http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1012061
ORIGINAL ARTICLE
Fetal loss following second trimester amniocentesis. Who is at greater risk? How to counsel pregnant women?
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Marianna Theodora, Aris Antsaklis, Panos Antsaklis, Konstantinos Blanas, Georgios Daskalakis, Michael Sindos, Spiros Mesogitis, and Nikolaos Papantoniou 1st Department of Obstetrics Gynecology, University of Athens, Athens, Greece
Abstract
Keywords
Objective: The purpose of this retrospective observational cohort study was to determine the impact of certain risk factors on fetal loss, after mid-trimester amniocentesis. Material and methods: Six thousand seven-hundred and fifty-two (6752) consecutive amniocenteses with known pregnancy outcome performed during a 7-year period (2004– 2010) were included in this study. Different maternal-, fetal- and procedure-related factors were evaluated in this study. Results: During this 7-year period, 6752 cases who underwent amniocentesis, with complete data available were evaluated for the outcome and risk factors mentioned. Total fetal loss rate (FLR) up to the 24th week was 1.19%. Risk factors associated with increased risk of fetal loss after amniocentesis were maternal age (OR:2.0), vaginal spotting (OR:2.2) and serious bleeding (OR:3.5) during pregnancy, history of 2nd trimester termination of pregnancy (OR:4.0), history of more than three spontaneous (OR:3.0) or surgical first trimester abortions (OR:2.1), fibromas (OR:3.0) and stained amniotic fluid (OR:6.1). Conclusions: Amniocentesis is a safe-invasive procedure for prenatal diagnosis with total FLR of 1.19% in our institution during the study period. The present study has emphasized the significance of certain risk factors for adverse outcome and therefore the need to individualize the risk.
Amniocentesis, fetal loss, risk factors
Introduction Amniocentesis is the oldest invasive procedure in prenatal medicine. It was first used in the end of the nineteenth century for evacuation of excessive amniotic fluid in pregnancies complicated by hydramnion [1]. Since the beginning of the 1950s, it was used to determine the amniotic composition in cases of Rhesus isoimmunization [2]. Amniocentesis was used for diagnostic reasons in the 1950s, as a method for sex determination by the identification of Barr bodies in the noncultured amniocytes [3]. Ten years later, the karyotype of the embryo was determined through a culture of fetal cells derived from the amniotic fluid [4]. Since then, amniocentesis has been established as a basic invasive method for the prenatal diagnosis of various pregnancy-related conditions, such as fetal karyotyping, diagnosis of metabolic or enzymatic diseases, assessment of the severity hemolytic disease, establishment of lung maturity and diagnosis of fetal infections. Although amniocentesis has been applied in prenatal diagnosis for half a century, its potential risk for adverse Address for correspondence: Dr Marianna Theodora, PhD, 1st Department of Obstetrics Gynecology, University of Athens, Vas Sofias 80, Athens 11527, Greece. E-mail: [email protected]
History Received 17 July 2014 Revised 30 November 2014 Accepted 22 January 2015 Published online 9 March 2015
perinatal outcome has not been established. The actual risk of fetal loss accounted to the procedure is yet not clear. Initial evaluation of procedure-related fetal loss rate (FLR) in the 1970s was 0.3–1.5% [5–7]. In the mid-1980s, the only prospective randomized trial showed a risk of 1% [8]. In the past decade, two metanalyses showed a risk of 0.6% [9,10], whereas significantly lower risk (0.03%) has been reported [11]. The diversity in defining the actual risk rate for miscarriage is due to the lack of data coming from randomized trials, as well as the diversity of the methodology and populations studied. It is known that miscarriage does not occur only in association with amniocentesis. Thus, it is essential to take into consideration the background loss rate which is associated with the gestational age, parity and any other underlying risk factors such as pathological conditions of the mother and the fetus as well. It is known that gestational age is an important determinant of the observed FLR, and that the earlier the pregnancy, the greater is the pre-procedure risk of miscarriage. Similarly, we hypothesized that other factors such as bleeding during current pregnancy, history of spontaneous or induced abortions, fibromas and discolored amniotic fluid may be responsible for a higher risk of fetal loss even without any invasive procedure.
