Amniocentesis not only increases the miscarriage risk but also causes long-term adverse perinatal outcomes

doi:10.21203/rs.3.rs-4161442/v1

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Amniocentesis not only increases the miscarriage risk but also causes long-term adverse perinatal outcomes

https://doi.org/10.21203/rs.3.rs-4161442/v1

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Background

This study aimed to evaluate the short- and long-term pregnancy outcomes of pregnant women who underwent amniocentesis.

Methods

In this retrospective cohort study, pregnancy outcomes of 2044 pregnant women who underwent amniocentesis and 7668 pregnant women who underwent non-invasive prenatal testing (NIPT) as a control group were evaluated using single center data. Perinatal outcomes of 377 amniocentesis and 2063 NIPT cases, whose birth data were available, were analyzed. Structural and genetic anomalies, maternal additional diseases and multiple pregnancies were excluded from the study. Pregnancy and perinatal outcomes, including fetal loss, preterm birth (PTB), pregnancy-induced hypertensive diseases (PIHD), low birth weight (LBW), small for gestational age (SGA), and low APGAR scores (< 7) were evaluated.

Results

Miscarriage (< 24 weeks) (0.68%) and intrauterine fetal demise (> 24 weeks) (0.88%) were significantly higher in amniocentesis cases (p = 0.005 and p < 0.001, respectively). PTB (< 37 weeks), extremely PTB (< 28 weeks), and late PTB (34–37 weeks) were higher in amniocentesis cases (p < 0.001, p = 0.011, and p < 0.001, respectively). Adverse neonatal outcomes, including SGA, LBW, and low APGAR scores (1st and 5th minutes), were higher in amniocentesis cases (p < 0.001, p = 0.014, and p < 0.001, respectively). There was no significant difference in PIHD between the two groups (p = 0.287).

Conclusions

Our findings showed that, apart from fetal loss, amniocentesis may lead to adverse perinatal outcomes such as PTB, LBW, SGA and low APGAR scores. However, further studies evaluating long-term pregnancy outcomes associated with the procedure are needed.

amniocentesis

non-invasive prenatal testing

fetal loss

preterm delivery

birth weight

perinatal outcomes

Amniocentesis is a prenatal diagnostic technique in which fetal cell samples are invasively obtained from amniotic fluid to examine the fetal genetic structure. It is the most commonly preferred prenatal diagnosis test, recommended for application after 15 weeks of gestation (1). Screening for fetal genetic diseases is important in prenatal follow-up, and prenatal screening has improved significantly over the last 20 years, especially for Down syndrome. The prenatal diagnosis of fetal chromosomal abnormalities in a fetus with risk factors for a genetic disorder provides information to the families about the fetus's preparation for birth and future outcomes. Prenatal diagnostic tests also help the clinicians to accurately diagnosing cases for further management planning. Most families want to make sure that a fetus at risk of genetic anomalies is healthy. However, in order to provide this assurance, it is important to provide accurate evidence-based information regarding the complications of these invasive procedures (2).

The most important complication of invasive procedures is fetal loss (3). However, there is still significant variation in the advice of professional organizations regarding the risk of fetal loss associated with transfer procedures to women. There is also significant evidence to suggesting that the risk of procedure-related fetal loss is much lower than currently stated by professionals (4–7). Recent studies have reported significantly smaller risks of fetal loss after amniocentesis, ranging from 0.06–0.13% (8, 9). Additionally, studies showing that this risk is even smaller after chorionic villus sampling (CVS) have been presented (10). Due to conflicting results of studies, the procedure-related loss rate after invasive tests is controversial. The main reason for this is methodological differences in retrospective controlled studies. Additionally, there are studies showing that maternal age, gestational age, multiple needle punctures, operator experience, and fetal genetic and structural anomalies are risk factors associated with these complications. The impact of these confounding factors on results varies between studies (3, 10).

A limited number of studies have examined the long-term outcomes of prenatal diagnostic tests during pregnancy. The study, published by the EuroPOP group revealed a significant difference in the prevalence of preterm birth in women who underwent amniocentesis (11). Some authors have suggested that CVS is associated with the subsequent development of preeclampsia in women (12, 13). Wisetmongkolchai et al. also suggested that low birth weight and fetal growth restriction increase in association with operator experience after amniocentesis (14). The most common indications for diagnostic testing are first-trimester screening test positivity and advanced maternal age (15). Additionally, advanced maternal age and first trimester screening test serum markers have been shown to be associated with adverse pregnancy outcomes (16).

