- Email: [email protected]
Chorionic villus sampling in continuing pregnancies I. Low fetal loss rates in initial 109 cases
Factors in colposcopic evaluation
Volume 154 Number 6
had Papanicolaou smears taken before being referred to the colposcopy clinic, and some had Papanicolaou smears after that. I do not have a detailed breakdown of data to answer his question, but in some cases, yes, the additional Papanicolaou smears showed more than
mild dysplasia. I cannot give you a more detailed breakdown on that specific question, but in some cases the patients had worse than mild dysplasia on subsequent or prior Papanicolaou smears.
Chorionic villus sampling in continuing pregnancies I. Low fetal loss rates in initial l 09 cases Sherman Elias, M.D., Joe Leigh Simpson, M.D., Alice 0. Martin, Ph.D., Rudy Sabbagha, M.D., Allan Bombard, M.D., Barbara J. Rosinsky, B.S., and Lora D. Baum, M.S. Chicago, Illinois Among the first 150 women who agreed to have chorionic villus sampling after receiving counseling and giving informed consent, 41 proved ineligible. In six (5.5%) of the remaining 109 cases in which chorionic villus sampling was performed, we were unsuccessful in obtaining an adequate amount of villi to permit diagnostic testing. In the single loss, fetal viability was confirmed 2 weeks after sampling; however, fetal death became evident 3 weeks later. In four (3.7%) cases the pregnancies were terminated because of abnormal results, and in one (0.9%) case the pregnancy was electively terminated after normal results. Among the 41 completed pregnancies no anomalies were evident in the infants. There were two premature deliveries; one of these two infants died shortly after birth following premature rupture of the membranes at 29 weeks' gestation. All undelivered cases were progressing normally at the time of submission. (AM J 0BSTET GYNECOL 1986;154:1349-52.)
Key words: Chorionic villus sampling safety At the 1984 annual meeting of The Central Association of Obstetricians and Gynecologists we presented our initial experience in developing a chorionic villus sampling program at Northwestern University. 1 At that time we stated the following: "Chorionic villus sampling for first-trimester prenatal diagnosis has the potential of becoming an attractive alternative to genetic amniocentesis. Prior to becoming a standard, however, considerable caution and monitoring is necessary to establish the accuracy and safety of the procedure." In this pursuit, we wish to present our continued experience in the technical aspects and safety of chorionic villus sampling. In our companion paper, 2 we present our From the Section of Human Genetics and the Diagnostic Ultrasound Center, Prentice Women's Hospital and Maternity Center of Northwestern Memorial Hospital, Northwestern University. Supported by the National Institutes of Health (HD 02840, 19866, 52903) and by the March of Dimes. Presented at the Fifty-third Annual Meeting of The Central Association of Obstetricians and Gynecologists, New Orleans, Louisiana, October 10-12, 1985. Reprint requests: Sherman Elias, M.D., Suite 1176, Prentice Women's Hospital and Maternity Center, 333 East Superior St., Chicago, IL 60611.
results with respect to cytogenetic reliability and accuracy. Material and methods
In August 1983 we initiated our chorionic villus sampling program at Northwestern University by developing surgical and laboratory experience in a series of 58 volunteers undergoing elective first-trimester abortion (6 to 12 weeks' gestation). 1 Our initial experience was sufficiently encouraging that in March 1984 we sought and obtained approval from the Institutional Review Board of Northwestern University to offer chorionic villus sampling in continuing pregnancies. The following were considered indications for the procedure: (I) advanced maternal age (usually age ~35 years; (2) previous trisomic offspring; (3) parent with a balanced structural chromosomal rearrangement; and (4) fetus at high risk for a detectable mendelian disorder (for example, Tay-Sachs disease, sickle cell disease). A preliminary ultrasound examination was performed on all patients fulfilling these criteria who were 1349
