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Chorionic villus sampling

Chorionic villus sampling
Author:
Alessandro Ghidini, MD
Section Editor:
Louise Wilkins-Haug, MD, PhD
Deputy Editor:
Alana Chakrabarti, MD
Literature review current through: Jul 2022. | This topic last updated: Jan 20, 2021.

INTRODUCTION — Chorionic villus sampling (CVS) refers to a procedure in which small samples of the placenta are obtained for prenatal genetic diagnosis, generally in the first trimester after 10 weeks of gestation. CVS results are available earlier in pregnancy than amniocentesis results, which provides privacy since the pregnancy has not begun to "show" and shortens the duration of anxiously waiting for information about the fetus. If the results lead to a decision to terminate the pregnancy, the termination can be performed at a gestational age when the procedure is more widely available and has lower risks than mid-second-trimester termination procedures. However, CVS results have higher diagnostic uncertainty than amniocentesis and the procedure may be less safe than second-trimester amniocentesis.

INDICATIONS — CVS enables prenatal diagnosis of any condition in which diagnostic cytogenetic, biochemical/molecular, or DNA analysis is possible. The American College of Obstetricians and Gynecologists states that invasive diagnostic testing should be available to all patients, regardless of age or risk [1].

The most common reasons for prenatal genetic diagnosis include [2]:

Maternal age 35 years or older at estimated date of delivery

Previous child with a chromosome abnormality or genetic disorder

Parent is a carrier of a balanced translocation or other structural chromosome disorder

Parent is a carrier of a monogenic (ie, single gene or Mendelian) disorder

Both parents are carriers of autosomal recessive disease

Female parent is a carrier of a sex-linked disease

Congenital anomaly on first-trimester ultrasound examination

Abnormal results at aneuploidy screen (eg, maternal serum analytes with/without sonographic markers of aneuploidy, cell-free DNA)

CONTRAINDICATIONS — Maternal alloimmunization is a relative contraindication to CVS because fetomaternal bleeding from the procedure may augment maternal antibody response, which may result in more severe fetal erythroblastosis [3]. The author avoids CVS if an intrauterine device (IUD) is in situ, but this is rare. One group reported removing the IUD at the time of CVS [4]. As with amniocentesis, there is a risk of vertical transmission of maternal infection, such as HIV, hepatitis B and C. This is likely influenced by the viral load. (See "Diagnostic amniocentesis", section on 'Vertical transmission'.)

ALTERNATIVES — Amniocentesis is an alternative to CVS as both procedures provide essentially the same genetic information. The choice of procedure depends on the patient's personal appraisal of the risks and benefits of each technique. CVS results (fetal karyotype) are available four to six weeks earlier in gestation than amniocentesis results. Although amniocentesis for prenatal diagnosis can be performed in the first trimester (ie, early amniocentesis, typically at 11 to 13 weeks of gestation but before 15 weeks), early amniocentesis is not recommended for most patients because it is associated with a higher rate of pregnancy loss and complications than either CVS or midtrimester procedure (see "Diagnostic amniocentesis"). CVS may be associated with a higher risk of fetal loss than midtrimester amniocentesis (see 'Total fetal loss rate' below) and a higher risk of diagnostic uncertainty. (See 'Confined placental mosaicism' below.)

Although not diagnostic, noninvasive prenatal testing using cell-free DNA has high sensitivity and specificity for trisomy 21. For this reason, many patients are reassured by a cell-free DNA screening test negative for Down syndrome and choose not to undergo an invasive diagnostic procedure. (See "Prenatal screening for common aneuploidies using cell-free DNA".)

PROCEDURE — CVS is an ambulatory procedure performed under real-time ultrasound guidance, usually at tertiary care centers or facilities specializing in prenatal diagnosis. The number of procedures that should be carried out annually to maintain competency is unclear; the Royal College of Obstetricians and Gynaecologists (RCOG) suggests an arbitrary minimum of 30 procedures per annum [5]. Others estimate that expertise is usually achieved after 250 procedures and maintained by systematic sampling [6].