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The goal of the present retrospective study was to evaluate the overall fetal loss risk after amniocentesis performed in a tertiary university centre with experienced physicians in a 7-year period and to determine the impact of certain risk factors on the perinatal outcome. To our knowledge, this is one of the few studies with significant number of cases that evaluates these parameters and provides useful information when counseling pregnant women, considering prenatal diagnosis.
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Material and methods Six-thousand seven-hundred and fifty-two (6752) cases of pregnant women who sought prenatal diagnosis for various reasons during the years 2004–2010 were included in this study. Indications for amniocentesis in this group arose from maternal age, 1st and 2nd trimester screening for aneuploidies, positive sonographic markers for aneuploidies and maternal infection with Toxoplasma gondii or Cytomegalovirus. Known metabolic and genetic diseases comprised another group of indications mainly in younger women in our series. Finally, maternal anxiety was the indication for a significant number of procedures. Women with multiple pregnancies were excluded from our study. A thorough medical, family and obstetric history was obtained from the woman and her partner before the procedure. Indication was noted as well as all screening tests previously performed during this pregnancy. Amniocentesis was postponed if bleeding had occurred within 2 weeks prior to the procedure. Women with history of vaginal bleeding during the 1st or early 2nd trimester regardless of the severity of bleeding, but not active bleeding were allowed to have an amniocentesis. A complete anatomical survey of the fetus was carried out before amniocentesis. Terminations due to congenital malformations were not included. The placental site was recorded and transplacental puncture was avoided when feasible. A 22-gauge, 8-cm spinal needle was used in all cases. The procedure was carried out under continuous ultrasonic guidance by means of high definition ultrasound apparatus, equipped with a 3.5-MHz curved linear transducer, by experienced physicians. The invasive procedure itself and related risks were thoroughly explained to the couple and written consent was obtained in all cases. Additionally, couples were informed that we are interested in the outcome of the pregnancy and we provided them with an outcome data form, to be completed by the obstetrician and posted to our department. We also informed them that we would contact them in case that the data form was not received or additional information was needed. Total FLR up to 24th week and its relation to certain risk factors were estimated, using the statistical model of multiple logistic regression analysis. Advanced maternal age, vaginal spotting and/or bleeding during pregnancy, previous history of first or second trimester abortions, fibroids, uterine scars, placental location, blood-stained amniotic fluid and number of needle insertions were risk factors evaluated in this study.
J Matern Fetal Neonatal Med, Early Online: 1–6
Statistical analysis Qualitative variables are presented with absolute and relative frequencies, while quantitative variables are presented with mean and standard deviation (SD). To test the effect of the factors under investigation on fetal loss, univariate logistic regression analyses were used and data were modeled using backward stepwise logistic regression analysis with variable removal set at p ¼ 0.1 and variable entry set at p ¼ 0.05. Odds ratios with 95% confidence intervals (CI) were computed from the results of the logistic regression analyses. Hypothesized interactions of variables in the models were not significant. All p values reported are two-tailed. Statistical significance was set at 0.05 and analyses were conducted using SPSS statistical software (version 13.0, SPSS Inc., Chicago, IL).
