Chorionic Villus Sampling and Amniocentesis: Recommendations for Prenatal Counseling (2024)

The following CDC staff members prepared this report:

Richard S. Olney, M.D., M.P.H.

Cynthia A. Moore, M.D.Muin J. Khoury, M.D., Ph.D.J. David Erickson, D.D.S., Ph.D.

Larry D. Edmonds, M.S.P.H.

Lorenzo D. Botto, M.D.

Division of Birth Defects and Developmental Disabilities

National Center for Environmental Health

Hani K. Atrash, M.D., M.P.H.Division of Reproductive HealthNational Center for Chronic Disease Prevention and Health Promotion

Summary

Chorionic villus sampling (CVS) and amniocentesis are prenataldiagnostic procedures that are performed to detect fetal abnormalities. In1991, concerns about the relative safety of these procedures arose afterreports were published that described a possible association between CVSand birth defects in infants. Subsequent studies support the hypothesisthat CVS can cause transverse limb deficiencies. Following CVS, rates ofthese defects, estimated to be 0.03%-0.10% (1/3,000-1/1,000), generallyhave been increased over background rates. Rates and severity of limbdeficiencies are associated with the timing of CVS; most of the birthdefects reported after procedures that were performed at greater than orequal to 70 days' gestation were limited to the fingers or toes.

The risk for either digital or limb deficiency after CVS is only oneof several important factors that must be considered in making complex andpersonal decisions about prenatal testing. For example, CVS is generallydone earlier in pregnancy than amniocentesis and is particularlyadvantageous for detecting certain genetic conditions. Another importantfactor is the risk for miscarriage, which has been attributed to 0.5%-1.0%of CVS procedures and 0.25%-0.50% of amniocentesis procedures. Prospectiveparents considering the use of either CVS or amniocentesis should becounseled about the benefits and risks of these procedures. The counselorshould also discuss both the mother's and father's risk(s) for transmittinggenetic abnormalities to the fetus.

INTRODUCTION

Chorionic villus sampling (CVS) and amniocentesis are prenataldiagnostic procedures used to detect certain fetal genetic abnormalities.Both procedures increase the risk for miscarriage (1). In addition, concernhas been increasing among health-care providers and public health officialsabout the potential occurrence of birth defects resulting from CVS (2).

This report describes CVS and amniocentesis, provides information onindications for their use, reviews studies about the safety of theprocedures, compares the benefits and risks of the two procedures (focusingparticularly on the risk for limb deficiency after CVS), and providesrecommendations for counseling about these issues. A public meeting wasconvened on March 11, 1994, to discuss the results of studies ofCVS-associated limb deficiencies and preliminary counseling recommendationsthat had been drafted at CDC (3). Participants included geneticists,obstetricians, pediatricians, epidemiologists, teratologists,dysmorphologists, and genetic counselors who had a particular interest inCVS studies or who represented professional organizations and governmentagencies. Participants provided diverse opinions about recommendations forcounseling both at the meeting and in subsequent written correspondence;input from participants has been incorporated into this document.

USE OF CVS AND AMNIOCENTESIS

CVS utilizes either a catheter or needle to biopsy placental cellsthat are derived from the same fertilized egg as the fetus. Duringamniocentesis, a small sample of the fluid that surrounds the fetus isremoved. This fluid contains cells that are shed primarily from the fetalskin, bladder, gastrointestinal tract, and amnion. Typically, CVS is doneat 10-12 weeks' gestation, and amniocentesis is done at 15-18 weeks'gestation. In the United States, the current standard of care inobstetrical practice is to offer either CVS or amniocentesis to women whowill be greater than or equal to 35 years of age when they give birth,because these women are at increased risk for giving birth to infants withDown syndrome and certain other types of aneuploidy. Karyotyping of cellsobtained by either amniocentesis or CVS is the standard and definitivemeans of diagnosing aneuploidy in fetuses. The risk that a woman will givebirth to an infant with Down syndrome increases with age. For example, forwomen 35 years of age, the risk is 1 per 385 births (0.3%), whereas forwomen 45 years of age, the risk is 1 per 30 births (3%) (1). The backgroundrisk for major birth defects (with or without chromosomal abnormalities)for women of all ages is approximately 3%.

Before widespread use of amniocentesis, several controlled studieswere conducted to evaluate the safety of the procedure. The major findingfrom these studies was that amniocentesis increases the rate formiscarriage (i.e., spontaneous abortions) by approximately 0.5%. Subsequentto these studies, amniocentesis became an accepted standard of care in the1970s. In 1990, more than 200,000 amniocentesis procedures were performedin the United States (4).

In the 1960s and 1970s, exploratory studies were conducted revealingthat the placenta (i.e., chorionic villi) could be biopsied through acatheter and that sufficient placental cells could be obtained to permitcertain genetic analyses earlier in pregnancy than through amniocentesis.In the United States, this procedure was initially evaluated in acontrolled trial designed to determine the miscarriage rate (5). Thedifference in fetal-loss rate was estimated to be 0.8% higher after CVScompared with amniocentesis, although this difference was not statisticallysignificant. Because that study was designed to determine miscarriagerates, it had limited statistical power to detect small increases in risksfor individual birth defects.