Given the decline in number of prenatal invasive diagnostic procedures, simulators can be used for training purposes and have been shown to improve the ability of clinicians to perform CVS [7].

Timing — CVS is typically performed between 10 and 13 weeks of gestation. The procedure is delayed until 10 weeks of gestation because most spontaneous pregnancy losses will have occurred by this time and performance very early in pregnancy is associated with an increased risk of limb-reduction defects (see 'Limb-reduction defects and oromandibular hypogenesis' below). Although CVS can be performed at 14 or more weeks of gestation, amniocentesis is preferred at gestations ≥15 weeks because it is technically easier, more comfortable for the patient, and avoids diagnostic uncertainty related to confined placental mosaicism. (See 'Complications' below.)

Patient preparation — An ultrasound examination should precede the procedure to determine the number of embryos and chorionicity (if twins are present), document fetal viability, and screen for fetal structural anomalies.

The maternal bladder should not be empty in order to provide an acoustic window.

Technique — Chorionic tissue can be obtained transabdominally (TA-CVS) (figure 1) or transcervically (TC-CVS) (figure 2). Operator preference generally guides the decision, but technical factors predominantly related to placental location favor one approach over the other in up to 5 percent of procedures [8,9]. The author believes TA-CVS is generally preferable to TC-CVS because it is associated with fewer procedure-related fetal losses, lower risk of bleeding and infectious complications, lower need for multiple insertions, higher sampling success rate at the first attempt, and less maternal cell contamination [8,10-12]. A fundal placenta is easier to sample with TA-CVS. In the United Kingdom, over 96 percent of CVS is TA-CVS [13].

TC-CVS is technically easier than TA-CVS when the uterus is severely retroflexed or the placenta is posterior. TC-CVS also results in less maternal discomfort and fetomaternal bleeding [14], and is probably safer than TA-CVS when intestinal loops are observed between the abdominal wall and uterus. Factors that increase the difficulty of TC-CVS include vaginismus, cervical stenosis, cervical polyps and myomas, and lower uterine segment myomas obstructing access to a fundal placenta. Severe anteflexion or retroflexion of the uterus can render the placenta inaccessible to the catheter despite uterine manipulation.

Transabdominal chorionic villus sampling — The patient is placed in the supine position, the placenta is localized by transabdominal ultrasonography, and the patient's lower abdomen is prepped with antiseptic solution. TA-CVS procedures are associated with minor pain, which is not significantly reduced by prior administration of analgesia or local anesthesia since use of a local anesthetic provides dermal but not uterine wall anesthesia [15].

The 19 to 20 gauge needle is inserted using either a free-hand technique or a needle-guide attached to the ultrasound probe. The needle is advanced at an angle that allows it to penetrate along the long axis of the placenta. The stylet is removed, the medium-containing syringe mounted on the holder, and the holder is then attached to the hub of the needle. The needle tip is moved back and forth inside the placenta until an adequate sample has been aspirated by the vacuum created in the syringe. The sampling system is then withdrawn under negative pressure. The medium is flashed onto a plastic tissue culture dish and the content evaluated at a nearby microscope. In a 2013 Cochrane review, clinically important outcomes were similar for continuous and discontinuous negative pressure needle aspiration systems [16].

Some clinicians use a double-needle technique: An 18 gauge needle is inserted as described above; then the stylet is removed and replaced with a 20 gauge needle, which is used to aspirate the sample [13].