1350 Elias et al.
June, 1986 Am J Obstet Gynecol
Table I. Screening for chorionic villus sampling Number of patients screened Subjects excluded Declined after counseling Advanced gestational age (> 11.3 weeks) Fetal death (missed abortion) Twins Active herpes cervicitis Severe vulvovaginitis (Candida albicans) Threatened abortion (uterine bleeding) Markedly retroverted and retroflexed uterus (posterior placenta) Inaccessible fundal placenta Leiomyomas Patients undergoing chorionic villus sampling
Table II. Indications for chorionic villus sampling (n = 109) 188 38 12 15 3 I I 3 3 I 2 109
interested in chorionic villus sampling. Only patients whose pregnancies were between 7 and 11 weeks' gestation, based on onset of the last menses and confirmed by ultrasonographic measurement of the fetal crownrump length (9 to 41 mm) remained eligible. Patients were excluded if ( 1) fetal viability was not confirmed by ultrasonographic visualization of fetal heart motion; (2) multiple gestation was detected; (3) pathologic conditions coexisted that conferred increased risk in performing chorionic villus sampling (for example, active genital herpes simplex infection, cervical pathologic findings, severe cervicitis, undiagnosed cervical lesion, active uterine bleeding); (4) large submucous uterine leiomyomas precluded reasonable access to the chorionic villi; (5) a markedly angulated cervical canal precluded ready catheter passage; and (6) the placenta was fundal and deemed inaccessible. (With increasing operator experience this last exclusion criterion became less applicable.) All eligible patients underwent formal genetic counseling and gave informed consent for chorionic villus sampling. We basically continue to perform the procedure, as previously described, 1 in an ambulatory surgical suite to minimize the risk of infection. We use a 2.1 mm outer-diameter radiopaque Teflon catheter (E-Z Cath, Deseret Pharmaceutical Co., Inc., Sandy, Utah), trimmed by scissors to fit snugly over a blunt-ended aluminum stylet. Use of the catheter for this purpose is under an investigational device exemption approval from the Food and Drug Administration. If additional attempts are required to obtain an adequate specimen, a fresh catheter is used each time. A real-time mechanical sector transducer (3.5 MHz) is employed to visualize the uterus and to guide the catheter into the optimal site of the placental substance. After aspiration, villi are transferred to a Petri dish containing 5 ml of modified Ham's F-12 media and inspected through a dissecting microscope (10 X). The quantity of tissue is judged to be adequate if at least 5 mg of villi were obtained. Optimal samples weigh 15
Maternal age >35 years Maternal age <35 years Previous trisomic offspring + 21, live-born + 13, live-born + 13, chorionic villus sampling + 21, amniocentesis Translocation heterozygote45,XX,-13,-13,+t(l3q;l3q) Niemann-Pick disease (two previous offspring) Total
96 4 2 I 1 3 1
109
to 20 mg. The quantity of tissue is estimated by comparison to a predetermined reference standard in which varying amounts of villi were weighed and photographed. Specimens are immediately transported to our laboratory for processing. The cytogenetic methods we are currently using are provided in our companion paper. Following this procedure, fetal heart movements are verified by ultrasonographic visualization, and the patient is monitored for at least 30 minutes for any untoward effects. (None has been observed.) Patients at risk for Rhesus isoimmunization receive 300 IJ.g of antiD immune globulin if their indirect Coombs' test is negative. Patients are also routinely contacted by telephone 3 days following the procedure. At 16 weeks' gestation an ultrasound examination is performed to detect overt fetal malformations and to assess fetal growth. Maternal serum a-fetoprotein is also determined. Because maternal cell contamination in the chorionic villus sampling specimen could lead to an erroneous fetal diagnosis, our investigative protocol provides the option for patients with a 46,XX complement to have a subsequent confirmatory genetic amniocentesis at no additional cost. Results
Among 188 women screened for chorionic villus sampling, 41 were considered ineligible, and 38 declined the procedure (Table 1). The indications for prenatal diagnosis in those 109 women who underwent the procedure are summarized in Table II. Sampling was usually carried out at the ninth or tenth week (Table III). In six of the 109 (5.5%) cases we were unsuccessful at obtaining an adequate amount of villi to permit diagnostic testing. All six subsequently underwent successful amniocentesis. Table IV correlates the number of transcervical catheter passes correlated with the success or failure of obtaining a specimen adequate for analysis. The overall success rate was 94.5%. Of the 103 successful samplings, 97 were cytogenetically normal: 46,XX (50); 46,XY (47). In six cases a
Chorionic villus sampling. I 1351
Volume 154 Number 6
Table III. Gestational age at time of chorionic villus sampling Weeks' gestation* 7 (49-55 days)
No. of subjects
8 (56-62 days)
9 (63-69 days)
10
11
(70-76 days)
(77-80 days)
5
55
41
7
*Assigned gestational age was the best estimate based upon the onset of the last menses correlated with ultrasonographic measurement of the fetal crown-rump length.
