Clinical Question: Are pregnant patients who receive an amniocentesis or CVS at higher risk, than woman who do not have these procedures, for having a miscarriage?

PICO Question:

Identify the PICO elements (Recalling that some questions do not have all the elements)

P  Pregnant female patients

I  Receiving an amniocentesis; receiving a CVS  

C  Not receiving an amniocentesis; not receiving a CVS   

O  pregnant patient having a miscarriage  

Search Strategy:

Terms Used: pregnant, amniocentesis, chronic villus sampling, miscarriage,

Database	Terms	Filter	Articles
PubMed	pregnant, amniocentesis, chronic villus sampling, miscarriage	3 years	53
Google Scholar	pregnant, amniocentesis, chronic villus sampling, miscarriage, morbidity	2 years,	1,400
ScienceDirect	pregnant, amniocentesis, chronic villus sampling, miscarriage, adult	3 years	62

Reason for chosen articles:  I chose my articles because they all were published recently and provided me with direct answers to my question. My search via PubMed provided me with a very limited number of articles and I was able to very carefully choose the ones that would really be the most significant for my question. However, Google Scholar yielded a greater search and I ended up filtering it by year and putting the most recent articles first. ScienceDirect was also able to narrow down my search to less than 100 articles and I was able to see a great scope of detailed articles that related to my topic. I wanted to make sure each one was MEDLINE approved and that each of the articles gave me new insight on my question.

Abstract #1

Objectives To estimate the procedure-related risks of miscarriage following chorionic villus sampling (CVS) and amniocentesis in a large unselected screened population, and to determine whether these risks are consistent with those reported in systematic reviews and meta-analyses. Methods This was a retrospective cohort study carried out on data obtained from a large fetal medicine unit in the UK between January 2009 and May 2018. We included all women with singleton pregnancy who booked for pregnancy care at our unit before 20 weeks’ gestation, after excluding those with multiple pregnancy, major fetal defect, pregnancy termination and loss to follow-up. We estimated the risk of miscarriage in women who underwent a CVS or amniocentesis as well as in those who did not have an invasive procedure. The procedure-related risk of miscarriage was estimated as risk difference (95% CI) between the two groups. Univariate and multivariate regression analyses were used to derive odds ratios (95% CI) and determine which maternal and pregnancy characteristics provided a significant contribution in the prediction of miscarriage and whether CVS or amniocentesis provided a significant independent contribution. Results During the study period, 45 120 singleton pregnancies were booked for pregnancy care at our hospital, of which 1546 had an invasive procedure. We excluded 1429 (3.2%) pregnancies due to fetal defects, termination of pregnancy or missing outcomes. Of the 43 691 pregnancies included in the study population, 861 underwent CVS and 375 amniocentesis. In pregnancies that underwent CVS, the risk of miscarriage was 1.5% (13/861), compared with 1.2% (476/39 152) in pregnancies that had first-trimester combined screening and did not have an invasive procedure (P = 0.437). In pregnancies that underwent an amniocentesis, the risk of miscarriage was 0.8% (3/375), compared with 1.2% (491/42 463) in those that did not undergo an invasive procedure (P = 0.520). Univariate and multivariate regression analysis demonstrated that there was no significant contribution in the prediction of the risk of miscarriage from CVS (P = 0.399 and P = 0.592, respectively) or amniocentesis (P = 0.543 and P = 0.550, respectively). The risk of procedure-related loss attributed to CVS was 0.29% (95% CI, −0.53 to 1.12%) and that following amniocentesis was −0.36% (95% CI, −1.26 to 0.55%), which was not significantly different from the risk in women who did not have any procedure. Conclusions The procedure-related risks of miscarriage following CVS and amniocentesis in our study are considerably lower than those currently quoted and are consistent with the estimates of such risks reported by systematic reviews and meta-analyses.