Transcervical chorionic villus sampling — The patient is placed in the lithotomy position, the external and internal genitalia are prepped with an antiseptic solution, and a speculum is inserted into the vagina. A single-toothed tenaculum or ring forceps is used to grasp the anterior lip of the cervix and gently pull it toward the operator to bring the uterus into a more axial configuration. If the uterus is sharply anteverted, filling the bladder may help to straighten the angle between the endocervical canal and the anterior uterine wall. Next, under direct transabdominal ultrasound visualization, a metal sound is introduced into the endocervical canal to define its course and curvature. The TC cannula is bent to assume a similar curve and then inserted under ultrasound guidance through the canal and into the placenta. The obturator of the cannula is removed and a 20 mL syringe containing medium is attached to the catheter. Chorionic villi are aspirated as the catheter is moved back and forth inside the placenta. After an adequate specimen is obtained, the catheter is withdrawn while keeping the syringe under negative pressure. An alternative transcervical method uses a biopsy forceps to obtain the placental sample [16,17]. The sample material is placed onto a plastic tissue culture dish and the content evaluated at a nearby microscope.

In a systematic review of randomized trials comparing different instruments for TC-CVS, aspiration by cannula was associated with a higher risk of an inadequate sample than biopsy by forceps (relative risk [RR] 3.81, 95% CI 1.52-9.56), but no greater need for instrument reinsertion (RR 2.44, 95% CI 0.83-7.20) and no difference in miscarriage rates (RR 1.00, 95% CI 0.14-6.96) [16]. For clinicians accustomed to cannula aspiration, evidence was not sufficiently strong to support a change in practice; however, those learning CVS may want to consider developing their expertise in the forceps technique.

Evaluation of the tissue sample — At least 5 mg of villus tissue is generally required. A trained assistant with an on-site microscope can provide rapid evaluation of sample adequacy, assess the quality of the specimen obtained, and select the chorionic villi. If a large amount of blood is in the sample, the blood should be removed promptly to avoid inclusion of villi in blood clots. Blood clots are removed and villi separated from maternal decidua with forceps under a dissecting microscope and the cleaned villi are transferred to an appropriate medium [18].

Genetic evaluation — The chorionic villi consist of outer syncytiotrophoblast cells, a middle layer of cytotrophoblast cells, and an inner mesenchymal cell core. Rapid karyotyping can be achieved within 2 to 48 hours of sampling by direct examination of cytotrophoblast (ie, direct method) since these cells have a high mitotic index and can be examined in metaphase. However, due to the risk of false positive results, long-term (one week) cultures of mesenchymal cells should be performed concurrently as these cells better reflect fetal, rather than the placental, genotype (see 'Diagnostic uncertainty and misdiagnosis' below). This is particularly important when CVS is performed because of a positive result from testing cell-free nucleic acids in maternal blood, since these nucleic acids also originate from cytotrophoblast. Conventional karyotype or microarray is performed on the cultured cells. Biochemical and molecular genetic analyses can also be performed if indicated.

The time required for the analyses depends on the specific test.

Test performance — Diagnostic accuracy of direct CVS preparations, long-term CVS cultures, and amniocentesis differs because of differences in the cell lines that are sampled. A systematic review of data from several trials published in different years concluded that the diagnostic accuracy of CVS and amniocentesis could not be accurately assessed because most trials had incomplete karyotype data [19].

Multiple gestations — Sonographic determination of chorionicity of multiple gestations is essential prior to CVS, as chorionicity determines the number of samples that need to be obtained. In addition, an accurate map of the fetal to placental relationship in multiple gestations is critical for accurate performance of selective termination later in pregnancy.

CVS in twins can be performed using a TA, TC, or combined approach (TA for one twin, TC for the other). One or two samplings are required, irrespective of the technique.

Only a single sample is required in the presence of monochorionic twins (ie, only one distinct placental site with either an absent dividing membrane or a "non-peaked" membrane insertion site and thin dividing membranes). However, case reports have reported discordant karyotypes in monozygotic twins; therefore, some clinicians sample both fetuses when an anomaly is present.