Our aim was to examine our single-center data on short- and long-term pregnancy outcomes of women who underwent amniocentesis by determining pregnant women with similar characteristics who underwent Noninvasive Prenatal Test (NIPT) as a control group.

This retrospective cohort study utilized data collected between January 2016 and December 2021 at the Department of Perinatology, University of Health Sciences Tepecik Training and Research Hospital, Turkey. The study received approval from the local ethics committee (Approval No: 2022/01–12) and written informed consent was obtained from each participant. The study included 2044 pregnant women who underwent amniocentesis for prenatal diagnosis. During the same period, 7668 pregnant women who underwent a NIPT in our hospital and whose pregnancy outcomes were determined as a control group. Exclusion criteria for the study included multiple pregnancies, fetal structural or genetic anomalies, suspected fetal infection, parental genetic abnormalities, maternal chronic disease, and missing data. The study assessed pregnancy outcomes for both groups and perinatal outcomes for women delivering at the hospital, as illustrated in Fig. 1.

Indications for amniocentesis were based on positive first- and second-trimester screening (> 1:1000), maternal age, maternal anxiety/request, and positive ultrasonographic markers for aneuploidies. The procedures were performed by perinatology residents in the last two years of their training under supervision. In all procedures, local antiseptic was applied to the skin without the use of anesthesia. Amniocentesis procedures were performed beyond the 15th week of gestation by inserting a 22 G needle transabdominally under ultrasound guidance. Depending on the indication, 15-25mL of fluid was aspirated. Ultrasound guidance was performed using the Samsung Ultrasound System HS70A (Samsung Medison Company, Republic of Korea) equipped with an abdominal 4–8 MHz curvilinear transducer.

NIPT was performed free of charge for pregnant women within the scope of health insurance at the Genetic Diagnosis Center of our hospital. NIPT was not a primary aneuploidy screening test. Indications for NIPT included; positive aneuploidy screening tests (> 1:1000), advanced maternal age (≥ 35 years), sonographic markers of aneuploidy, and maternal anxiety. Cases were examined by NextSeq (Illumina, USA) or MiSeq (Illumina, USA) next-generation sequencing platforms. The low fetal fraction threshold for not reporting the test was determined as 2.8, and no results were provided in cases below 2.8. (17).

Pregnancy outcomes of women who underwent NIPT and amniocentesis were examined from the hospital's digital registration system. Adverse pregnancy outcomes included; miscarriage, intrauterine fetal demise (IUD), preterm delivery, pregnancy-induced hypertensive diseases (PIHD), and low APGAR scores. Based on the birth weight of newborns, those below the 10th percentile were classified as small for gestational age (SGA), those between the 10th and 90th percentiles were classified as appropriate for gestational age (AGA), and those greater than the 90th percentile were classified as large for gestational age (LGA) (18). Additionally, newborns with a birth weight below 2500 g were classified as low birth weight (LBW), and newborns with a birth weight above 4000 g were classified as macrosomia. Miscarriage was defined as death of the fetus before 24 weeks of gestation. IUD was defined as fetal death ≥ 24 weeks, prior to delivery. PIHD, encompassing gestational hypertension and preeclampsia, was defined according to the International Society for the Study of Hypertension in Pregnancy guidelines (19). Preterm birth (PTB) was defined as delivery at < 37 weeks' gestation, and there are subcategories of preterm birth based on gestational age: extremely preterm (< 28 weeks), very preterm (28–32 weeks), moderately preterm (32–34 weeks), and late preterm (34–37 weeks). Newborns with APGAR values < 7 at 1st and 5th minutes were considered to have low APGAR scores.

Statistical analyses

Statistical Package for Social Sciences version 26.0 (IBM Corporation, Armonk, New York, USA) was used for statistical analysis of the data, and a significance level of p < 0.05 was adopted for all analyses. Student's T test was used to evaluate parametric data, and the results are presented as mean ± SD. Comparison of categorical variables between groups was made using the chi-square test, and data are presented as n, %.

A total of 7668 pregnancies that underwent NIPT and 2044 pregnancies that underwent amniocentesis were examined. Perinatal and neonatal outcomes were evaluated for 2063 pregnant women whose birth data were available and who underwent NIPT, and 377 pregnant women who underwent amniocentesis. The demographic and clinical characteristics of pregnant women in both groups are presented in Table 1. Mean maternal age and mean body mass index (BMI) were similar in both groups (p = 0.120 and p = 0.220, respectively). Multiparity was significantly higher in amniocentesis cases (82.2% vs 73.4%, p < 0.001). Gestational age at delivery was significantly higher in NIPT cases (38.1 ± 2.8 vs 36.8 ± 3.1, p < 0.001). Cesarean section rate was significantly higher in amniocentesis cases (76.7% vs 63.5%, p < 0.001). Mean birth weight was significantly higher in NIPT cases (3105.9 ± 644.4 vs 2913 ± 751, p < 0.001).