Link

https://obgyn-onlinelibrary-wiley-com.york.ezproxy.cuny.edu/doi/pdfdirect/10.1002/uog.20293

Abstract #2

ObjectiveTo estimate the procedure‐related risk of miscarriage after amniocentesis and chorionic villus sampling (CVS) based on a systematic review of the literature and an updated meta‐analysis.MethodsA search of MEDLINE, EMBASE and The Cochrane Library was carried out to identify studies reporting complications following CVS or amniocentesis. Eligible for inclusion were large controlled studies reporting data for pregnancy loss prior to 24 weeks’ gestation. Study authors were contacted when required to identify additional necessary data. Data for cases that had an invasive procedure and controls were inputted into contingency tables and the risk of miscarriage was estimated for each study. Summary statistics based on a random‐effects model were calculated after taking into account the weighting for each study included in the systematic review. Procedure‐related risk of miscarriage was estimated as a weighted risk difference from the summary statistics for cases and controls. Subgroup analyses were performed according to the similarity in risk levels for chromosomal abnormality between the invasive‐testing and control groups. Heterogeneity was assessed using the I2 statistic. Egger’s bias was estimated to assess reporting bias in published studies.ResultsThe electronic search yielded 2943 potential citations, from which 12 controlled studies for amniocentesis and seven for CVS were selected for inclusion in the systematic review. A total of 580 miscarriages occurred following 63 723 amniocentesis procedures, resulting in a weighted risk of pregnancy loss of 0.91% (95% CI, 0.73–1.09%). In the control group, there were 1726 miscarriages in 330 469 pregnancies with a loss rate of 0.58% (95% CI, 0.47–0.70%). The weighted procedure‐related risk of miscarriage following amniocentesis was 0.30% (95% CI, 0.11–0.49%; I2 = 70.1%). A total of 163 miscarriages occurred following 13 011 CVS procedures, resulting in a risk of pregnancy loss of 1.39% (95% CI, 0.76–2.02%). In the control group, there were 1946 miscarriages in 232 680 pregnancies with a loss rate of 1.23% (95% CI, 0.86–1.59%). The weighted procedure‐related risk of miscarriage following CVS was 0.20% (95% CI, −0.13 to 0.52%; I2 = 52.7%). However, when studies including only women with similar risk profiles for chromosomal abnormality in the intervention and control groups were considered, the procedure‐related risk for amniocentesis was 0.12% (95% CI, −0.05 to 0.30%; I2 = 44.1%) and for CVS it was −0.11% (95% CI, −0.29 to 0.08%; I2 = 0%).ConclusionsThe procedure‐related risks of miscarriage following amniocentesis and CVS are lower than currently quoted to women. The risk appears to be negligible when these interventions were compared to control groups of the same risk profile.