If there are separate placentas, the procedure is similar to CVS for a singleton pregnancy (but with two separate needle insertions). Combined TA-CVS and TC-CVS may be necessary in some cases to avoid twin-twin contamination: a typical example is when one placenta is anterior and the other posterior. If access to the posterior placenta with a TA approach requires passing through the anterior placenta, a TC-CVS to the posterior placenta should be employed. The cytogenetic results (if fetal sex is discordant) and DNA polymorphisms, if requested, will confirm the separate origin of chorionic tissue from each twin.

If the placentas are fused and either dichorionic or of uncertain chorionicity, the tip of the aspirating device should be inserted either close to the insertion of the umbilical cord or at the placental margin, far away from the area of fusion, to minimize the possibility of sampling the same fetus twice. The device should not pass through the placenta of one twin to reach the other twin's placenta. The cytogenetic results and DNA polymorphism may permit differentiation between the samples. However, if the results are identical and chorionicity remains uncertain, confirmation that each fetus has been sampled is advisable; this can be achieved by amniocentesis later in pregnancy. Follow-up amniocentesis is required in up to 6 percent of cases [20,21].

Uncertain results requiring further investigation (such as sampling one fetus twice, cross contamination due to mixed sampling, and maternal cell contamination) are more frequent in multiple gestations assessed by CVS than by amniocentesis. The risk of a sampling error in twin gestation is small (0.6 to 0.8 percent) [20-23], and lower than in triplets and higher order gestations (1.2 percent) [24]. Despite these limitations, CVS offers the advantage of earlier selective fetal reduction, if requested because of abnormal results.

Postprocedure care — Patients may resume normal physical activity after the procedure. We generally advise them to avoid strenuous activity and sexual intercourse for 24 hours. We also inform them that some spotting is normal, but they should call for persistent bleeding, pain, fever, or other concerns.

COMPLICATIONS — The most serious complications from CVS are fetal loss or injury. Other concerns relate to bleeding, infection, and uncertain results.

Total fetal loss rate — To determine the total fetal loss rate in patients undergoing CVS and amniocentesis, patients should be allocated to the CVS or amniocentesis group early in pregnancy (eg, <10 weeks and excluding those not eligible at allocation because of a nonviable fetus or multiple pregnancy) and all losses between allocation and a predefined endpoint (eg, 20 or 24 weeks of gestation) should be determined. This approach accounts for spontaneous losses occurring at the end of the first trimester and early second trimester in both groups. Because CVS is performed approximately four to six weeks earlier in gestation than amniocentesis, simply comparing the rate of spontaneous loss after CVS versus after amniocentesis is not an appropriate method of determining whether CVS results in a higher rate of loss than amniocentesis. If this method were used, spontaneous losses occurring in the gestational time period between performance of CVS and performance of amniocentesis would be counted as possible CVS-related losses in patients undergoing CVS but would not be accounted for in patients undergoing amniocentesis.

The bulk of evidence from randomized trials, performed over 30 years ago, suggests that CVS is associated with a higher rate of fetal loss than amniocentesis (table 1) [19,25]. However, the excess risk appears to be confined to transcervical (TC)-CVS, which is riskier than amniocentesis (table 2) [26-29] and riskier than transabdominal (TA)-CVS (table 3) [19,30-33]. TA-CVS and amniocentesis appear to be associated with similar rates of fetal loss [25,26]. The higher risk of fetal loss after TC-CVS should be interpreted with caution because of significant heterogeneity among the trials [19].

A systematic review of 16 cohort studies on complications of CVS calculated total fetal loss rates of 0.7 percent within 14 days of TA-CVS [25]. By comparison, the total rate of fetal loss within 14 days of amniocentesis was 0.6 percent (range: 1/200 to 1/143, 95% CI 0.5-0.7 percent). The number of losses that were procedure-related could not be determined. Because of limitations in study design, particularly selection of appropriate controls (ie, patients of similar risk who do not undergo an invasive procedure), an accurate determination of procedure-related risk of loss is unavailable. This risk is probably very small, as a systematic review of studies with unselected control populations reported no significant difference in the rate of miscarriage between the CVS and unselected control groups not undergoing an invasive procedure; the pooled procedure-related risk of miscarriage before 24 weeks following CVS was estimated to be 0.22 percent (95% CI -0.71 to 1.16 percent) [34].

