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Questions and answers about fetal loss and complications associated with chorionic villus sampling and amniocentesis.
Dr. Stone is Director of Perinatal Ultrasound and Division Director of Maternal-Fetal Medicine at Mount Sinai Hospital, New York, NY.
This opinion was developed by the Publications Committee of the Society for Maternal-Fetal Medicine with the assistance of Joanne Stone, MD, and was approved by the Executive Committee of the Society. Neither Dr. Stone nor any member of the Publications Committee (see the list of 2014 members at www.smfm.org) has a conflict of interest to disclose with regard to the content of this article.
Disclaimer: The practice of medicine continues to evolve and individual circumstances will vary. Clinical practice also may vary. This opinion reflects information available at the time of acceptance for publication and is not designed nor intended to establish an exclusive standard of perinatal care. This publication is not expected to reflect the opinions of all members of the Society for Maternal-Fetal Medicine.
A 31-year-old underwent first-trimester screening with nuchal translucency and maternal serum PAPP-A and beta-hCG. Her risk for Down syndrome is increased at 1 in 80. She received genetic counseling, opted to undergo diagnostic testing, and is deciding between chorionic villus sampling (CVS) and amniocentesis.
Q: What is the risk of fetal loss associated with CVS or amniocentesis in a singleton pregnancy?
A: Fetal loss after CVS
CVS is a procedure in which a small sample of placental tissue (chorionic villi) is obtained either transcervically (TC) or transabdominally (TA) under ultrasound guidance. It is performed at 10 to 13 weeks’ gestation. Advances in first-trimester aneuploidy screening have increased the need for early prenatal diagnosis, and CVS is the only diagnostic test currently available in the first trimester.1,2
One study suggested that, of women who would consider pregnancy termination, 50% would only undergo termination in the first trimester.3 The maternal death rate is 1/100,000 following first-trimester termination, compared with 7/100,000 to 10/100,000 in mid-pregnancy.4 While there are clear advantages to earlier diagnosis, CVS is not widely utilized, partly because of its limited availability, and partly because of the perception that CVS confers increased risks compared with amniocentesis.5
In order to make an informed decision about invasive testing, patients need accurate information on risks of fetal loss. The total pregnancy loss after an invasive procedure consists of a procedure-related loss plus the background loss rate. Unfortunately, spontaneous fetal loss rates are difficult to estimate, as large populations have not been followed from early pregnancy.6 Attempts to estimate background loss rates are biased by different definitions of fetal loss, variability in length of follow-up and different intervals between ultrasound assessment of viability and fetal demise.6,7
The majority of data about fetal loss after CVS come from studies comparing loss rates in patients undergoing CVS with those undergoing amniocentesis (Table 1).8-11 Rather than evaluating procedure-related losses, these studies looked at total pregnancy losses, which include losses related to the procedure plus background losses. In some studies, termination for aneuploidy was also included in the definition of a pregnancy loss.8,10
The total pregnancy loss rate is necessarily higher following CVS than following amniocentesis, because CVS is performed at an earlier gestational age (GA), when the risk of spontaneous pregnancy loss is higher. However, procedure-related losses following CVS, particularly transabdominal CVS, are not generally considered to be greater than procedure-related losses following amniocentesis.
Large series have varied in reporting no significant differences, small differences, or moderate differences in pregnancy loss following CVS and amniocentesis (Table 1).8-11 One study demonstrated a substantially higher loss rate in women undergoing CVS compared to amniocentesis.10 Several factors may help to explain this finding. First, recruitment was across 31 centers, with some centers having a disparately small number of subjects. In addition, 17% of CVS procedures were described as difficult vs. 5% of amniocenteses, and 31% of CVS procedures involved more than one insertion, compared with only 6% of amniocenteses.10
Considering that the criteria for performing CVS were limited to only 30 cases, these findings together suggest that there may have been less operator experience with CVS than with amniocentesis.
A large national registry-based cohort study in singletons who had an amniocentesis (n=32,852) or CVS (n=31,355) in Denmark between 1996 and 2000 also demonstrated a higher loss rate with CVS compared to amniocentesis. A significant difference in loss rates between CVS and amniocentesis was identified (1.9% vs. 1.4%), but it was attributed to the difference in GA at the time of procedures, with the earlier GA of CVS allowing for a greater time for loss to occur.