Link

https://obgyn.onlinelibrary.wiley.com/doi/full/10.1002/uog.20353

Abstract #3

BackgroundDuring pregnancy, fetal cells suitable for genetic testing can be obtained from amniotic fluid by amniocentesis (AC), placental tissue by chorionic villus sampling (CVS), or fetal blood. A major disadvantage of second trimester amniocentesis is that the results are available relatively late in pregnancy (after 16 weeks’ gestation). Earlier alternatives are chorionic villus sampling (CVS) and early amniocentesis, which can be performed in the first trimester of pregnancy.ObjectivesThe objective of this review was to compare the safety and accuracy of all types of AC (i.e. early and late) and CVS (e.g. transabdominal, transcervical) for prenatal diagnosis.Search methodsWe searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (3 March 2017), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP; 3 March 2017), and reference lists of retrieved studies.Selection criteriaAll randomised trials comparing AC and CVS by either transabdominal or transcervical route.Data collection and analysisTwo review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach.Main resultsWe included a total of 16 randomised studies, with a total of 33,555 women, 14 of which were deemed to be at low risk of bias. The number of women included in the trials ranged from 223 to 4606.Studies were categorized into six comparisons: 1. second trimester AC versus control; 2. early versus second trimester AC; 3. CVS versus second trimester AC; 4. CVS methods; 5. Early AC versus CVS; and 6. AC with or without ultrasound.One study compared second trimester AC with no AC (control) in a low risk population (women = 4606). Background pregnancy loss was around 2%. Second trimester AC compared to no testing increased total pregnancy loss by another 1%. The confidence intervals (CI) around this excess risk were relatively large (3.2% versus 2.3 %, average risk ratio (RR) 1.41, 95% CI 0.99 to 2.00; moderate‐quality evidence). In the same study, spontaneous miscarriages were also higher (2.1% versus 1.3%; average RR 1.60, 95% CI 1.02 to 2.52; high‐quality evidence). The number of congenital anomalies was similar in both groups (2.0% versus 2.2%, average RR 0.93, 95% CI 0.62 to 1.39; moderate‐quality evidence).One study (women = 4334) found that early amniocentesis was not a safe early alternative compared to second trimester amniocentesis because of increased total pregnancy losses (7.6% versus 5.9%; average RR 1.29, 95% CI 1.03 to 1.61; high‐quality evidence), spontaneous miscarriages (3.6% versus 2.5%, average RR 1.41, 95% CI 1.00 to 1.98; moderate‐quality evidence), and a higher incidence of congential anomalies, including talipes (4.7% versus 2.7%; average RR 1.73, 95% CI 1.26 to 2.38; high‐quality evidence).When pregnancy loss after CVS was compared with second trimester AC, there was a clinically significant heterogeneity in the size and direction of the effect depending on the technique used (transabdominal or transcervical), therefore, the results were not pooled. Only one study compared transabdominal CVS with second trimester AC (women = 2234). They found no clear difference between the two procedures in the total pregnancy loss (6.3% versus 7%; average RR 0.90, 95% CI 0.66 to 1.23, low‐quality evidence), spontaneous miscarriages (3.0% versus 3.9%; average RR 0.77, 95% CI 0.49 to 1.21; low‐quality evidence), and perinatal deaths (0.7% versus 0.6%; average RR 1.18, 95% CI 0.40 to 3.51; low‐quality evidence). Transcervical CVS may carry a higher risk of pregnancy loss (14.5% versus 11.5%; average RR 1.40, 95% CI 1.09 to 1.81), but the results were quite heterogeneous.Five studies compared transabdominal and transcervical CVS (women = 7978). There were no clear differences between the two methods in pregnancy losses (average RR 1.16, 95% CI 0.81 to 1.65; very low‐quality evidence), spontaneous miscarriages (average RR 1.68, 95% CI 0.79 to 3.58; very low‐quality evidence), or anomalies (average RR 0.68, 95% CI 0.41 to 1.12; low‐quality evidence). We downgraded the quality of the evidence to low due to heterogeneity between studies. Transcervical CVS may be more technically demanding than transabdominal CVS, with more failures to obtain sample (2.0% versus 1.1%; average RR 1.79, 95% CI 1.13 to 2.82, moderate‐quality evidence).Overall, we found low‐quality evidence for outcomes when early amniocentesis was compared to transabdominal CVS. Spontaneous miscarriage was the only outcome supported by moderate‐quality evidence, resulting in more miscarriages after early AC compared with transabdominal CVS (2.3% versus 1.3%; average RR 1.73, 95% CI 1.15 to 2.60). There were no clear differences in pregnancy losses (average RR 1.15, 95% CI 0.86 to 1.54; low‐quality evidence), or anomalies (average RR 1.14, 95% CI 0.57 to 2.30; very low‐quality evidence).We found one study that examined AC with or without ultrasound, which evaluated a type of ultrasound‐assisted procedure that is now considered obsolete.Authors’ conclusionsSecond trimester amniocentesis increased the risk of pregnancy loss, but it was not possible to quantify this increase precisely from only one study, carried out more than 30 years ago.Early amniocentesis was not as safe as second trimester amniocentesis, illustrated by increased pregnancy loss and congenital anomalies (talipes). Transcervical chorionic villus sampling compared with second trimester amniocentesis may be associated with a higher risk of pregnancy loss, but results were quite heterogeneous.Diagnostic accuracy of different methods could not be assessed adequately because of incomplete karyotype data in most studies.

Link

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003252.pub2/full

Abstract #4

Introduction: Introduction: To estimate the procedure-related risks of pregnancy loss following chorionic villus sampling (CVS) and amniocentesis (AC) compared to pregnancies without procedure. Methods: This cohort study enrolled all women who underwent CVS or AC at the Department of Perinatology, University Medical Centre, Ljubljana, Slovenia (from January 2013 to June 2015). For each group we obtained a maternal age and gestational age (11–14 weeks for CVS and >15 weeks for AC) for a matched control group without invasive procedures from the national database. The data was obtained from hospital records and telephone surveys concerning pregnancy outcomes. Pregnancy loss rates in intervention vs. control groups were compared by generating relative risk (RR) with a 95% confidence interval. Results: During the study period, 828 women underwent CVS and 2,164 women underwent AC. Complete outcome data was available in 2,798 cases (93.5%, 770 CVS, 2,028 AC). Pregnancy loss occurred in 8/770 (1.04%, 95% CI 0.4–2.0%) after CVS vs. 15/1130 (1.33%, 95% CI 0.8–2.2%) in matched control (RR 0.8, 95% CI 0.33–1.8, p=0.6). It occurred in 16/2028 (0.79%, 95% CI 0.5–1.3%) after AC vs. 14/395 (3.29%, 95% CI 2.1–5.8%) in matched control (RR 0.2, 95% CI 0.11–0.45, p