CVS had become widely used worldwide by the early 1980s. The WorldHealth Organization (WHO) sponsors an International Registry of CVSprocedures; data in the International Registry probably represent less thanhalf of all procedures performed worldwide (6). More than 80,000 procedureswere reported to the International Registry from 1983-1992 (6);approximately 200,000 procedures were registered from 1983-1995 (L.Jackson, personal communication). CVS is performed in hospitals, outpatientclinics, selected obstetricians' offices, and university settings; thesefacilities are often collectively referred to as prenatal diagnosticcenters. Some investigators have reported that the availability of CVSincreased the overall utilization of prenatal diagnostic procedures amongwomen greater than or equal to 35 years of age, suggesting that access tofirst-trimester testing may make prenatal chromosome analysis appealing toa larger number of women (7). Another group of obstetricians did not see anincrease in overall utilization when CVS was introduced (8). The increasein CVS procedures was offset by a decrease in amniocentesis, suggestingthat the effect of CVS availability on the utilization of prenataldiagnostic testing depends on local factors. In the United States, anestimated 40% of pregnant women greater than or equal to 35 years of ageunderwent either amniocentesis or CVS in 1990 (9).

Although maternal age-related risk for fetal aneuploidy is the usualindication for CVS or amniocentesis, prospective mothers or fathers of anyage might desire fetal testing when they are at risk for passing on certainmendelian (single-gene) conditions. In a randomized trial conducted in theUnited States, 19% of women who underwent CVS were <35 years of age (10). DNA-based diagnoses of mendelian conditions, such as cystic fibrosis, hemophilia, muscular dystrophy, and hemoglobinopathies, can be made by direct analysis of uncultured chorionic villus cells (a more efficient method than culturing amniocytes) (11). However, amniocentesis is particularly useful to prospective parents who have a family history of neural tube defects, because alphafetoprotein (AFP) testing can be done on amniotic fluid but cannot be done on CVS specimens.

When testing for chromosomal abnormalities resulting from advancedmaternal age, CVS may be more acceptable than amniocentesis to some womenbecause of the psychological and medical advantages provided by CVS throughearlier diagnosis of abnormalities. Fetal movement is usually felt anduterine growth is visible at 17-19 weeks' gestation, the time whenabnormalities are detected by amniocentesis; thus, deciding what action totake if an abnormality is detected at this time may be more difficultpsychologically (12). Using CVS to diagnose chromosomal abnormalitiesduring the first trimester allows a prospective parent to make thisdecision earlier than will amniocentesis.

Maternal morbidity and mortality associated with induced abortionincrease significantly with increasing gestational age; thus, the timing ofdiagnosis of chromosomal abnormalities is important. Results of studies ofabortion complications conducted by CDC from 1970 through 1978 indicatedthat the risk for major abortion complications (e.g., prolonged fever,hemorrhage necessitating blood transfusion, and injury to pelvic organs)increases with advancing gestational age. For example, from 1971 through1974, the major complication rate was 0.8% at 11-12 weeks' gestation,compared with 2.2% at 17-20 weeks' gestation (13). However, the risk fordeveloping major complications from abortion at any gestational agedecreased during the 1970s. More contemporary national morbidity data basedon current abortion practices are not yet available. CDC surveillance dataalso indicate an increase in the risk for maternal death with increasinggestation. From 1972 through 1987, the risk for abortion-related death was1.1 deaths per 100,000 abortions performed at 11-12 weeks' gestationcompared with 6.9 deaths per 100,000 abortions for procedures performed at16-20 weeks' gestation (14). The lower risk associated with first-trimesterabortions may be an important factor for prospective parents who aredeciding between CVS and amniocentesis.

Amniocentesis is usually performed at 15-18 weeks' gestation, but moreamniocentesis procedures are now being performed at 11-14 weeks' gestation."Early" amniocentesis (defined as <15 weeks' gestation) remains investigational, because the safety of the procedure is currently being evaluated with controlled trials (15).

Risk estimates for miscarriage caused by either CVS or midtrimesteramniocentesis have been adjusted to account for spontaneous fetal lossesthat occur early in pregnancy and are not procedure-related. Although onerandomized trial indicated that the amniocentesis-related miscarriage ratemay be as high as 1%, counselors usually cite risks for miscarriage fromother amniocentesis studies ranging from 0.25%-0.50% (1/400-1/200) (1,15).Rates of miscarriage after CVS vary widely by the center at which CVS wasperformed (16). Adjusting for confounding factors such as gestational age,the CVS-related miscarriage rate is approximately 0.5%-1.0% (1/200-1/100)(1).