Table 1

Demographic and clinical characteristics of the study population
	Non-Invasive Prenatal Test n = 2063	Amniocentesis n = 377	p
Maternal age (year)	32 ± 6.5	31 ± 7	0.120
BMI (kg/m2)	26.6 ± 5.1	26.3 ± 4.5	0.220
Parity		-
Nulliparous	548 (26.6%)	67 (17.8%)	< 0.001
Multiparous	1515 (73.4%)	310 (82.2%)
Gestational age at delivery (weeks)	38.1 ± 2.8	36.8 ± 3.1	< 0.001
Delivery type		-	< 0.001
Vaginal delivery	753 (36.5%)	88 (23.3%)
Cesarean section	1310 (63.5%)	289 (76.7%)
Birth weight (g)	3105.9 ± 644.4	2913 ± 751	< 0.001
BMI: Body mass index

Maternal and perinatal adverse outcomes of both groups are presented in Table 2. The PTB (< 37 weeks) rate was significantly higher in amniocentesis cases. Extremely preterm birth (< 28 weeks) was significantly higher in amniocentesis cases (3.4% vs 1.5%; p = 0.011). Additionally, late preterm delivery (34–37 weeks) was significantly higher in amniocentesis cases (23.1% vs 11.5%; p < 0.001). There was no significant difference in PIHD between the two groups (p = 0.287). Composite maternal and perinatal adverse outcomes, including the presence of at least one of PTB and PIHD, were significantly higher in amniocentesis cases (p < 0.001).

Table 2

Comparison of maternal and perinatal adverse outcomes
		Non-Invasive Prenatal Test n = 2063		Amniocentesis n = 377		p
		n	%	n	%
PTB	No	1702	82.5%	257	68.2%	< 0.001
PTB	Yes	361	17.5%	120	31.8%	< 0.001
Extremely preterm (< 28 weeks)	No	2031	98.5%	364	96.6%	0.011
Extremely preterm (< 28 weeks)	Yes	32	1.5%	13	3.4%	0.011
Very preterm (28–32 weeks)	No	2011	97.5%	364	96.6%	0.303
Very preterm (28–32 weeks)	Yes	52	2.5%	13	3.4%	0.303
Moderately preterm (32–34 weeks)	No	2008	97.4%	370	98.1%	0.358
Moderately preterm (32–34 weeks)	Yes	55	2.6%	7	1.9%	0.358
Late preterm (34–37 weeks)	No	1826	88.5%	290	76.9%	< 0.001
Late preterm (34–37 weeks)	Yes	237	11.5%	87	23.1%	< 0.001
PIHD	No	1851	89.8%	345	91.5%	0.287
PIHD	Yes	212	10.2%	32	8.5%	0.287
Composite maternal and perinatal adverse outcomes	No	1565	74.8%	238	63.1%	< 0.001
Composite maternal and perinatal adverse outcomes	Yes	528	25.2%	139	36.9%	< 0.001
PTB: Preterm birth, PIHD: Pregnancy-induced hypertensive diseases
Composite maternal and perinatal adverse outcomes includes: Presence of at least one of the adverse outcome; preterm birth, pregnancy-induced hypertensive diseases

The analysis of fetal and neonatal adverse outcomes for both groups is presented in Table 3. Miscarriage was significantly higher in amniocentesis cases (0.68% vs 0.27%, p = 0.005). IFD was also significantly higher in amniocentesis cases (0.88% vs 0.22%, p < 0.001). LBW was significantly higher in amniocentesis cases (23.6% vs 2.8%, p < 0.001). In intrauterine fetal development, SGA newborns were higher in amniocentesis cases, and LGA newborns were higher in NIPT cases (p = 0.014 and p = 0.024, respectively). Low APGAR scores (1st and 5th minutes) were significantly higher in amniocentesis cases (p < 0.001 for both). Composite fetal and neonatal adverse outcomes, including the presence of at least one of the following adverse outcomes: low birth weight, small for gestational age, 1st minute APGAR scores < 7 and 5th minute APGAR scores < 7, were significantly higher in amniocentesis cases (32.3% vs 17.3%, p < 0.001).