Table IV. Correlation between number of transcervical passes required for successful chorionic villus sampling and the time during program at which sample was attempted (operator success improved with experience) Number of attempts Order of cases
1-20 21-40 41-60 61-80 81-100 100-109 Total
1
3 13 15 13
2
7
II
4 3 5 6
7
I
62
26
3 4 3
Failed
2
2
2 I I
2 10
chromosomal abnormality was detected from the chorionic villus sampling specimen, as will be discussed in our companion paper. In one of our early cases (No. 8) the chorionic villus specimen showed a 46,XX complement, but the infant was male. Analysis was based on three cultures; no metaphases from the direct method were available. This finding suggested maternal cell contamination. The pregnancy at risk for Niemann-Pick disease was determined to be unaffected (biochemical assay performed by Dr. David Wenger, Denver, Colorado). This pregnancy was still undelivered at the time of submission. Pregnancy outcomes of all 109 women undergoing chorionic villus sampling are summarized in Table V. Only one fetal loss has occurred, that being detected 5 weeks following the procedure. An ultrasound scan was normal 2 weeks after chorionic villus sampling, indicating that fetal death occurred 2 to 5 weeks after the sampling. In this case, two catheter passes were required to obtain an adequate sample that subsequently proved to be 46,XX. The patient experienced intermittent vaginal spotting during the first week after the procedure, but fetal heart tones were confirmed by Doppler ultrasound 2 weeks later. However, fetal heart tones were absent 5 weeks after chorionic villus sampling; fetal death was confirmed by ultrasonographic examination. In two cases several milliliters of clear yellow fluid was inadvertently aspirated from the catheter during the initial passage, and the procedures were discontinued. However, in neither case did the gestational sac
2
2
6
Table V. Pregnancy outcomes of the 109 women undergoing chorionic villus sampling % Number of patients sampled Unsuccessful samplings Fetal losses Terminated because of abnormal results Elective abortion after normal results Delivered at term Delivered prematurely* Continuing pregnancies
109 6 l 4 I 41
5.5 .9 3.7 .9
2 54
*In one case delivery was at 34 weeks with normal outcome; in the second case neonatal death occurred at 29 weeks.
collapse, and in each fetal heart motion was normal. Both patients were followed with serial ultrasonographic examinations, with no evidence of oligohydramnios, leakage of fluid, or infection. The first patient underwent subsequent amniocentesis at 16 weeks, which showed normal46,XY complement. This patient has been delivered of a healthy 4665 gm infant. The second patient also underwent amniocentesis with results pending at the time of submission; this pregnancy is progressing normally.
Comment Although still investigational, chorionic villus sampling is already welcomed as an important advance in prenatal diagnosis. However, despite worldwide experience with more than 7000 procedures, 3 precise data with respect to safety are not yet available. We have
1352
Elias et al.