Results Seven-thousand two-hundred and twenty (7220) amniocenteses were performed in our center during the seven years period. The outcome of the pregnancy was known in 6752 cases (93.5%). These procedures were performed between 16 + 0 and 19 + 6 weeks of gestation (Table 1). Fetal loss rate was evaluated as the number of miscarriages or intrauterine deaths up to 24 weeks of pregnancy. Terminations of pregnancy due to oligohygramnios and preterm premature rupture of membranes were also included. On the contrary, terminations due to fetal congenital malformations and/or pathology of the fetus were excluded. Mean maternal age was 35.6 years (SD ¼ 4.4 years) and 82.3% of the women (5557/6752) were older than 34 years. Three or more miscarriages during the 1st trimester were recorded in 8.5% (574/6752) of the pregnancies studied. Second trimester termination of pregnancy was noted in 2.5% (169/6752), while first trimester terminations were noted in 25.5% (1722/6752). Spotting and serious hemorrhage during the current pregnancy, was observed in 13.6% (918/6752) and 3.7% (250/6752), respectively. Anterior placenta was observed in 48.4% (3268/6752) of our cases and placental puncture has been avoided in 92% (3006/3268) of these cases. Other characteristics regarding our study population are presented in Table 1. Total FLR up to 24th week was 1.19% (95% CI: 0.92– 1.45). FLR according to all factors under investigation and their impact on adverse pregnancy outcome are presented in Table 2. Fetal loss was significantly greater for women older than 34 years old (1.3%, 72/5557) compared to women younger than 34 years (0.6%, 7/1195). Women with spotting or serious hemorrhage during the current pregnancy had significantly greater fetal loss in univariate analysis compared to those without hemorrhage (2.0% and 3.3%, versus 1.0%, respectively). In our series, FLR after amniocentesis was seriously affected by history of miscarriages and surgical abortions. It is noteworthy that the FLR was 4.0% (5/129) for women with three or more surgical abortions which is significantly greater from the 1% (50/5030) fetal loss observed in women without previous surgical abortions. In a similar way, univariate analysis revealed that three or more 1st trimester
How to counsel pregnant women after amniocentesis?
DOI: 10.3109/14767058.2015.1012061
Table 1. Sample characteristics (N ¼ 6752).
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Table 2. Fetal loss rate (%) and associations derived by univariate logistic regression analysis.
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N (%) Age (years) 534 34 Gestational age at the procedure (weeks) 16 + 0–16 + 6 17 + 0–17 + 6 18 + 0–18 + 6 19 + 0–19 + 9 History of uterine scars No Yes Hemorrhage during this pregnancy No Minor (spotting) Serious No of needle insertions 1 2 Number of surgical abortions None 1–2 3 TOP (415 weeks) No Yes Number of miscarriages in the 1st trimester None 1–2 3 Miscarriages after the 2nd trimester No Yes Indication Maternal age Maternal request High risk for aneuploidies screening test Single genes genetic disorders Other Placenta location Anterior Posterior Uterine fibroids No Yes Stained amniotic fluid No Yes
1195 (17.7) 5557 (82.3)
Fetal loss %
6587 (97.5) 165 (2.5)
Age (years) 534 0.6 34 1.3 History of uterine surgery No 1.1 Yes 1.4 Hemorrhage during pregnancy No 1.0 Minor (spotting) 2.0 Serious 3.3 Number of needle insertions One 1.2 Two 0.6 Number of surgical abortions None 1.0 1–2 1.5 3 4.0 TOP (415 weeks) No 1.1 Yes 3.0 Number of miscarriages in 1st trimester None 1.0 1–2 1.3 3 2.1 Miscarriages after the 2nd trimester No 1.2 Yes 1.6 Indication for amniocentesis Maternal age 1.3 Maternal request 1.6 High-risk result in aneuploidy0.7 screening tests Single gene genetic disorders 0.4 Placenta location Anterior 1.3 Posterior 1.1 Uterine fibroids No 1.1 Yes 3.0 Stained amniotic fluid No 1.1 Yes 6.1
6703 (99.3) 49 (0.7)
OR, odds ratio; CI, 95% confidence interval. *Indicates reference category.