A Cochrane review of amniocentesis and CVS found that the total pregnancy loss rate following TA CVS was equivalent to that of second-trimester amniocentesis, whereas TC CVS was associated with a slightly higher risk of miscarriage.12 The most recent systematic review of complications after prenatal diagnostic procedures included 29 observational studies of amniocentesis and 16 studies of CVS, all published after 1995.13 Pregnancy loss rates for CVS vs. amniocentesis were 0.7% vs. 0.6% within 2 weeks post-procedure, 1.3% vs. 0.9% up to 24 weeks, and 2.0% vs. 1.9% for the entire pregnancy, suggesting similar risks.
Series have compared patients undergoing CVS with a control group of women who did not undergo any invasive procedure (Table 2). After adjusting for potential confounding variables, and when data were limited to pregnancies since 1998, the loss rate following CVS was not significantly increased above the background pregnancy loss rate.14,15
Notably, these series were conducted by centers with expertise in CVS, which has a learning curve for safety (loss rates) and efficiency (number of passes and adequacy of sample).16
Fetal loss after amniocentesis
Amniocentesis is usually performed between 15 and 18 weeks for diagnosis of aneuploidy, although it can be performed at any GA at or beyond 15 weeks. The procedure-related fetal loss rate following amniocentesis has ranged from 1/100 to 1/1,600 in randomized and nonrandomized trials, a difference which failed to reach statistical significance in the majority of series (Table 3).17-24
An exact number is difficult to provide due to the paucity of prospective trials. The only prospective randomized study, which was performed in the 1980s, identified a 1% increase risk of fetal loss.17 In contrast, 3 recent retrospective series comparing losses in women undergoing amniocentesis with those not undergoing any procedure did not detect any difference in loss rates between groups.21,23,24
Eddleman et al compared pregnancy losses between 31,907 women in the FASTER trial who did not undergo amniocentesis with 3096 who did, and found that the difference between the 2 groups was 0.06% or 1/1600.21
Odibo et al compared outcomes in 11,746 women undergoing amniocentesis with 39,811 controls not having amniocentesis.23 The fetal loss rate prior to 24 weeks was not significantly different between the 2 groups (0.97% in the amniocentesis group and 0.84% among controls), and the loss rate attributable to amniocentesis was 0.13% or 1/769.23
Finally, Towner et al found no difference in loss rates <24 weeks in women with abnormal serum screening who underwent amniocentesis (69/15,005 or 0.46%) compared with controls not undergoing a procedure (90/17,045 or 0.53%).24
Compared to amniocentesis, CVS may be associated with a higher pregnancy loss rate (defined either as total losses or losses up to 28 weeks) of 0.9% (Table 1). These data seem to be driven by a slightly higher rate of loss associated with TC compared to TA CVS. In fact, fetal loss rates following amniocentesis and transabdominal CVS appear to be similar, and they are probably lower than the often-quoted rate of 1/200.
Additional contributors to the slightly higher loss rate may be operator experience and earlier GA at time of CVS, allowing for more time for a loss to occur. Compared to no procedure, CVS is associated with a difference in loss rate (defined as loss <24 or <28 weeks) of 0.7% (Table 2).
Compared to no procedure, amniocentesis is associated with a difference in loss rate (mostly defined as loss <24 weeks) of 0.1% (Table 3). Several nonrandomized observational studies suggest that loss rates from either TA CVS or amniocentesis are somewhat similar to those in women not undergoing invasive procedures.
While precise estimates are difficult, based on the more recent, albeit imperfect literature, the procedure-related loss rate following mid-trimester amniocentesis appears to be no higher than about 1/300-500 or even 1/1000 and may be even lower in experienced centers (Table 1).25
Q: Besides fetal loss, what other complications and management concerns can occur after CVS?