previously addressed the complexities of attempting to assess the safety of chorionic villus sampling.'· 4 Suffice it to repeat that the rate of 4% to 5% fetal losses observed worldwide after chorionic villus sampling is an absolute rate that must be corrected for a host of confounding variables: (I) accuracies in the identification and timing of spontaneous fetal loss rates, (2) maternal history of prior induced abortions, (3) parental cytogenetic factors (recurrent aneuploidy, translocations, inversions), (4) maternal age, (5) gravidity, (6) smoking, (7) alcohol consumption, and (8) environmental factors (for example, exposure to infectious agents, drugs, or chemical toxins). In this context our own initial experience is still most encouraging. The overall success rate of obtaining a specimen adequate for analysis was 94.5%, but in 56.9% of samplings an adequate specimen was obtained with a single catheter pass. In an additional 23.9% of cases, two catheter passes were required; 13.8% of cases required three or more passes; in 5.5% we were unsuccessful. Only one fetal loss occurred among our first 109 cases, and this took place at least 2 weeks after the procedure. The fetus was determined to be chromosomally normal, and no cause could be documented for the loss. Of special interest are the two cases in which fluid was inadvertently aspirated during chorionic villus sampling. In each, expectant obstetric management was successfully followed. Although the exact origin of the aspirated fluid could not be determined, failure of the gestational sac to collapse suggests to us that the fluid could have been derived from the space between the amnion and chorion. Alternatively, early amniocentesis may not necessarily be deleterious. In neither case was there evidence of oligohydramnios, transcervical fluid leakage, or infection. If there is documentation of an intact gestational sac by ultrasound, we now believe that expectant management is a reasonable option provided ( 1) couples are informed of potential maternal and fetal risk (for example, oligohydramnios, infection, spontaneous abortion); and (2) close fetal and maternal surveillance is possible to monitor indices of developing infection, fetal growth, and amniotic fluid volume. On the other hand, we would predict the risk of intrauterine or deformation infection to be great if the gestational sac is observed to collapse at the time of chorionic villus sampling. If such a pregnancy were allowed to continue, the risk of continued amniotic fluid leakage and oligohydramnios leading to fetal deformations would be substantial. 5 Accordingly, we would recommend that pregnancy termination be seriously considered in such cases. Our overall low complication rate following chorionic villus sampling could be attributed to various factors. First, it could merely reflect the vicissitudes of yet rei-
June, 1986 Am J Obstet Gynecol
atively small numbers. However, we believe that our low total fetal loss rate (0.9%) in the first 109 cases may be compared favorably with the 2.0% to 4.4% absolute loss rates reported to the International Fetal Diagnosis Registry by the four most experienced centers worldwide.' Of course, we again emphasize that neither their data nor ours take into account the background fetal loss rates, nor are they corrected for the numerous confounding variables alluded to earlier. Best estimates at this time suggest that procedurally related losses will be in the range of 1% to 2%. Second, our sample (that is, primarily upper socioeconomic, white) could have been selected from a group of women less likely to undergo complications than other groups. Differences in nutritional status, number of sexual partners, parity, and other factors could exist. Third, our experience in performing chorionic villus sampling in a large series of women immediately before elective abortions could have permitted the two obstetricians performing the procedure to become adept with its technical nuances. Fourth, our conservative approach in not even attempting chorionic villus sampling in certain cases (for example, multiple gestation, large uterine leiomyomas, cervicitis, spotting) may have reduced the potential for complications. Fifth, the risk for infection could have been minimized by performing chorionic villus sampling in an ambulatory surgical suite and in using a new catheter for each attempt at obtaining villi. In conclusion, we remain optimistic that chorionic villus sampling will eventually become a standard diagnostic technique for first-trimester prenatal diagnosis. At present, however, it must still be regarded as investigational and not yet an accepted alternative to mid trimester amniocentesis. More definitive data comparing risks and accuracy of chorionic villus sampling as compared to amniocentesis will have to await data from collaborative studies under way in the United States, Canada, and Europe. REFERENCES l. Elias S, Simpson JL, Martin AO, Sabbagh RE, Gerbie AB,
2. 3. 4.
5.
Keith LG. Chorionic villus sampling for first-trimester prenatal diagnosis: Northwestern University Program. AM J 0BSTET GYNECOL 1985;152:204-10. Martin AO, Simpson JL, Rosinsky BJ, Elias S. Chorionic villus sampling in continuing pregnancies: II. Cytogenetic reliability. AMJ 0BSTET GYNECOL 1986;154:1353-62. CVS Newsletter, August 28, 1985 (c/o Dr. Laird Jackson, Division of Medical Genetics, Jefferson Medical College, Philadelphia, PA 190 17). Simpson JL, Mills JL. Methodologic problems in determining fetal loss rates. In: Brambati B, Simoni G, Fabro S, eds. Fetal diagnosis during the first trimester. New York: Marcel Dekker, Inc., 1986:227-57. Thomas IT, Smith DW. Oligohydramnios, cause of the nonrenal features of Potter's syndrome, including pulmonary hypoplasia. J Pediatr 1974;84:811-4.