Subsequently, in a large national cohort study analyzing risk of fetal losses, patients undergoing first-trimester combined screening plus TA-CVS or amniocentesis had similar rates of miscarriage or stillbirth compared with patients undergoing first-trimester combined screening alone [35].

The importance of an appropriate control group is critical. In one cohort study including over 22,000 patients undergoing first-trimester combined screening, the risk of miscarriage in patients undergoing CVS (3613 patients) was approximately 1 percent higher than those patients not undergoing the procedure (2.1 versus 0.9 percent); however, this excess risk was influenced by particular demographic and pregnancy characteristics, specifically aneuploidy [36]. When the risk of aneuploidy was low, the risk of miscarriage after CVS increased (odds ratio [OR] 2.87, 95% CI 1.13-7.30), and when the risk of aneuploidy was high, the risk of miscarriage after CVS was paradoxically reduced (OR 0.47, 95% CI 0.28-0.76). This inverse relationship is presumably due to the termination of pregnancies with major aneuploidies that would otherwise have resulted in spontaneous miscarriage. After accounting for these risk factors and confining the analysis to low-risk pregnancies, CVS increased the risk of miscarriage approximately three times above the patient's background risk (an increase from 0.1 to 0.3 percent). Although this is a substantial increase in relative terms, in absolute terms, it remains small.

Of note, the safety/risks of CVS (TA or TC), as reported in literature before 2011, may not be applicable in the current practice of cell-free DNA screening, as the increasing use of this test has significantly decreased the rate of invasive testing [37-39]. As a result, it is increasingly difficult for operators to learn and maintain appropriate technical skills, which may affect procedure-related fetal loss rates [33,40].

Predictors of fetal loss — In addition to the effect of sampling route, the following additional predictors of fetal loss have been suggested [33,40-42]:

Small for gestational age fetus at the time of the procedure

Number of times the sampling device is introduced to obtain adequate tissue

Use of transcervical cannula instead of a biopsy forceps

Operator skill and experience

Pregnancies after assisted reproductive techniques

Perinatal loss — The cumulative perinatal mortality rate (PNM) is not significantly higher after CVS than amniocentesis (7 versus 6 per 1000 live births), independent of the type of CVS (TC or TA) [19].

Only one of the trials cited above described the rate of liveborn infants, which was 4.6 percent lower in patients undergoing CVS compared with amniocentesis (86 versus 91 percent, p<0.01) [27]. This difference primarily reflected more spontaneous fetal deaths before 28 weeks of gestation (2.9 percent), which may have been procedure-related, and more terminations of pregnancies for chromosomal anomalies (1 percent), which may have reflected a higher detection rate of abnormal diagnoses due to earlier sampling with CVS.

Loss of multiple gestation — The safety of CVS in multiple gestation is unclear, as it has been addressed only by small case-control or cohort studies. In one systematic review, the rate of pregnancy loss before 20 weeks was 2.75 percent (95% CI 1.28-4.75 percent, three studies), and before 28 weeks, it was 3.44 percent (95% CI 1.67-5.81 percent, three studies) [22]. In a subsequent meta-analysis limited to studies published after the year 2000, the overall rate of fetal loss was 2 percent (95% CI 0.0-6.5 percent) [43]. Of the two studies directly comparing patients undergoing versus not undergoing CVS, the overall fetal loss rate was similar between groups (3/201 versus 5/218); all fetal losses occurred before 24 weeks of gestation. The small number of study subjects, heterogeneity of the published data, and the overall lack of matching between CVS subjects and controls prevent any meaningful conclusion on risk of CVS in twins.