Although uterine infection (i.e., chorioamnionitis) is one possiblereason for miscarriage after either CVS or amniocentesis, infection hasoccurred rarely after either procedure. In one study, no episodes of septicshock were reported after 4,200 CVS procedures, although less severeinfections may have been associated with 12 of the 89 observed fetal losses(5). Overall infection rates have been <0.1% after either CVS or amniocentesis (15).

Cytogenetically ambiguous results caused by factors such as maternalcell contamination or culture-related mosaicism are reported more oftenafter CVS than after amniocentesis (2). In these instances, follow-upamniocentesis might be required to clarify results, increasing both thetotal cost of testing and the risk for miscarriage. However, ambiguous CVSresults also may indicate a condition (e.g., confined placental mosaicism)that has been associated with adverse outcomes for the fetus (11). Thus, inthese situations, CVS may be more informative than amniocentesis alone.

LIMB DEFICIENCIES AMONG INFANTS WHOSE MOTHERS UNDERWENT

CVS Certain congenital defects of the extremities, known as limbdeficiencies or limb-reduction defects, have been reported among infantswhose mothers underwent CVS. This section addresses 1) the expectedfrequency and classification of these birth defects, 2) the physicalfeatures of reported infants in relation to the timing of associated CVSprocedures, and 3) cohort and case-control studies that have been done tosystematically examine whether CVS increases the risk for limbdeficiencies.

Population-Based Rates and Classification of Limb Deficiencies

Population-based studies indicate that the risk for all limbdeficiencies is from 5-6 per 10,000 live births (17). Limb deficienciesusually are classified into distinct anatomic and pathogenetic categories.The most common subtypes are transverse terminal defects, which involveabsence of distal structures with intact proximal segments, with the axisof deficiency perpendicular to the extremity. Approximately 50% of all limbdeficiencies are transverse, and 50% of those defects are digital,involving the absence of parts of one or more fingers or toes. Transversedeficiencies occur as either isolated defects or with other major defects.The rare combination of transverse limb deficiencies with either absence orhypoplasia of the tongue and lower jaw -- usually referred to asoromandibular-limb hypogenesis or hypoglossia/hypodactyly -- occurs at arate of approximately 1 per 200,000 births. Although the cause of manyisolated limb deficiencies and multiple anomalies that include transversedeficiencies is unknown, researchers have hypothesized that thesedeficiencies are caused by vascular disruption either during the formationof embryonic limbs or in already-formed fetal limbs (17,18).

Limb Deficiencies Reported in Infants Exposed to CVS

Reports of clusters of infants born with limb deficiencies after CVSwere first published in 1991 (19). Three studies illustrate the spectrum ofCVS-associated defects (19-21). Data from these studies suggest that theseverity of the outcome is associated with the specific time of CVSexposure. Exposure at greater than or equal to 70 days' gestation has beenassociated with more limited defects, isolated to the distal extremities,whereas earlier exposures have been associated with more proximal limbdeficiencies and orofacial defects. For example, in a study involving 14infants exposed to CVS at 63-79 days' gestation and examined by a singlepediatrician, 13 had isolated transverse digital deficiencies (20). Inanother study in Oxford of five infants exposed to CVS at 56-66 days'gestation, four had transverse deficiencies with oromandibular hypogenesis(19). In a review of published worldwide data, associated defects of thetongue or lower jaw were reported for 19 of 75 cases of CVS-associated limbdeficiencies (21). Of those 19 infants with oromandibular-limb hypogenesis,17 were exposed to CVS before 68 days' gestation. In this review, 74% ofinfants exposed to CVS at greater than or equal to 70 days' gestation haddigital deficiencies without proximal involvement.

Cohorts of CVS-Exposed Pregnancies

Cohort studies usually measure rates of a specified outcome in anexposed group compared with an unexposed group. Ideally, both groups shouldbe selected randomly from the same study population. The three largestcollaborative trials of CVS in Europe, Canada, and the United States weredesigned originally in this way; however, in these studies, the outcome ofinterest was fetal death. The report of the first U.S. collaborative trialincluded no mention of any structural defects; such outcomes were reportedlater (5).

After the initial case reports in 1991, neonatal outcomes from thecollaborative trials were analyzed more intensively (22). However, ratherthan comparing rates for limb defects in the CVS-exposed cohorts with thoseof amniocentesis-exposed cohorts from the same study population, the ratesin the CVS groups were compared with population-based rates. Consequently,these comparisons must be interpreted with caution because population-basedrates are derived differently (i.e., usually from birth-defect registries).CVS-associated risk for limb deficiencies could be underestimated by thesecomparisons if follow-up of pregnancies in the exposed cohort isincomplete. Other epidemiologic issues must also be considered wheninterpreting comparisons of crude rates. Unless a formal meta-analysis isperformed, these comparisons neither account for heterogeneity betweenstudies nor assign individual "weights" to studies. Comparisons of cruderates also do not adjust for potential confounding variables, such asmaternal age. Methods of anatomic subclassification also vary betweenregistries and can differ from methods applied to CVS-exposed cohorts. Inaddition, comparing overall rates of limb deficiency in groups exposed toCVS with groups unexposed to CVS might overlook an association with aspecific phenotype, such as transverse deficiency.