Discussion of part I and part II begins on page 1358.
Volume 154 Number 6
had Papanicolaou smears taken before being referred to the colposcopy clinic, and some had Papanicolaou smears after that. I do not have a detailed breakdown of data to answer his question, but in some cases, yes, the additional Papanicolaou smears showed more than
mild dysplasia. I cannot give you a more detailed breakdown on that specific question, but in some cases the patients had worse than mild dysplasia on subsequent or prior Papanicolaou smears.
Chorionic villus sampling in continuing pregnancies I. Low fetal loss rates in initial l 09 cases Sherman Elias, M.D., Joe Leigh Simpson, M.D., Alice 0. Martin, Ph.D., Rudy Sabbagha, M.D., Allan Bombard, M.D., Barbara J. Rosinsky, B.S., and Lora D. Baum, M.S. Chicago, Illinois Among the first 150 women who agreed to have chorionic villus sampling after receiving counseling and giving informed consent, 41 proved ineligible. In six (5.5%) of the remaining 109 cases in which chorionic villus sampling was performed, we were unsuccessful in obtaining an adequate amount of villi to permit diagnostic testing. In the single loss, fetal viability was confirmed 2 weeks after sampling; however, fetal death became evident 3 weeks later. In four (3.7%) cases the pregnancies were terminated because of abnormal results, and in one (0.9%) case the pregnancy was electively terminated after normal results. Among the 41 completed pregnancies no anomalies were evident in the infants. There were two premature deliveries; one of these two infants died shortly after birth following premature rupture of the membranes at 29 weeks' gestation. All undelivered cases were progressing normally at the time of submission. (AM J 0BSTET GYNECOL 1986;154:1349-52.)
Key words: Chorionic villus sampling safety At the 1984 annual meeting of The Central Association of Obstetricians and Gynecologists we presented our initial experience in developing a chorionic villus sampling program at Northwestern University. 1 At that time we stated the following: "Chorionic villus sampling for first-trimester prenatal diagnosis has the potential of becoming an attractive alternative to genetic amniocentesis. Prior to becoming a standard, however, considerable caution and monitoring is necessary to establish the accuracy and safety of the procedure." In this pursuit, we wish to present our continued experience in the technical aspects and safety of chorionic villus sampling. In our companion paper, 2 we present our From the Section of Human Genetics and the Diagnostic Ultrasound Center, Prentice Women's Hospital and Maternity Center of Northwestern Memorial Hospital, Northwestern University. Supported by the National Institutes of Health (HD 02840, 19866, 52903) and by the March of Dimes. Presented at the Fifty-third Annual Meeting of The Central Association of Obstetricians and Gynecologists, New Orleans, Louisiana, October 10-12, 1985. Reprint requests: Sherman Elias, M.D., Suite 1176, Prentice Women's Hospital and Maternity Center, 333 East Superior St., Chicago, IL 60611.
results with respect to cytogenetic reliability and accuracy. Material and methods
In August 1983 we initiated our chorionic villus sampling program at Northwestern University by developing surgical and laboratory experience in a series of 58 volunteers undergoing elective first-trimester abortion (6 to 12 weeks' gestation). 1 Our initial experience was sufficiently encouraging that in March 1984 we sought and obtained approval from the Institutional Review Board of Northwestern University to offer chorionic villus sampling in continuing pregnancies. The following were considered indications for the procedure: (I) advanced maternal age (usually age ~35 years; (2) previous trisomic offspring; (3) parent with a balanced structural chromosomal rearrangement; and (4) fetus at high risk for a detectable mendelian disorder (for example, Tay-Sachs disease, sickle cell disease). A preliminary ultrasound examination was performed on all patients fulfilling these criteria who were 1349