1329 2893 1932 598
(19.7) (42.8) (28.6) (8.9)
5481 (80.7) 1271 (19.3) 5584 (82.7) 918 (13.6) 250 (3.7) 6570 (97.3) 182 (2.7) 5030 (74.5) 1593 (23.6) 129 (1.9) 6583 (97.5) 169 (2.5) 4071 (60.3) 2107 (31.2) 574 (8.5) 6629 (98.1) 123 (1.9) 5054 519 458 701 20
(74.9) (7.7) (6.8) (10.4) (0.3)
3268 (48.4) 3484 (51.6)
miscarriages were associated with increased fetal loss estimated at 2.1% (12/574). Finally, history of terminations of pregnancy in gestational ages of415 weeks was associated with 3.0% (5/169) fetal loss before 24 weeks. The crude odds ratios for the aforementioned factors were 4.07, 2.69 and 2.15, respectively (Table 2). The presence of intramural fibromas also increased the risk of fetal loss after amniocentesis. Women who had fibromas had 3.0% FLR, whereas in cases where myomas were not seen the FLR was 1.1%. One of the most important factors for increased risk of pregnancy loss was stained amniotic fluid. In particular, when old blood-stained amniotic fluid was aspirated during the procedure the risk of pregnancy loss prior to the 24th week was 6.0% (3/49) compared with 1.1% (74/6730) in cases, where the amniotic fluid was clear or fresh blood-stained. Other factors, however, do not seem to have a negative effect on pregnancy outcome. More specifically, gestational
OR (95% CI)
p value
1.0* 2.20 (1.01–4.79)
0.047
1.0 1.25 (0.74–2.13)
0.402
1.0 2.12 (1.24–3.64) 3.51 (1.65–7.47)
0.006 0.001
1.0 0.46 (0.06–3.31)
0.439
1.0 1.46 (0.89–2.4) 4.07 (1.6–10.4)
0.135 0.003
1.0 2.69 (1.07–6.76)
0.035
1.0 1.26 (0.77–2.07) 2.15 (1.12–4.12)
0.365 0.021
1.0 1.39 (0.34–5.71)
0.651
1.0 1.22 (0.58–2.56) 0.52 (0.16–1.65)
0.600 0.265
0.33 (0.1–1.07)
0.065
1.0 0.84 (0.54–1.32)
0.458
1.0 2.71 (1.08–6.80)
0.034
1.0 5.61 (1.71–18.42) 0.005
age at the procedure, history of uterine surgery (previous caesarean section, fibromas excision), indication for amniocentesis, placental location and number of needle insertions did not increase the risk of fetal loss after amniocentesis in our series. Finally, we evaluated if there was any difference in the total fetal loss after amniocentesis over different time periods since the total period of our study covers 7 years and operators’ experience is determinative for pregnancy outcome [10,12]. The total fetal loss after amniocentesis, before 24 weeks was stable in this 7-year period at the rate of 1%. This is due to the extensive experience of the operators in our department. When backward stepwise logistic regression analysis was conducted with fetal loss as the dependent variable, it was found that maternal age 434 years, spotting or serious bleeding, three of more surgical abortions, fibroids and
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J Matern Fetal Neonatal Med, Early Online: 1–6
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Table 3. Odds ratios and 95% confidence intervals derived from multiple logistic regression analysis with fetal loss as the dependent variable.
Age (years) 534 34 Hemorrhage during pregnancy No Minor (spotting) Serious Number of surgical abortions None 1–2 3 Number of miscarriages in 1st trimester None 1–2 3 Uterine fibroid No Yes Stained amniotic fluid No Yes
OR (95% CI)
p value
1.0* 2.19 (1.00–4.77)
0.049
1.0 1.96 (1.14–3.38) 2.74 (1.23–6.11)
0.015 0.014
1.0 1.32 (0.8–2.18) 3.44 (1.32–8.94)
0.280 0.011
1.0 1.25 (0.75–2.06) 1.93 (1.00–3.73)
0.391 0.050
1.0 2.52 (1.01–6.40)
0.048
1.0 3.74 (1.05–13.29)
0.041
OR, odds ratio; CI, 95% confidence interval. *Indicates reference category.
stained amniotic fluid, were risk factors with statistical significance (Table 3). More specifically, maternal age was independently associated with fetal loss, with odds ratio equal to 2.19 (95% CI: 1.00–4.77). Hemorrhage during pregnancy was another independent predictor for fetal loss indicating that women with spotting or serious bleeding had 1.96 and 2.74 times greater odds for fetal loss. Also, the likelihood for fetal loss was 3.44 times greater for women with more than three surgical abortions. The same pattern was found for women with three or more miscarriages in the 1st trimester, with 1.93 times greater odds for fetal loss compared to those with no miscarriages. Multiple regression analysis showed that uterine fibroids and stained amniotic fluid were risk factors that could predict independently fetal loss and the adjusted odds ratios for the aforementioned factors were 2.52 and 3.74.