Published CVS cohort studies of >1,000 CVS procedures include datafrom 65 CVS centers (Table_1). These rates include studies thatdescribe affected limbs in sufficient detail to exclude nontransversedefects. Rates calculated for the smaller cohorts (i.e., centers performing<3,500 procedures) are less stable, but the overall rate of nonsyndromic transverse limb deficiency from these centers was 7.4 per 10,000 procedures. This crude rate can be compared with rates of transverse deficiencies from Victoria (Australia) and Boston, Massachusetts (United States), where cases were classified to resemble the phenotype of CVS-exposed infants with limb deficiencies, including deficiencies of single digits (Table_2). The range of rates for these two populations(1.5-2.3 per 10,000 births) is representative of rates reported for otherpopulations. The threefold to fivefold increase in the overall rate for the65 centers compared with the rates for Victoria or Boston is statisticallysignificant (chi-square: p<0.001) (17,32).

Investigators participating in the International Registry also havecombined birth-defect data from multiple CVS centers, including some of the65 CVS centers (16,35). An abstract published in 1994 includes informationabout 138,000 procedures reported to the International Registry. The rateof transverse deficiencies in the reporting centers was 1.4 per 10,000procedures, lower than most population-based rates; the distribution oflimb-deficiency subtypes was similar to the results of a study of limbdeficiencies in British Columbia.

The variability in limb-deficiency rates could be related to threepossible explanations:

1. Different methods of classification. The method of classification of limb deficiencies for the International Registry resulted in a smaller proportion of transverse deficiencies (compared with all limb deficiencies) than some population based studies (17,32,36,37). The reason for this smaller proportion is that the definition of "transverse terminal deficiencies" is more restrictive and includes only defects that extend across the complete width of a limb and excludes terminal deficiencies of fewer than five digits.

2. Ascertainment of outcomes. Ascertainment of outcomes may be incomplete in CVS registries because deliveries can occur at a hospital remote from where the CVS was performed and might not be reported back to the CVS center. The effect of this incomplete ascertainment would be to underestimate risk for adverse outcomes.

3. Differences among centers in the performance of CVS. Investigators have compared rates of miscarriages and rates of limb deficiencies at individual facilities. This comparison is based on the assumption that the causes of both miscarriage and limb defects might be related to particular techniques of sampling by individual obstetricians. The association between high miscarriage and limb-deficiency rates in one U.S. CVS center was cited as potential evidence of the role of surgical inexperience (24). A cluster of limb deficiencies in another U.S. teaching hospital (five after 507 CVS procedures) was not associated with elevated miscarriage rates; chorionic villus sample sizes were larger at this hospital than at another hospital affiliated with the same university that reported no infants with limb defects (38).

Case-Control Studies

Case-control approaches with a minimum of 100 case and 100 controlpatients have greater statistical power than cohort studies of 10,000 orfewer births to detect a fourfold increase in risk for transversedeficiencies (the degree of relative risk suggested by data from the 65 CVScenters) (36). Investigators participating in multicenter birth-defectstudies have used this case-control approach both to measure the strengthof the association between CVS and limb deficiency and to determine if adose-response (or gradient) effect of risk exists. The latter effect wouldbe indicated by an increased relative risk for limb deficiency afterearlier procedures, suggested in case reports of CVS-associated limbdeficiencies by the high frequency of early exposures to CVS. Threecase-control studies have used infants with limb deficiencies registered insurveillance systems and control infants with other birth defects toexamine and compare exposure rates to CVS (36,37,39). The odds ratios forCVS exposure (an estimate of the relative risk for limb deficiency afterCVS) are summarized in Table_3.

The U.S. Multistate Case-Control Study and the study of the ItalianMulticentric Birth Defects Registry both indicated a significantassociation between CVS exposure and subtypes of transverse limbdeficiencies (36,37). The EUROCAT study did not analyze risk for transverselimb deficiencies (39); the risk for all limb deficiencies (odds ratio{OR}=1.8, 95% confidence interval {CI}=0.7-5.0) was similar to thatmeasured in the U.S. Multistate Case-Control Study for all limbdeficiencies (OR=1.7, 95% CI=0.4-6.3) (36). Analysis of subtypes in theU.S. study indicated a sixfold increase in risk for transverse digitaldeficiencies (36). In the U.S. study, no association between limbdeficiencies and amniocentesis was observed. In the study of the ItalianMulticentric Birth Defects Registry, the association between CVS exposureand transverse limb deficiencies was stronger (Table_3) (37).