1350 Elias et al.
June, 1986 Am J Obstet Gynecol
Table I. Screening for chorionic villus sampling Number of patients screened Subjects excluded Declined after counseling Advanced gestational age (> 11.3 weeks) Fetal death (missed abortion) Twins Active herpes cervicitis Severe vulvovaginitis (Candida albicans) Threatened abortion (uterine bleeding) Markedly retroverted and retroflexed uterus (posterior placenta) Inaccessible fundal placenta Leiomyomas Patients undergoing chorionic villus sampling
Table II. Indications for chorionic villus sampling (n = 109) 188 38 12 15 3 I I 3 3 I 2 109
interested in chorionic villus sampling. Only patients whose pregnancies were between 7 and 11 weeks' gestation, based on onset of the last menses and confirmed by ultrasonographic measurement of the fetal crownrump length (9 to 41 mm) remained eligible. Patients were excluded if ( 1) fetal viability was not confirmed by ultrasonographic visualization of fetal heart motion; (2) multiple gestation was detected; (3) pathologic conditions coexisted that conferred increased risk in performing chorionic villus sampling (for example, active genital herpes simplex infection, cervical pathologic findings, severe cervicitis, undiagnosed cervical lesion, active uterine bleeding); (4) large submucous uterine leiomyomas precluded reasonable access to the chorionic villi; (5) a markedly angulated cervical canal precluded ready catheter passage; and (6) the placenta was fundal and deemed inaccessible. (With increasing operator experience this last exclusion criterion became less applicable.) All eligible patients underwent formal genetic counseling and gave informed consent for chorionic villus sampling. We basically continue to perform the procedure, as previously described, 1 in an ambulatory surgical suite to minimize the risk of infection. We use a 2.1 mm outer-diameter radiopaque Teflon catheter (E-Z Cath, Deseret Pharmaceutical Co., Inc., Sandy, Utah), trimmed by scissors to fit snugly over a blunt-ended aluminum stylet. Use of the catheter for this purpose is under an investigational device exemption approval from the Food and Drug Administration. If additional attempts are required to obtain an adequate specimen, a fresh catheter is used each time. A real-time mechanical sector transducer (3.5 MHz) is employed to visualize the uterus and to guide the catheter into the optimal site of the placental substance. After aspiration, villi are transferred to a Petri dish containing 5 ml of modified Ham's F-12 media and inspected through a dissecting microscope (10 X). The quantity of tissue is judged to be adequate if at least 5 mg of villi were obtained. Optimal samples weigh 15
Maternal age >35 years Maternal age <35 years Previous trisomic offspring + 21, live-born + 13, live-born + 13, chorionic villus sampling + 21, amniocentesis Translocation heterozygote45,XX,-13,-13,+t(l3q;l3q) Niemann-Pick disease (two previous offspring) Total
96 4 2 I 1 3 1
109
to 20 mg. The quantity of tissue is estimated by comparison to a predetermined reference standard in which varying amounts of villi were weighed and photographed. Specimens are immediately transported to our laboratory for processing. The cytogenetic methods we are currently using are provided in our companion paper. Following this procedure, fetal heart movements are verified by ultrasonographic visualization, and the patient is monitored for at least 30 minutes for any untoward effects. (None has been observed.) Patients at risk for Rhesus isoimmunization receive 300 IJ.g of antiD immune globulin if their indirect Coombs' test is negative. Patients are also routinely contacted by telephone 3 days following the procedure. At 16 weeks' gestation an ultrasound examination is performed to detect overt fetal malformations and to assess fetal growth. Maternal serum a-fetoprotein is also determined. Because maternal cell contamination in the chorionic villus sampling specimen could lead to an erroneous fetal diagnosis, our investigative protocol provides the option for patients with a 46,XX complement to have a subsequent confirmatory genetic amniocentesis at no additional cost. Results
Among 188 women screened for chorionic villus sampling, 41 were considered ineligible, and 38 declined the procedure (Table 1). The indications for prenatal diagnosis in those 109 women who underwent the procedure are summarized in Table II. Sampling was usually carried out at the ninth or tenth week (Table III). In six of the 109 (5.5%) cases we were unsuccessful at obtaining an adequate amount of villi to permit diagnostic testing. All six subsequently underwent successful amniocentesis. Table IV correlates the number of transcervical catheter passes correlated with the success or failure of obtaining a specimen adequate for analysis. The overall success rate was 94.5%. Of the 103 successful samplings, 97 were cytogenetically normal: 46,XX (50); 46,XY (47). In six cases a
Chorionic villus sampling. I 1351
Volume 154 Number 6
Table III. Gestational age at time of chorionic villus sampling Weeks' gestation* 7 (49-55 days)
No. of subjects
8 (56-62 days)
9 (63-69 days)
10
11
(70-76 days)
(77-80 days)
5
55
41
7
*Assigned gestational age was the best estimate based upon the onset of the last menses correlated with ultrasonographic measurement of the fetal crown-rump length.