Link

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780764/

Author (Date)	Level of Evidence	Sample/Setting(# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
J. BETA, W. ZHANG, S. GERIS, V. KOSTIV, and R. AKOLEKAR(2019)	Retrospective Cohort Study	In total the study included 43,691 pregnancies. Of them, 861 underwent a CVS and 375 underwent an amniocentesis.	Estimating the procedure-related risks of miscarriage via CVS and amniocentesis.	Ultimately, 43,691 women were included in the study. The data was obtained from January 1, 2009 to May 31, 2018. CVS is offered as the procedure of choice for women who are at high risk for fetal aneuploidy or a major fetal defect and an amniocentesis is offered after that gestational age. Miscarriage is defined as pregnancy loss prior to 24 weeks of gestation. Interestingly, in the women that did have miscarriages they had a smaller median maternal height, were more of Afro-Caribbean, South Asian, East Asian or mixed racial origin, and more women had conceived following assisted conception. In the study the risk of miscarriage following an CVS was 1.5% compared to 1.3%. Following an amniocentesis the risk of miscarriage was .8% compared with 1.2% for women who did not have an invasive procedure during their pregnancy. Ultimately, it found that there was no significant increase in the risk of miscarriage following either of these procedures than pregnancies that do not undergo invasive procedures.	The limitation related to the idea of the retrospective study and there potentially could have been selection bias when it came to choosing cases. Also these procedures were all done transabdominally and therefore the study only focuses on transabdominal procedures. It presents as no issues when comparing with other studies.
L. J. Salomon  A. Sotiriadis  C. B. Wulff  A. Odibo  R. Akolekar(2019)	Systematic Review and meta-analyses	12 controlled studies followed the risks of amniocentesis and seven studies were selected for CVS.	The study tried to calculate the risk that an amniocentesis or CVS would have on pregnancy.	Twelve controlled studies for amniocentesis and seven studies for CVS were selected to be included. In the control group there were 1726 miscarriages in 330,469 pregnancies for a rate of 0.58%. A total of 580 miscarriages occurred following 63,723 amniocentesis procedures for a  rate of 0.91%. A total of 163 miscarriages occurred following 13,011 CVS procedures resulting in a loss risk of 1.39%. Although, CVS has a higher rate the study found that there is no higher risk for miscarriage in CVS than in an amniocentesis. The procedure related risks of miscarriage following the procedures mentioned above are ultimately, insignificant in their risk for miscarriage.	A limitation of this study is that the comparison of the risks of miscarriage between the two groups was mainly for high-risk women and therefore the study cannot comment on low-risk patients.
Zarko AlfirevicKate NavaratnamFaris Mujezinovic(2017)	Cochrane Study	16 randomized studies, with a total of 33,555 women.	To see if an amniocentesis or CVS would put a pregnant woman at greater risk for having a miscarriage.	Very often parents want to be reassured that their fetus is healthy. And it is important to ensure that tests used to rule out an abnormal fetus is healthy and safe for both the mother and the fetus. The study ultimately included 16 randomized controlled trials (which totaled 33,555 women). In one of the 16 studies it was found that second trimester amniocentesis increased spontaneous miscarriages and pregnancy losses. However, the estimate was still very low and not very precise and was maximum 2%. Early amniocenteses was not as safe as second trimester. Ultimately, the article supports the use of second trimester amniocentesis as the procedure of choice for testing a fetus. It found that transcervical CVS may increase the loss of pregnancy when compared to second trimester amniocenteses.	For one of the studies the proportion of the cases where the operator deviated from the allocated procedure increased during the study.
Ivana PALJK LIKAR1,2, Ksenija SLAVEC JERE1 , Teja MOŽINA1 , Ivan VERDENIK1 , Nataša TUL3* (2020)	Cohort Study	828 women underwent a CVS and 2,164 women underwent amniocentesis	The study was to estimate the risk of pregnancy loss following an amniocentesis and chorionic villus sampling compared to women who did not receive this procedure	Ultimately, the study found that loss of pregnancy between both the control group and the group that received the procedures were similar. Therefore, women should be counseled that when needed these procedures are safe.	The limitations stated by the reviewers included “biases introduced owing to differences in study design, inclusion of studies carried out over a period of time, publication bias, heterogeneity between studies and methods used for the analysis of data”. Furthermore, the reviewers specified that they were unable to derive estimates of procedure‐related loss due to the “inability to adjust for maternal and pregnancy characteristics in the invasive and control groups”. This limits the ability to generalize findings for use of this data for the purpose of counselling mothers.