GESTATIONAL AGE AT CVS

The lower risk observed in the United States may be related to thelater mean gestational age of exposure. Increased risk was associated withdecreased gestational age at the time of exposure (Table_4). The riskfor transverse deficiencies was greatest at less than or equal to 9 weeks'gestation. An analysis of cohort studies regarding the timing of CVSindicated a similar gradient with a relative risk for transversedeficiencies of 6.2 at <10 weeks' and 2.4 at greater than or equal to 10 weeks' gestation (40). Because of reports of high rates of severe limb deficiencies after CVS at 6-7 weeks' gestation, a WHO-sponsored committee recommended that CVS be performed at 9-12 weeks after the last menstrual period (16).

POSSIBLE MECHANISMS OF CVS-ASSOCIATED LIMB DEFICIENCY

Several biological events have been proposed to explain the occurrenceof limb deficiency after CVS, the variation in severity, and the riskassociated with the timing of the procedure. These mechanisms, whichinclude thromboembolization or fetal hypoperfusion through hypovolemia orvasoconstriction, are based on the assumption that the defects associatedwith CVS were caused by some form of vascular disruption. The limbs andmandible are susceptible to such disruption before 10 weeks' gestation(17); however, isolated transverse limb deficiencies related to fetalhypoperfusion have been reported at 11 weeks' gestation (18).

The rich vascular supply of chorionic villi can potentially bedisrupted by instrumentation. Data from one study of embryoscopicprocedures demonstrated fetal hemorrhagic lesions of the extremitiesfollowing placental trauma, which produced subchorionic hematomas (41).Placental hemorrhage following CVS could lead to substantial fetalhypovolemia with subsequent hypoperfusion of the extremities. Becauseanimal models show that limb deficiencies have been produced by eithervasoconstrictive agents or occlusion of uterine vessels, some researchershave hypothesized that CVS-associated defects might be caused byuteroplacental insufficiency (42). Although the period of highest embryonicsusceptibility appears to be when CVS is performed before 9 weeks'gestation (i.e., early CVS), these mechanisms also can disrupt limbstructures at later gestational ages.

ABSOLUTE RISK FOR LIMB DEFICIENCY

Subtypes of limb deficiencies rarely occur in the population ofinfants not exposed to CVS. Thus, even a sixfold increase in risk for suchtypes as digital defects (the finding of the U.S. Multistate Case-ControlStudy) is comparable to a small absolute risk (i.e., 3.46 cases per 10,000CVS procedures {0.03%}) (36). The upper 95% confidence limit for thisabsolute risk estimate is approximately 0.1%. A range of absolute risk from1 per 3,000 to 1 per 1,000 CVS procedures (0.03%-0.10%) for all transversedeficiencies is consistent with the overall increase in risk reported bythe 65 centers (Table_1). In cohort studies that reported the timing ofthe CVS, the absolute risk for transverse limb deficiencies was 0.20% atless than or equal to 9 weeks, 0.10% at 10 weeks, and 0.05% at greater thanor equal to 11 weeks (0.07% at greater than or equal to 10 weeks ofgestation) (40).

The absolute risk for CVS-related birth defects is lower than theprocedure-related risk for miscarriage that counselors usually quote toprospective parents (i.e., 0.5% to 1.0%) and also is lower than the riskfor Down syndrome at age 35 (0.3%). Data from a decision analysis studysupported the conclusion that, weighing a range of possible risksassociated with prenatal testing, amniocentesis was preferred to CVS (43).This study was published in 1991 and did not consider risk for limbdeficiency. Data indicate that publication of the initial case reports oflimb deficiency decreased subsequent utilization of CVS (44,45). However,one study demonstrated that prospective parents who were provided withformal genetic counseling, including information about limb deficienciesand other risks and benefits, chose CVS at a rate similar to a group ofprospective parents who were counseled before published reports ofCVS-associated limb deficiencies (44).

RECOMMENDATIONS

An analysis of all aspects of CVS and amniocentesis indicates that theoccasional occurrence of CVS-related limb defects is only one of severalfactors that must be considered in counseling prospective parents aboutprenatal testing. Factors that can influence prospective parents' choicesabout prenatal testing include their risk for transmitting geneticabnormalities to the fetus and their perception of potential complicationsand benefits of both CVS and amniocentesis. Prospective parents who areconsidering the use of either procedure should be provided with currentdata for informed decision making. Individualized counseling should addressthe following:

Indications for procedures and limitations of prenatal testing

1. Counselors should discuss the prospective parents' degree of risk for transmitting genetic abnormalities based on factors such as maternal age, race, and family history.

2. Prospective parents should be made aware of both the limitations and usefulness of either CVS or amniocentesis in detecting abnormalities.

   See Also

   Is It Time To Consider Buying CVS Group plc (LON:CVSG)?

Potential serious complications from CVS and amniocentesis

1. Counselors should discuss the risk for miscarriage attributable to both procedures: the risk from amniocentesis at 15-18 weeks' gestation is approximately 0.25%- 0.50% (1/400-1/200), and the miscarriage risk from CVS is approximately 0.5%-1.0% (1/200-1/100).