Table IV. Correlation between number of transcervical passes required for successful chorionic villus sampling and the time during program at which sample was attempted (operator success improved with experience) Number of attempts Order of cases
1-20 21-40 41-60 61-80 81-100 100-109 Total
1
3 13 15 13
2
7
II
4 3 5 6
7
I
62
26
3 4 3
Failed
2
2
2 I I
2 10
chromosomal abnormality was detected from the chorionic villus sampling specimen, as will be discussed in our companion paper. In one of our early cases (No. 8) the chorionic villus specimen showed a 46,XX complement, but the infant was male. Analysis was based on three cultures; no metaphases from the direct method were available. This finding suggested maternal cell contamination. The pregnancy at risk for Niemann-Pick disease was determined to be unaffected (biochemical assay performed by Dr. David Wenger, Denver, Colorado). This pregnancy was still undelivered at the time of submission. Pregnancy outcomes of all 109 women undergoing chorionic villus sampling are summarized in Table V. Only one fetal loss has occurred, that being detected 5 weeks following the procedure. An ultrasound scan was normal 2 weeks after chorionic villus sampling, indicating that fetal death occurred 2 to 5 weeks after the sampling. In this case, two catheter passes were required to obtain an adequate sample that subsequently proved to be 46,XX. The patient experienced intermittent vaginal spotting during the first week after the procedure, but fetal heart tones were confirmed by Doppler ultrasound 2 weeks later. However, fetal heart tones were absent 5 weeks after chorionic villus sampling; fetal death was confirmed by ultrasonographic examination. In two cases several milliliters of clear yellow fluid was inadvertently aspirated from the catheter during the initial passage, and the procedures were discontinued. However, in neither case did the gestational sac
2
2
6
Table V. Pregnancy outcomes of the 109 women undergoing chorionic villus sampling % Number of patients sampled Unsuccessful samplings Fetal losses Terminated because of abnormal results Elective abortion after normal results Delivered at term Delivered prematurely* Continuing pregnancies
109 6 l 4 I 41
5.5 .9 3.7 .9
2 54
*In one case delivery was at 34 weeks with normal outcome; in the second case neonatal death occurred at 29 weeks.
collapse, and in each fetal heart motion was normal. Both patients were followed with serial ultrasonographic examinations, with no evidence of oligohydramnios, leakage of fluid, or infection. The first patient underwent subsequent amniocentesis at 16 weeks, which showed normal46,XY complement. This patient has been delivered of a healthy 4665 gm infant. The second patient also underwent amniocentesis with results pending at the time of submission; this pregnancy is progressing normally.
Comment Although still investigational, chorionic villus sampling is already welcomed as an important advance in prenatal diagnosis. However, despite worldwide experience with more than 7000 procedures, 3 precise data with respect to safety are not yet available. We have
1352
Elias et al.