Table 3

Comparison of fetal and neonatal adverse outcomes
		Non-Invasive Prenatal Test n = 2063		Amniocentesis n = 377		p
		n	%	n	%
No *		7630	99.51%	2012	98.44%	< 0.001
Miscarriage *		21	0.27%	14	0.68%	0.005
Intrauterine fetal demise *		17	0.22%	18	0.88%	< 0.001
LBW (< 2500 grams)	No	2005	97.2%	288	76.4%	< 0.001
LBW (< 2500 grams)	Yes	58	2.8%	89	23.6%	< 0.001
2500–4000 grams	No	170	8.2%	104	27.6%	< 0.001
2500–4000 grams	Yes	1893	91.8%	273	72.4%	< 0.001
Macrosomia (≥ 4000 grams)	No	1951	94.6%	362	96%	0.243
Macrosomia (≥ 4000 grams)	Yes	112	5.4%	15	4%	0.243
SGA	No	1855	89.9%	323	85.7%	0.014
SGA	Yes	208	10.1%	54	14.3%	0.014
AGA	No	549	26.6%	99	26.3%	0.886
AGA	Yes	1514	73.4%	278	73.7%	0.886
LGA	No	1722	83.5%	332	88.1%	0.024
LGA	Yes	341	16.5%	45	11.9%	0.024
1st minute APGAR scores < 7	No	1876	90.9%	322	85.4%	< 0.001
1st minute APGAR scores < 7	Yes	187	9.1%	55	14.6%	< 0.001
5th minute APGAR scores < 7	No	2014	97.6%	352	93.4%	< 0.001
5th minute APGAR scores < 7	Yes	49	2.4%	25	6.6%	< 0.001
Composite fetal and neonatal adverse outcomes	No	1705	82.7%	259	68.7%	< 0.001
Composite fetal and neonatal adverse outcomes	Yes	358	17.3%	118	32.3%	< 0.001
LBW: Low birth weight, SGA: Small for gestational age, AGA: Appropriate for gestational age, LGA: Large for gestational age
Composite fetal and neonatal adverse outcomes includes: Presence of at least one of the adverse outcome; low birth weight, small for gestational age, 1st minute APGAR scores < 7, 5th minute APGAR scores < 7.
* The number of participants in the non-invasive prenatal test group was n = 7668, and the number of participants in the amniocentesis group was n = 2044.

In this study, we evaluated the pregnancy and neonatal outcomes of cases who underwent amniocentesis, comparing them with NIPT cases with similar indications. Miscarriage and IFD were significantly higher in amniocentesis cases. PTB (< 37 weeks), extremely PTB (< 28 weeks), and late PTB (34–37 weeks) were higher in amniocentesis cases. Additionally, adverse neonatal outcomes, including SGA, LBW, and low APGAR scores, were higher in amniocentesis cases. We also investigated the association between PIHD and amniocentesis but did not find a significant association.

Amniocentesis is the most common procedure in prenatal diagnosis, and its most serious complication is pregnancy loss. Previous studies have reported procedure-related pregnancy loss rates ranging from 0.19–1.53% (10). However, most studies included mixed populations, which may affect complication rates. The first prospective randomized study by Tabor et al showed that the procedure-related risk for the safety of amniocentesis was 1% (20). Twenty-two years later, the same author published data reporting a fetal loss rate of 0.5% from 32,852 women who underwent amniocentesis (21). The authors used a selected control group without amniocentesis as a background risk of fetal loss. They showed that gestational age at the time of the procedure and the experience of the departments affected complication rates. Backer et al., in their studies including a control group, showed that the risk of fetal loss was in the range of 0.17–0.52% and tended to decrease with operator experience (22). Beta et al. demonstrated that the fetal loss rate due to amniocentesis was 0.36% and showed that advanced maternal age, weight, height, race, assisted reproductive technology, chronic hypertension, and serum pregnancy associated plasma protein-A (PAPP-A) multiples of the median (MoM) ≤ 0.3 were associated with the risk of miscarriage (23). In our study, we evaluated procedure-related fetal loss rates in patient groups with similar risk factors. The risk of fetal loss was 0.68% before the 24th week and 0.88% after the 24th week. Although the demographic characteristics of the participants and test indications were similar, the study had limitations due to its retrospective design. Our study did not include maternal serum PAPP-A levels. Additionally, data on the mode of conception were not included in the study.