2. Current data indicate that the overall risk for transverse limb deficiency from CVS is 0.03%-0.10% (1/3,000-1/1,000). Current data indicate no increase in risk for limb deficiency after amniocentesis at 15-18 weeks' gestation.

3. The risk and severity of limb deficiency appear to be associated with the timing of CVS: the risk at <10 weeks' gestation (0.20%) is higher than the risk from CVS done at greater than or equal to 10 weeks' gestation (0.07%). Most defects associated with CVS at greater than or equal to 10 weeks' gestation have been limited to the digits.

Timing of procedures

1. The timing of obtaining results from either CVS or amniocentesis is relevant because of the increased risks for maternal morbidity and mortality associated with terminating pregnancy during the second trimester compared with the first trimester (13,14).

2. Many amniocentesis procedures are now done at 11-14 weeks' gestation; however, further controlled studies are necessary to fully assess the safety of early amniocentesis.

References

1. Verp MS. Prenatal diagnosis of genetic disorders. In: Gleicher N., ed. Principles and practice of medical therapy in pregnancy. 2nd ed. Norwalk, CT: Appleton and Lange, 1992:159-70.

2. Lilford RJ. The rise and fall of chorionic villus sampling: midtrimester amniocentesis is usually preferable {Comment}. Br Med J 1991;303:936-7.

3. CDC. Chorionic Villus Sampling Meeting. Federal Register 1994;59:8994.

4. Meaney FJ, Riggle SM, Cunningham GC, Stern KS, Davis JG. Prenatal genetic services: toward a national data base. Clin Obstet Gynecol 1993;36:510-20.

5. Rhoads GG, Jackson LG, Schlesselman SE, et al. The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnormalities. N Engl J Med 1989;320:609-17.

6. Kuliev AM, Modell B, Jackson L, et al. Risk evaluation of CVS. Prenat Diagn 1993;13:197-209.

7. Abramsky L, Rodeck CH. Women's choices for fetal chromosome analysis. Prenat Diagn 1991;11:23-8.

8. Brandenburg H, Gho CG, Jahoda MGJ, Stijnen T, Bakker H, Wladimiroff JW. Effect of chorionic villus sampling on utilization of prenatal diagnosis in women of advanced maternal age. Clin Genet 1992;41: 239-42.

9. Meaney FJ, Knutsen T, Riggle SM, Cunningham GC. A comparison and evaluation of two national surveys of genetic services {Abstract}. Am J Hum Genet 1993;53(Suppl 3):93.

10. Jackson LG, Zachary JM, Fowler SE, et al. A randomized comparison of transcervical and transabdominal chorionic-villus sampling. N Engl J Med 1992;327:594-8.

11. Cohen MM, Rosenblum-Vos LS, Prabhakar G. Human cytogenetics: a current overview. Am J Dis Child 1993;147:1159-66.

12. Burke BM, Kolker A. Clients undergoing chorionic villus sampling versus amniocentesis: contrasting attitudes toward pregnancy. Health Care Women Int 1993;14(2):193-200.

13. Cates W Jr, Grimes DA. Morbidity and mortality of abortion in the United States. In: Hodgson JE, ed. Abortion and sterilization: medical and social aspects. London: Academic Press Inc., 1981:155-80.

14. Lawson HW, Frye A, Atrash HK, Smith JC, Shulman HB, Ramick M. Abortion mortality, United States, 1972 through 1987. Am J Obstet Gynecol 1994;171:1365-72.

15. Schemmer G, Johnson A. Genetic amniocentesis and chorionic villus sampling. Obstet Gynecol Clin North Am 1993;20:497-521.

16. World Health Organization Regional Office for Europe (WHO/EURO). Risk evaluation of chorionic villus sampling (CVS): report on a meeting. Copenhagen: WHO/EURO, 1992.

17. Report of National Institute of Child Health and Human Development Workshop on Chorionic Villus Sampling and Limb and Other Defects, October 20, 1992. Am J Obstet Gynecol 1993;169:1-6.

18. Hoyme HE, Jones KL, Van Allen MI, Saunders BS, Benirschke K. Vascular pathogenesis of transverse limb reduction defects. J Pediatr 1982;101:839-43.

19. Firth HV, Boyd PA, 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.

20. Burton BK, Schulz CJ, Burd LI. Spectrum of limb disruption defects associated with chorionic villus sampling {published erratum appears in Pediatrics 1993;92:722}. Pediatrics 1993;91:989-93.

21. Firth HV, Boyd PA, Chamberlain PF, MacKenzie IZ, Morriss-Kay GM, Huson SM. Analysis of limb reduction defects in babies exposed to chorionic villus sampling. Lancet 1994;343:1069-71.

22. Mahoney MJ, for the USNICHD Collaborative CVS Study Group. Limb abnormalities and chorionic villus sampling {Letter}. Lancet 1991;337:1422-3.