Diagnostic uncertainty and misdiagnosis — The false negative rate with CVS is extremely low (0.03 percent in one series of over 62,000 procedures [44]); therefore, patients can be reassured of an unaffected fetus if CVS is normal or the mosaic karyotype is confined to direct preparations (ie, trophoblastic cells) and the long-term cultures (ie, mesenchymal cells) have a normal chromosome complement (see 'Confined placental mosaicism' below). By contrast, amniocentesis should be performed to rule out a false positive test when the mosaic karyotype is found in mesenchymal cells. If the chorionic villus sample is inadequate for both direct preparations and long-term cultures, long-term culture appears to be more reliable than a direct preparation [45].

The need for follow-up samples is significantly higher after CVS than after amniocentesis [19] because the certainty that the established karyotype reflects the fetal genotype is lower with CVS [46]. The presence of normal results from amniocytes (cells floating in the amniotic fluid) confirms a normal fetal karyotype.

Failure to obtain a sample — Overall, the CVS procedure has more sampling failure than amniocentesis (4.8 versus 1.6 percent, relative risk [RR] 3.1, 95% CI 2.0-4.8) [19]. The sampling success rate in the majority of the studies is at least 99 percent after fewer than three insertions and is not different for TC-CVS versus TA-CVS. However, the sampling success rate at the first attempt is significantly higher with TA-CVS than with TC-CVS [26]. Moreover, TC-CVS is associated with significantly more multiple insertions and need for second tests than TA-CVS or amniocentesis [19]. For cytogenetic analysis, TC-CVS has more laboratory failure than amniocentesis (comparison between TA-CVS and TV-CVS or between TA-CVS and amniocentesis is not available).

Maternal cell contamination — Maternal contamination is more frequent after CVS than amniocentesis (3.8 versus 0.3 percent, RR 12.3, 95% CI 3.8-39.7) [19]. Guidelines have been developed for detection, interpretation, and reporting of maternal cell contamination in long-term cultures [47], but are beyond the scope of this review. The direct preparation method has a lower risk of misdiagnosis due to maternal cell contamination than long-term culture because maternal decidua has a low mitotic index.

Confined placental mosaicism — Confined placental mosaicism refers to a discrepancy between the genotype of the placenta and the genotype of the embryo/fetus. CVS has a higher risk of confined placental mosaicism than amniocentesis (2.3 versus 0.4 percent, RR 5.7, 95% CI 1.9-16.2) [19].Mosaicism on CVS has both diagnostic and prognostic implications because placental function can be affected, leading to miscarriage, fetal growth restriction, fetal death, or stillbirth [48]. Mosaicism is identified in 1 to 2 percent of CVS samples, but confirmed in the fetus in only 11 to 13 percent of these cases [44,46,49-52]. Factors associated with true fetal mosaicism include mosaicism on mesenchymal core culture and the type of chromosome abnormality involved.

One mechanism for confined placental mosaicism involves postzygotic nondisjunction during mitosis leading to formation of an abnormal cell line in the morula; another mechanism involves meiotic error with postzygotic "correction" or "rescue" of the abnormal cell line leading to a normal cell line in the morula. In both cases, both abnormal and normal cell lines are present in the morula, but differentially segregate between the developing embryo and the extraembryonic tissues and within the extraembryonic tissues. In type 1 placental mosaicism, the mosaic cells are confined to cytotrophoblast; in type 2 placental mosaicism, the mosaic cells are confined to the mesodermal villus stroma; and in type 3 placental mosaicism, the mosaic cells involve both cytotrophoblast and mesodermal villus stroma [53].

Type 1 placental mosaicism is most common, almost never involves a true fetal abnormality, and is usually associated with a good pregnancy outcome. Types 2 and 3 placental mosaicisms are more likely to be associated with a true fetal chromosomal abnormality, but the probability of an affected fetus depends on the chromosome involved. An aneuploidy of chromosomes 13, 18, 21 or a sex chromosome is almost always associated with a cytogenetically abnormal fetus, whereas aneuploidy of chromosomes 2, 3, 7 or 8 is usually associated with a euploid fetus. Type 2 or 3 placental mosaicism, especially involving chromosome 16 or tetraploidy, has been associated with a high risk of fetal growth restriction and death [54-57]. Mosaicism of any chromosome may be associated with uniparental disomy, but this is clinically important only for those chromosomes with imprinted gene regions, including chromosomes 7, 11, 14, and 15 [58]. Further molecular studies may help to resolve this issue.