A: Limb-reduction defects: Historically, CVS was associated with an increased risk of limb-reduction defects, but this complication was limited to procedures performed before 10 weeks GA.26-28 A World Health Organization review of more than 200,000 CVS procedures did not identify an increase in limb reduction defects following CVS.29
Current evidence suggests that performing CVS between 10 and 13 weeks does not increase the risk of limb reduction defects.30
Bleeding: Vaginal spotting may occur in up to one-third of women undergoing CVS. However, frank bleeding has been reported in less than 6%, and is more common after TC CVS than TA CVS.10,12,31 A subchorionic hematoma may be seen on ultrasound exam following as many as 4% of TC CVS procedures.32
Fetomaternal hemorrhage: Placental disruption from the CVS procedure may result in fetomaternal hemorrhage. The actual amount of bleeding is usually small relative to the total fetoplacental blood volume.30 However, red blood cell and platelet alloimmunization may develop in susceptible pregnancies, and unsensitized Rh-negative women should receive anti-D immunoglobulin following CVS.33-36 Amniocentesis is considered a better alternative for prenatal diagnosis in pregnancies at risk of alloimmunization because of the increased risk of inciting or worsening alloimmunization with CVS.36
Confined placental mosaicism (CPM): CPM is a condition in which more than one cell line is present in the placenta but not in the fetus. It is not a complication of CVS. CPM is reported to occur in 1% to 2% of CVS samples.37 It is associated with increased risk of fetal growth restriction, and, depending on the chromosome involved, may confer increased risk of fetal abnormalities due to uniparental disomy.37 If mosaicism is identified, amniocentesis is suggested to determine whether it is indeed confined to the placenta or culture results indicate an abnormal fetal karyotype.
Q: Besides fetal loss, what other complications and management concerns can occur after amniocentesis?
A: Leakage of amniotic fluid: In 1.7% of pregnancies after amniocentesis compared with 0.4% of controls, leakage of amniotic fluid has been reported, although many practitioners would quote a lower figure.17,39
The leakage usually stops within 1 week, with normalization of amniotic fluid volume within 3 weeks.40,41 Perinatal survival is reported in more than 90% of cases.41
Fetal injury and neonatal complications: Direct injury to the fetus is extremely rare. When amniocentesis was performed between 11 and 13 weeks in the Canadian Early and Mid-Trimester Amniocentesis Trial (CEMAT), higher rates of talipes equinovarus, amniotic-fluid leakage, and fetal loss were observed, compared with mid-trimester amniocentesis.42
Based on these risks, early amniocentesis–prior to 15 weeks-is neither recommended nor indicated.25
Q: What are the risks of transmission of hepatitis and HIV following CVS or amniocentesis?
A: Limited information is available regarding the risk of transmission of HIV, hepatitis B (HBV), and hepatitis C (HCV) with invasive procedures, with only observational data available for amniocentesis.43 Among 4 series that included 125 HBV-infected pregnancies, there were 6 cases of HBV transmission (4%).44,47
Ko et al found that transmission was non-significantly increased in women who were HBeAg-positive (30% vs. 14%).44
The risk of transmission of HCV is similarly unknown.45 In one series of 10 pregnancies with infant follow-up, there were no cases of HCV transmission after mid-trimester amniocentesis.48
Somewhat more information is available about HIV transmission rates. The rate of vertical HIV transmission following amniocentesis appears to be lowest in those receiving highly active antiretroviral therapy (HAART).
Of 166 pregnancies followed through the French Perinatal Cohort, there were no cases of mother-to-child transmission in 81 women receiving HAART at time of amniocentesis.49 However, vertical transmission tended to be higher in the amniocentesis group among women not receiving antiretroviral therapy (25% vs. 16%), as well as in women receiving zidovudine monotherapy or a double-nucleoside reverse transcriptase inhibitor combination (6.1% vs. 3.3%).
No cases of mother-to-child transmission following amniocentesis were reported in women receiving HAART in other recent series that included 78 women.50-53
Counseling for pregnant women with HIV who are considering amniocentesis should include the potential for a small increased risk of transmission, as this cannot be excluded.53 If an amniocentesis is anticipated, it is best to first try to achieve viral suppression with HAART. An amniocentesis procedure performed in an HIV-infected pregnancy should be done only if the patient is on HAART, and preferably when the viral load is undetectable.54,55
Data are not available for transmission risk associated with CVS procedures, but amniocentesis is preferred because of the lower theoretical risk of all viral transmission.
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