23. USNICHD Collaborative CVS Study Group. Limb defects, cavernous hemangiomas and other congenital anomalies in infants born to women in the United States Collaborative Trials of Chorionic Villus Sampling (CVS) {Abstract}. Teratology 1993;47:400.

24. Blakemore K, Filkins K, Luthy D, et al. Cook obstetrics and gynecology catheter multicenter chorionic villus sampling trial: comparison of birth defects with expected rates. Am J Obstet Gynecol 1993;169: 1022-6.

25. Jahoda MGJ, Brandenburg H, Cohen-Overbeek T, Los FJ, Sachs ES, Wladimiroff JW. Terminal transverse limb defects and early chorionic villus sampling: evaluation of 4,300 cases with completed follow-up. Am J Med Genet 1993;46:483-5.

26. Ibba RM, Monni G, Lai R, et al. Total fetal malformations following chorion villus sampling {Abstract}. Prenat Diag 1992;12(suppl):S98.

27. Williams J III, Wang BBT, Rubin CH, Aiken-Hunting D. Chorionic villus sampling: experience with 3016 cases performed by a single operator. Obstet Gynecol 1992;80:1023-9.

28. Schloo R, Miny P, Holzgreve W, Horst J, Lenz W. Distal limb deficiency following chorionic villus sampling? Am J Med Genet 1992;42:404-13.

29. GIDEF (Gruppo Italiano Diagnosi Embrio-Fetali). Transverse limb reduction defects after chorion villus sampling: a retrospective cohort study. Prenat Diagn 1993;13:1051-6.

30. Godmilow L, Librizzi RJ, Donnenfeld AE. Congenital abnormalities following chorionic villus sampling {Abstract}. Am J Hum Genet 1992;51(Suppl 4):A409.

31. Smidt-Jensen S, Permin M, Philip J, et al. Randomised comparison of amniocentesis and transabdominal and transcervical chorionic villus sampling. Lancet 1992;340:1237-44.

32. Halliday J, Lumley J, Sheffield LJ, Lancaster PAL. Limb deficiencies, chorion villus sampling, and advanced maternal age. Am J Med Genet 1993;47:1096-8.

33. MRC Working Party on the Evaluation of Chorion Villus Sampling. Medical Research Council European Trial of chorion villus sampling. Lancet 1991;337:1491-9.

34. Silver RK, Macgregor SN, Muhlbach LH, Knutel TA, Kambich MP. Congenital malformations subsequent to chorionic villus sampling: outcome analysis of 1048 consecutive procedures. Prenat Diagn 1994;14:421-7.

35. Froster UG, Jackson L. Safety of chorionic villus sampling: results from an International Registry {Abstract}. Am J Hum Genet 1994;55(Suppl 3):A3.

36. Olney RS, Khoury MJ, Alo CJ, et al. Increased risk for transverse digital deficiency after chorionic villus sampling: results of the United States Multistate Case-Control Study, 1988-1992. Teratology 1995;51:20-9.

37. Mastroiacovo P, Botto LD. Chorionic villus sampling and transverse limb deficiencies: maternal age is not a confounder. Am J Med Genet 1994;53:182-6.

38. Bissonnette JM, Busch WL, Buckmaster JG, Olson SB, Nesler CL. Factors associated with limb anomalies after chorionic villus sampling {Letter}. Prenat Diagn 1993;13:1163-5.

39. Dolk H, Bertrand F, Lechat MF, for the EUROCAT Working Group. Chorionic villus sampling and limb abnormalities {Letter}. Lancet 1992;339:876-7.

40. Olney RS, Khoury MJ, Botto LD, Mastroiacovo P. Limb defects and gestational age at chorionic villus sampling {Letter}. Lancet 1994;344:476.

41. Quintero RA, Romero R, Mahoney MJ, Vecchio M, Holden J, Hobbins JC. Fetal haemorrhagic lesions after chorionic villus sampling {Letter}. Lancet 1992;339:193.

42. Lipson AH, Webster WS. Transverse limb deficiency, oro-mandibular limb hypogenesis sequences, and chorionic villus biopsy: human and animal experimental evidence for a uterine vascular pathogenesis {Letter}. Am J Med Gen 1993;47:1141-3.

43. Heckerling PS, Verp MS. Amniocentesis or chorionic villus sampling for prenatal genetic testing: a decision analysis. J Clin Epidemiol 1991;44:657-70.

44. Cutillo DM, Hammond EA, Reeser SL, et al. Chorionic villus sampling utilization following reports of a possible association with fetal limb defects. Prenat Diagn 1994;14:327-32.

45. James D, Bickley D, Davies T, McDermott A. Influence of The Lancet on chorionic villus sampling {Letter}. Lancet 1992;340:180-1.

Table_1
Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size.

