the necessary groundwork to justify their presentation to the community of competence in the new procedure. Boehm et al. have detailed their multidisciplinary approach to the development of their chorionic villus sampling program with the deliberate inclusion of regular evaluation of their progress. They are to be congratulated for, in fact, reinventing the wheel in an area where anything less can be a recipe for disaster. It is also reassuring that these authors found no increase in birth defects. In spite of the hype coming mostly from here in Chicago, there is no increased risk of birth defects for chorionic villus sampling patients. The principle of continuous quality improvement is one that is not often appreciated in clinical medicine, although it is becoming a more cogently developed philosophy in laboratory medicine. Many of the points flow from the original principles of management, as described by Deming, concerning employee errors. (An error is not an employee's fault unless the employee was taught how to do it properly in the first place, there is immediate feedback saying there is an error, and there is opportunity to correct the error. Otherwise, the error is management's fault.) Clinical training is no different. As new physicians learn procedures, there needs to be close supervision, assessment, and modifications. The key elements are measuring both successes and errors and using the information to improve outcomes. Medicine is accustomed to focusing on individual errors
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through morbidity and mortality conferences, Aggregate success and errors are often less formally surveyed, My only serious problem with the authors' presentation is the issue of the so-called 24% wrong sex rate with small samples. Unfortunately, their lab did not get the wrong sex: they were testing the wrong patients. They were very lucky that those six fetuses had normal chromosomes just like their mothers, who were mistakenly karyotyped, because had there been an aneuploid condition, it would not have been recognized until after birth. Even with small samples, their error rate is still too high. Overall, the authors are to be applauded for showing a model for second- and third-generation centers to incorporate tertiary techniques. My questions to the authors therefore are (1) If you had to do it over again, what would you do differently? (2) How would you advise other centers who are about to begin today? and (3) What can you do to insure that serious errors such as karyotyping the mother can be avoided? Technology assessment is a multilevel phenomenon. The individual must assess his or her own success; a program must then inspect itself as a whole. A more global interpretation is only as good as the data that are used to form the impressions. A serious attempt at quality control will not only detect errors such as described above but will help mitigate the potential damage of such occurrences. The model here should be used in clinical medicine more than it has been. DR. BOEHM (Closing). First of all, to Dr. Ginsberg's comment, we agree with your assessment and your concern about the 24% error with our small sample specimens. After we first started, I believe our genetic team began to feel very confident with very small sample sizes, including those with :s; 3 mg. Because of that, we ran into maternal cell contamination. Once we recognized this, we refused to be satisfied with anything but at least a 5-mg sample. Since then the problem has not occurred. We also believe a direct and a long-term study is necessary because each can be associated with error. If only a direct analysis is performed, there may be problems with a normal direct and an abnormal longterm and vice versa. So I believe both are necessary. As far as the concern of Dr. Ginsberg about our first 50 cases and what was our sampling experience, we read in the literature that only 50 cases were needed; so we went to Planned Parenthood to perform our first 50 chorionic villus sampling procedures. Each of the two operators learning this technique were there for each procedure. In retrospect, this clearly is not enough for learning. We did not try to assess how many times it took us to get the sample, but clearly when we started our first series of cases, more experience would have been helpful. However, we were beginning a new technique and thought that 50 would be sufficient. We have subse-
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quently trained our fellows in such a way as to increase the experience needed to perform chorionic villus sampling independently. As far as the rate of mosaicism, it was compatible with what's in the literature, and we dealt with it much as most other centers do with backup amniocentesis or periumbilical blood sampling. As far as Dr. Evans' questions of what would we do different if we had to do it all over again, clearly, we would have initially added transabdominal chorionic villus sampling. We believed we could get samples transcervically even with a fundal placenta. We're not sure why a fundal placenta sampled transcervically increases miscarriage rates. It may be a trauma to the amniotic chorion as the catheter moves along that area before it reaches the placenta. Clearly our data, however, indicate that with an anterior fundal placenta, it's important to use a transabdominal route. In addition if I had to do it all over again, I would also like to be at the place I am now. After 2500 chorionic villus sampling procedures, I have become adept at selecting patients. We have learned something very important with chorionic villus sampling, and that is which patients to tell, "Go home and wait for amniocentesis." I think that's been a very valuable experience. The question of Dr. Evans on how to correct wrong sex reporting was solved by obtaining an adequate sample of at least 5 mg and performing a direct and long-term culture procedure. What would we recommend to individuals starting up this process? I think we outlined that in our conclusion. First, if an individual has been fully trained, that individual can lead the team, but it's important that other members of the team know what's going on as well. I believe there must be some type of data base to know what the experience is. Patients want to know what the risks are. That's the most important thing they want to know. They're willing to do almost anything to get an early diagnosis and therefore chorionic villus sampling is a very popular procedure. If you do not have such an individual, then I think you should refer your patients to someone with experience. This is not a procedure that's easy to do. You need a considerable amount of back-up with ultrasonography, genetics, counseling, secretarial, and nursing support. Because there is a background spontaneous miscarriage rate, patients are going to miscarry in the majority of cases because they are pregnant and not because of the procedure itself. However, every time a person miscarries after a chorionic villus sampling procedure, both patient and physician believes it was the procedure that caused the problem. Because of this, guilt often becomes a problem for patient as well as health care provider.