The prenatal diagnosis of CPM in otherwise normal fetuses is not associated with an increased long-term risk of developmental problems, but may be associated with decreased pre- and postnatal growth [59].

Limb-reduction defects and oromandibular hypogenesis — Ten weeks of gestation is the generally accepted lower limit for CVS procedures because an increased rate of transverse limb abnormalities has been reported when CVS is performed before 9 weeks of gestation [60-63]. This risk is independent of the expertise of the operator, the route of the procedure (TA versus TC), or gauge of the needle or cannula used [60-63]. The risk falls with advancing gestational age and approaches the background population rate at ≥11 weeks of gestation [64]. In some cases, the limb reduction is associated with oromandibular hypogenesis (called the oromandibular-limb hypogenesis syndrome) [65].

Bleeding — Vaginal spotting after CVS is reported in up to one-third of patients [41]. More persistent bleeding occurs in 7 to 10 percent of TC-CVS procedures and in less than 6 percent of TA-CVS procedures [8,19,27].

Infection — Rare cases of clinically-evident infectious complications have been reported [41,66,67]. Clinical or subclinical intrauterine infection can cause fetal loss.

The TC catheter may become contaminated by the cervicovaginal flora; the TA catheter may become contaminated by skin flora or as a result of bowel puncture.

Mother-to-infant transmission of infections, such as hepatitis virus, cytomegalovirus, toxoplasmosis, and HIV, can also occur during CVS. No cases of vertical transmission of HIV have been reported among patients receiving highly active antiretroviral therapy (HAART) at the time of procedure [68,69].

Fetomaternal hemorrhage — Fetomaternal hemorrhage (FMH) has been documented based upon an increase in maternal serum alpha-fetoprotein (MSAFP) following CVS. It has been proposed as one cause of fetal loss after CVS, particularly when MSAFP is very high or continues to rise after CVS [14]. Release of fetal blood into the maternal circulation can also cause isoimmunization; therefore, RhD-negative patients should receive anti-D Rh immunoglobulin following the procedure. CVS-related FMH may augment the maternal immune response in patients already sensitized and lead to early, severe erythroblastosis fetalis [3]. MSAFP levels should drop to baseline levels by 16 to 18 weeks of gestation [2].

Although FMH occurs in a substantial percent of cases [70], the amount of fetal bleeding is small in relation to the total fetoplacental blood volume. TA-CVS is associated with a greater risk of FMH than TC-CVS [14].

Rupture of membranes — Acute rupture of membranes is rare. Delayed rupture of membranes days to weeks after the procedure has been reported in 0.3 percent of cases [67,71].

Other pregnancy complications and outcomes — An association between CVS and pregnancy complications (other than fetomaternal bleeding) and adverse outcomes is unproven; studies have reported generally reassuring but discordant findings.

Data from the randomized trials show higher rates of preterm delivery after CVS than amniocentesis (RR 1.3, 95% CI 1.1-1.6) [19].

A nationwide Finnish study including 887,439 births, of which 3346 were complicated by abruption, reported that exposure to CVS was significantly more frequent among patients with abruption than in those without (OR 1.48, 95% CI 1.12-1.96) [72].

Several studies have reported that undergoing CVS is associated with a significantly increased risk of developing preeclampsia, especially severe preeclampsia [73-75], but others have not observed this association [76,77]. If an association exists between placental disruption due to CVS and subsequent preeclampsia, it is likely modest.