TABLE 1. Rates of transverse terminal limb-deficiencies at 65 CVS centers * -- selectedgeographical locations, 1984-1992==================================================================================================== CVS ------------------- No. of No. of No. ofLocation + Centers Cases Procedures Rate---------------------------------------------------------------------------U.S. (NICHD &) (22,23) 10 7 9,588 7.3U.S. (24) 9 3 4,105 7.3Netherlands -- Rotterdam (25) 1 3 3,973 7.6Italy -- Sardinia (26) 1 3 3,082 9.7U.S. -- Beverly Hills, CA (27) 1 1 3,016 3.3Germany -- Munster (28) 1 2 2,836 7.1Italy (GIDEF @) (29) 5 3 2,759 10.9U.S. -- Philadelphia, PA (30) 1 1 2,710 3.7Denmark (31) 2 0 2,624 0.0Australia -- Victoria (32) 2 3 2,071 14.5Europe (MRC **) (33) 31 2 1,609 12.4U.S. -- Evanston, IL (34) 1 1 1,048 9.5Total 65 29 39,421 7.4--------------------------------------------------------------------------- * Per 10,000 CVS procedures. + Excluded were centers (i.e., collaborating hospitals or other health-care facilities) reporting either <=1,000 procedures or incomplete information about birth-defect outcomes. & National Institute of Child Health and Human Development (combined data from two trials {5,10}). @ Gruppo Italiano Diagnosi Embrio-Fetali.** Medical Research Council, United Kingdom.====================================================================================================

Table_2

TABLE 2. Comparison of rates* of transverse limb deficiencies in chorionic villussampling (CVS) cohorts and unexposed populations -- selected sites and studyperiods================================================================================================ CVS cohorts --------------------- Study No. of No. ofLocation Period Cases Procedures Rate *-------------------------------------------------------------------------------------International Registry + (35) 1983-94 20 138,000 1.4 (0.9- 2.2)Table 1 cohorts & (22-34) 1984-92 29 39,421 7.4 (4.9-10.6)------------------------------------------------------------------------------------- Unexposed populations --------------------- Study No. of No. ofLocation Period Cases Births Rate *-------------------------------------------------------------------------------------Australia -- Victoria (32) 1990-91 30 129,765 2.3 (1.6- 3.3)U.S. -- Boston, MA (17) @ 1972-74 1979-90 18 123,489 1.5 (0.9- 2.3)-------------------------------------------------------------------------------------* Per 10,000 procedures, 95% confidence interval.+ Method of classification of limb deficiencies differs from that in the unexposed populations listed (L. Jackson, personal communication).& Method of classification similar to that in the unexposed populations listed.@ Retabulated from original publication (L. Holmes, personal communication).================================================================================================

Table_3

TABLE 3. Risk for limb deficiencies and subtypes, by selected case-control studies oflimb defects after chorionic villus sampling -- by selected registries, 1984-1993============================================================================================================== Subsets of All limb Transverse limb transverse deficiencies deficiencies deficienciesRegistry OR * (95% CI) + OR * (95% CI) + OR * (95% CI) +------------------------------------------------------------------------------------------------------------U.S. Multistate Case-Control 1.7 (0.4-6.3) 4.7 (0.8-28.4) Digital: 6.4 (1.1-38.6) Study (36)EUROCAT (European 1.8 (0.7-5.0) Not subclassified Not subclassified Registration of Congenital Anomalies and Twins) (39)IMBDR (Italian Multicentric Not included & 12.6 (6.2-23.9) OMLH @ :223.8 (48.9-1006.8) Birth Defects Registry) ** (37)------------------------------------------------------------------------------------------------------------ * Odds ratios. + Confidence interval. & Case definition included only transverse limb deficiencies. @ Oromandibular-limb hypogenesis (hypoglossia/hypodactyly) (P. Mastroiacovo, personal communication).** IPIMC (Indagine Policentrica Italiana sulle Malformazioni Congenite).==============================================================================================================

Table_4

TABLE 4. Risk for transverse limb deficiency after chorionic villus sampling (CVS), bygestational age -- United States and Italy, 1988-1993======================================================================================== United States * Italy + ------------------------------- ----------------------------- No. of No. ofGestational age CVS-exposed CVS-exposed (weeks) cases OR & (95% CI) @ cases OR & (95% CI) @-------------------------------------------------------------------------------------<=9 2 11.3 (1.0-131.6) 8 21.6 (9.0-47.7)10 4 7.5 (1.5- 36.7) 3 14.3 (3.2-47.2)>=11 1 5.6 (0.3- 94.7) 0 -- **------------------------------------------------------------------------------------- * Includes transverse digital deficiencies only (36). + Includes all types of transverse deficiencies (37). & Odds ratio. @ Confidence interval.** No CVS-exposed cases.========================================================================================

Disclaimer All MMWR HTML versions of articles are electronic conversions from ASCII text into HTML. This conversion may have resulted in character translation or format errors in the HTML version. Users should not rely on this HTML document, but are referred to the electronic PDF version and/or the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.

Page converted: 09/19/98