previously addressed the complexities of attempting to assess the safety of chorionic villus sampling.'· 4 Suffice it to repeat that the rate of 4% to 5% fetal losses observed worldwide after chorionic villus sampling is an absolute rate that must be corrected for a host of confounding variables: (I) accuracies in the identification and timing of spontaneous fetal loss rates, (2) maternal history of prior induced abortions, (3) parental cytogenetic factors (recurrent aneuploidy, translocations, inversions), (4) maternal age, (5) gravidity, (6) smoking, (7) alcohol consumption, and (8) environmental factors (for example, exposure to infectious agents, drugs, or chemical toxins). In this context our own initial experience is still most encouraging. The overall success rate of obtaining a specimen adequate for analysis was 94.5%, but in 56.9% of samplings an adequate specimen was obtained with a single catheter pass. In an additional 23.9% of cases, two catheter passes were required; 13.8% of cases required three or more passes; in 5.5% we were unsuccessful. Only one fetal loss occurred among our first 109 cases, and this took place at least 2 weeks after the procedure. The fetus was determined to be chromosomally normal, and no cause could be documented for the loss. Of special interest are the two cases in which fluid was inadvertently aspirated during chorionic villus sampling. In each, expectant obstetric management was successfully followed. Although the exact origin of the aspirated fluid could not be determined, failure of the gestational sac to collapse suggests to us that the fluid could have been derived from the space between the amnion and chorion. Alternatively, early amniocentesis may not necessarily be deleterious. In neither case was there evidence of oligohydramnios, transcervical fluid leakage, or infection. If there is documentation of an intact gestational sac by ultrasound, we now believe that expectant management is a reasonable option provided ( 1) couples are informed of potential maternal and fetal risk (for example, oligohydramnios, infection, spontaneous abortion); and (2) close fetal and maternal surveillance is possible to monitor indices of developing infection, fetal growth, and amniotic fluid volume. On the other hand, we would predict the risk of intrauterine or deformation infection to be great if the gestational sac is observed to collapse at the time of chorionic villus sampling. If such a pregnancy were allowed to continue, the risk of continued amniotic fluid leakage and oligohydramnios leading to fetal deformations would be substantial. 5 Accordingly, we would recommend that pregnancy termination be seriously considered in such cases. Our overall low complication rate following chorionic villus sampling could be attributed to various factors. First, it could merely reflect the vicissitudes of yet rei-
June, 1986 Am J Obstet Gynecol
atively small numbers. However, we believe that our low total fetal loss rate (0.9%) in the first 109 cases may be compared favorably with the 2.0% to 4.4% absolute loss rates reported to the International Fetal Diagnosis Registry by the four most experienced centers worldwide.' Of course, we again emphasize that neither their data nor ours take into account the background fetal loss rates, nor are they corrected for the numerous confounding variables alluded to earlier. Best estimates at this time suggest that procedurally related losses will be in the range of 1% to 2%. Second, our sample (that is, primarily upper socioeconomic, white) could have been selected from a group of women less likely to undergo complications than other groups. Differences in nutritional status, number of sexual partners, parity, and other factors could exist. Third, our experience in performing chorionic villus sampling in a large series of women immediately before elective abortions could have permitted the two obstetricians performing the procedure to become adept with its technical nuances. Fourth, our conservative approach in not even attempting chorionic villus sampling in certain cases (for example, multiple gestation, large uterine leiomyomas, cervicitis, spotting) may have reduced the potential for complications. Fifth, the risk for infection could have been minimized by performing chorionic villus sampling in an ambulatory surgical suite and in using a new catheter for each attempt at obtaining villi. In conclusion, we remain optimistic that chorionic villus sampling will eventually become a standard diagnostic technique for first-trimester prenatal diagnosis. At present, however, it must still be regarded as investigational and not yet an accepted alternative to mid trimester amniocentesis. More definitive data comparing risks and accuracy of chorionic villus sampling as compared to amniocentesis will have to await data from collaborative studies under way in the United States, Canada, and Europe. REFERENCES l. Elias S, Simpson JL, Martin AO, Sabbagh RE, Gerbie AB,
2. 3. 4.
5.
Keith LG. Chorionic villus sampling for first-trimester prenatal diagnosis: Northwestern University Program. AM J 0BSTET GYNECOL 1985;152:204-10. Martin AO, Simpson JL, Rosinsky BJ, Elias S. Chorionic villus sampling in continuing pregnancies: II. Cytogenetic reliability. AMJ 0BSTET GYNECOL 1986;154:1353-62. CVS Newsletter, August 28, 1985 (c/o Dr. Laird Jackson, Division of Medical Genetics, Jefferson Medical College, Philadelphia, PA 190 17). Simpson JL, Mills JL. Methodologic problems in determining fetal loss rates. In: Brambati B, Simoni G, Fabro S, eds. Fetal diagnosis during the first trimester. New York: Marcel Dekker, Inc., 1986:227-57. Thomas IT, Smith DW. Oligohydramnios, cause of the nonrenal features of Potter's syndrome, including pulmonary hypoplasia. J Pediatr 1974;84:811-4.
Discussion of part I and part II begins on page 1358.