There were few studies evaluating perinatal outcomes after amniocentesis procedures and they contained conflicting results. In the first study to evaluate the risk of PTB after amniocentesis, Tongsong et al. suggested that there was no increased risk of procedure-related PTB (24). Similarly, Tabor et al. found no increased risk of PTB in a randomized controlled study involving 4606 women (20). Despite Theodora et al. noting a higher incidence of premature delivery (PTB) after amniocentesis compared to the control group, this difference did not achieve statistical significance (25). In contrast, Sant-Cassia et al., in a matched controlled study, reported a higher rate of PTB after amniocentesis (26). In a study containing multicenter data, the EuroPOP group showed that there was an association between amniocentesis and PTB. The authors hypothesized that amniocentesis may lead to PTB, especially due to a chronic inflammatory response associated with membrane perforation and an increase in metalloproteinase and prostaglandin levels, which are responsible for the onset of labor (11). Consistent with these findings, our study showed that the amniocentesis procedure was associated with an increased risk of PTB. We found that the risk of PTB was significantly higher in the extremely PTB (< 28 weeks) and late PTB (34–37 weeks) subgroups.

In our study, we also evaluated neonatal outcomes and found that LBW, SGA, and low APGAR scores increased significantly in amniocentesis cases. Limited studies have examined neonatal outcomes of pregnancies that underwent amniocentesis. Studies have shown the association of PTB with LBW and lower APGAR scores (27). However, Wisetmongkolchai et al., in their study evaluating the amniocentesis results of expert and non-expert operators, showed that LBW and fetal growth restriction were significantly higher in the non-expert group. The authors concluded that this increased risk may be due to placental damage, considering the multiple needle insertions, long procedure times, and increases in bloody amnion content in the non-expert group (14). In our center, all amniocentesis interventions were performed by non-expert Perinatology residents in the last two years of their training under expert supervision. However, our data did not allow us to establish a link between procedure-related complications and operator experience. Additionally, our study could not provide results on multiple needle insertions, placental needle passage, and amniotic fluid content. Nevertheless, our results indicate that the amniocentesis procedure may be associated with long-term adverse neonatal outcomes beyond fetal loss, underscoring the need for further studies examining such outcomes.

Previous studies have primarily examined the association between prenatal diagnostic tests and PIHD, with a focus on CVS. To our knowledge, no study evaluating the association of the amniocentesis procedure with PIHD has been published yet. Studies evaluating the association between CVS and PIHD presented conflicting results. Maruotti et al. and Odibo et al. suggested that the risk of PIHD was less in cases undergoing CVS (28, 29). On the other hand, studies showing that the risk of PIHD increases in cases where CVS was applied were also presented (30–32). The authors attributed this association to early damage to the placenta that may occur due to the procedure. In our study, we found that there was no association between PIHD and the amniocentesis procedure. As stated in the guidelines, placental needle passage in amniocentesis increases the risk of complications (1). Therefore, there is a need for larger-scale studies examining the relationship between amniocentesis and PIHD, and including procedure duration, placental placement, and needle entry localization data.

This study had some limitations. Most importantly, the study's retrospective data are limited by the type and quality of information contained in the patient records. Perinatal outcomes of women who did not delivery in our center could not be evaluated in both the case and control groups. In addition, details of the procedures such as the number of needle entries, placental placement, and operator differences could not be evaluated. This study also had strengths. Cases with similar risk factors who underwent NIPT testing were determined as the control group. Procedures with indications of structural and genetic anomalies were excluded from the study. Additionally, this study was one of the few studies evaluating the perinatal outcomes of amniocentesis cases.

In conclusion, our study showed that the risk of fetal loss after amniocentesis was significantly higher than the control group (0.68%-0.88%). Additionally, our findings showed that amniocentesis may lead to adverse perinatal outcomes such as PTB, LBW, SGA and, low APGAR scores. However, further studies evaluating long-term pregnancy outcomes associated with the procedure are needed.

Consent for publication: Not applicable.

Acknowledgements: None.

Research funding: None declared.

Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

Competing interests: Authors state no conflict of interest.

Data Availability Statement: Data is not available due to ethical reasons. Further inquiries can be directed to the corresponding author.

Informed consent: Written informed consent was obtained from all individuals included in this study.

Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013), and has been approved by the authors. The study protocol was approved by Health Sciences University Tepecik Training and Research Hospital Ethics Committee (Approval number: (2022/01-12).

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Amniocentesis not only increases the miscarriage risk but also causes long-term adverse perinatal outcomes

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