A study that surveyed 1509 patients who underwent TC-CVS, with an 87 percent response rate and an average infant age of 4.2 years at follow-up, reported no increase in rates of congenital malformations, neonatal morbidity, pediatric morbidity requiring hospital admission or outpatient treatment, functional disturbance, and physical growth below the 10th percentile compared with control patients undergoing second-trimester amniocentesis [78]. Of interest, only 10 percent of all congenital malformations had been detected at the routine follow-up shortly after birth.

A population-based cohort study of patients 35 to 49 years of age that compared infant morbidity of those exposed to CVS versus those not exposed reported no increase in fetal and infant mortality, prematurity, low birth weight, nonreassuring fetal status, or limb reduction defects associated with CVS [79].

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SUMMARY AND RECOMMENDATIONS

Chorionic villus sampling (CVS) is an ambulatory procedure in which small samples of the placenta are obtained for prenatal genetic diagnosis under real-time ultrasound guidance, typically between 10 and 13 weeks of gestation. If direct preparations are performed, preliminary results are available within 48 hours and final results (based on long-term culture) are reported in 7 to 10 days. (See 'Procedure' above and 'Genetic evaluation' above.)

Amniocentesis is an alternative to CVS, as both procedures provide the same genetic information. Compared with midtrimester amniocentesis, CVS offers greater privacy (ie, the pregnancy has not begun to "show"), a shorter duration of anxiety since results are available earlier in gestation and, if pregnancy termination is performed, termination at an earlier gestational age is more widely available and has lower risks than mid-second-trimester termination procedures. However, CVS is associated with a higher rate of diagnostic uncertainty than amniocentesis. The choice of procedure depends on the patient's personal appraisal of the risks and benefits of each technique. (See 'Timing' above and 'Complications' above.)

Chorionic tissue can be obtained transabdominally (TA-CVS) or transcervically (TC-CVS). Operator preference generally guides the decision, but technical factors favor one approach over the other in up to 5 percent of procedures. TA-CVS is generally preferable to TC-CVS because it appears to be associated with fewer procedure-related fetal losses, lower risk of bleeding and infectious complications, lower need for multiple insertions, higher sampling success rate at the first attempt, and less maternal cell contamination. A fundal placenta is easier to sample with TA-CVS. TA-CVS is as safe as amniocentesis, whereas TC-CVS seems to carry at least a 1 percent higher risk of loss than amniocentesis.

TC-CVS is technically easier than TA-CVS when the uterus is severely retroflexed or the placenta is posterior. TC-CVS results in less maternal discomfort and fetomaternal bleeding, and is probably safer than TA-CVS when intestinal loops are observed between the abdominal wall and uterus. However, cervicovaginal factors (eg, polyp, myoma, stenosis, vaginismus) increase the difficulty of TC-CVS. (See 'Technique' above.)

Complications of CVS include pregnancy loss, spotting/bleeding, infection, rupture of membranes, and fetomaternal hemorrhage. There is no strong evidence that other pregnancy outcomes are affected. Bleeding, membrane rupture, and infection can lead to pregnancy loss. (See 'Complications' above.)

Based on pooled data from cohort studies, the pregnancy loss rate is 0.7 percent within 14 days of a TA-CVS procedure (see 'Total fetal loss rate' above). Procedure-induced limb defects have been associated with CVS, but the risk is negligible when the procedure is performed after 10 weeks of gestation. (See 'Limb-reduction defects and oromandibular hypogenesis' above.)

By comparison, the total rate of pregnancy loss within 14 days of amniocentesis appears to be 0.6 percent (95% CI 0.5-0.7). (See "Diagnostic amniocentesis", section on 'Fetal loss'.)

Fetomaternal bleeding can cause alloimmunization, worsen preexisting alloimmunization, and cause a rise in maternal serum alpha-fetoprotein. RhD-negative patients without alloimmunization should receive anti-D Rh immunoglobulin prophylaxis after the procedure. (See 'Fetomaternal hemorrhage' above.)

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