Conclusion:

1. There is ultimately no significant risk in these procedures causing increased pregnancy loss when compared with women who did not receive these procedures.
2. The two procedures, CVS and amniocentesis do not pose a significant risk in causing miscarriage. CVS has a slightly higher percentage than that of amniocentesis.
3. Early amniocentesis is more dangerous and poses a greater risk to pregnant women. Second trimester amniocentesis is safe and does not pose a significant risk for miscarriage. CVS falls into this category as well, but it found that transcervical CVS may increase the loss of pregnancy when compared to second trimester amniocentesis.
4. CVS and amniocentesis are both safe in pregnancy and their rates of losses in pregnancy were comparable to the rates in women who did not receive these procedures. Women should be educated that these tests are safe when they are necessary.

Overall conclusion: If a woman, who is healthy, young and with no risk factors comes in to the office concerned about these tests you could very strongly explain that these tests, while invasive, do not pose extreme risk for miscarriage. It would be interesting to further delve into the research to really break down on what type of women had the miscarriages after these tests to see if their maternal age or other co-morbidities came into play. Ultimately, I would tell the woman who entered the office not to be concerned about the risk of a potential miscarriage due to her medical history.

Weight of evidence:

1. This article was a retrospective cohort study and was published recently. It had a large unselected cohort of consecutively screened pregnancies. The procedures were each carried out by a specialist or supervised by a specialist. This study had to deal with the possibility of recall bias and also this study only focused on procedures that were performed transabdominally. Therefore, the results are only geared towards the risks that arise from transabdominal procedures.
2. This study was a systematic review and meta-analysis which contributes to the weight of the article. It also had a sample size to be able to truly gain  great insight into the risks of these procedures. It was published very recently and added to the validity of the study. It also compared the risk between CVS and amniocentesis which I appreciated. Each study included in this meta-analysis. The issue of heterogeneity was addressed via different measures.
3. This article was a Cochrane review which I valued as a high level of evidence. This article was also published fairly recently though it was the latest article that I provided. Due to the different in skill levels of the providers the study decided to apply random-effects for all analyses. They could not assume that each study was estimating the same treatment effect or intervention and that the methods were similar. Also because there were so few studies that were included in this review  they did not perform any subgroup analyses because they didn’t feel that that review would be meaningful and so there were no sub-analyses results provided in the study.
4. The last article chosen was published very recently and is a cohort study which supports the weight of evidence. It is important to note that this study took place in a foreign country. Although, this study did not focus on the United States I still believe because of the type of study, the publishing date and the studies that were included, we could hold this study with much weight. The study interestingly noted that it was impossible to adjust for pregnancy and maternal characteristics for the two groups. Therefore, it wasn’t possible to generalize the different findings in order to counsel the pregnant mothers.

Magnitude of effects: The magnitude of the articles was not large. All of the studies ultimately agreed that there was no significant difference in these two procedures and their impact on pregnancy loss. The second and third article did note that the while there is no significant difference the risk of CVS is slightly greater than the risk of an amniocentesis.

Clinical Bottom Line:

The clinical bottom line that I have derived from these articles is that while an amniocentesis and CVS are both invasive procedures, they do not put the mother at an increased risk for pregnancy loss that a mother should deny these tests. They do put mothers at an increased risk for anxiety and stress, due to the nature of the procedure and the pending results of the tests. The expenses for an amniocentesis and CVS are both usually covered by Medicaid for each state. There are only 2 states that don’t cover amniocentesis and 3 states that don’t cover a CVS. If a mother lives in a state that does not cover the cost it could range up to $7,000. It is also important to guide the patient that the tests may be uncomfortable but the pain is tolerable. Most of the studies noted that the higher maternal age or higher comorbidities was directly correlated to a higher level of anxiety or pain in the procedures. Each patient should be educated on these aspects of the tests and their medical history should be taken into account when counseling the patient.