Discussion Amniocentesis is the most common invasive procedure for prenatal diagnosis. It has been performed for almost half a century and carries a small additional risk for miscarriage, above the background risk estimated for pregnancies without invasive procedures. The actual risk of fetal loss, however, is still blare and different databases report procedure-related miscarriage ranging from 1% in the mid-1980s [8] down to 0.035% recently [11]. The etiology for this differentiation is mainly the absence of prospective randomized trials. Additional reasons for the diversity of results are the diversity of methodology and populations studied. It is accepted that miscarriage does not occur only in association with amniocentesis. When estimating the fetal loss after a procedure, it is essential to take into consideration the background loss rate which is associated with gestational
age, parity and other underlying risk factors such as pathological conditions of the mother and the fetus. In general, the background risk is overestimated because fetuses with chromosomal and other anomalies (with and without following termination of pregnancy) are not usually excluded from the control group of the studies. The present study provides a significant study group of 6752 cases performed in a tertiary centre by experienced operators, with standard procedure protocols and detailed information regarding pregnancy outcomes. A limitation of the present study is its non-randomized design. Despite this limitation, our study provides the best possible contemporary information about relative risk of fetal loss after amniocentesis, attributed to common risk factors which complicate pregnancies. In our study, total fetal loss up to 24th week was 1.19%. This result is in accordance with other recent studies. Though earlier studies [5–7] have shown higher risk for fetal loss both in amniocentesis and no amniocentesis groups, more recent studies reported that the total risk for miscarriage in women who had amniocentesis ranged from 1% [11] up to 1.6% [8]. Accordingly, a systematic review [9] has shown that pooled relative risks for total fetal loss before 28 weeks was estimated at 1.46%. A recent meta-analysis (2000–2014) showed that the procedure-related risk of miscarriage before 24th week following amniocentesis is 0.81% [12]. Our study determined the relative risk of various maternal and pregnancy factors which are alleged to correlate with increased FLR such as maternal age, fibroids, history of vaginal bleeding, history of induced or spontaneous abortion, indication for the amniocentesis and stained amniotic fluid. Additionally, various factors related to the procedure itself such as location and puncture of the placenta, number of punctures in the same procedure, bloody amniotic fluid and operators’ experience have been studied in order to determine the possible added risk. In the present study, we found that women older than 34 years had greater risk of miscarriage than younger women. In particular, pregnant women aged from 34 to 36 years had 3.7 times greater odds for fetal loss when compared to women younger than 34 years. Accordingly, the odds ratio for women aged from 36.5 to 38 years and women over 38 are 4.79 and 2.08, respectively, when compared with women 534 years old. This increased risk for fetal loss with increased maternal age is in agreement with a previous study from our centre [13]. Other studies found no difference in FLR related to maternal age [14–16]. However, our experience with significant number of procedures shows that maternal age is a significant factor that should be taken under consideration when consulting women. This has been shown by other studies in which advanced maternal age was a risk for second trimester miscarriages not only due to chromosomal abnormalities but due to hormonal and anatomical reasons as well [17,18]. Another known risk factor for adverse outcome after invasive diagnostic procedures is previous bleeding. Serious bleeding has been reported as a risk factor for pregnancy loss even without an invasive procedure. In our centre active bleeding, 2 weeks before the procedure is a contraindication for the procedure while history of bleeding is not. Both
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DOI: 10.3109/14767058.2015.1012061
spotting and serious bleeding during first and early second trimester were found to be independent risk factors for fetal loss after amniocentesis in our study. This has also been reported in other studies [14,19]. Women reporting history of three or more miscarriages or induced abortions were identified as having greater odds of fetal loss after undergoing amniocentesis. It is noteworthy that women with induced abortions have almost 4 times greater risk of losing their baby after amniocentesis than women without history of abortions. It is known that women with recurrent miscarriages are in greater risk of fetal loss in every pregnancy. The reason why women with recurrent abortions have higher ratio of miscarriage after amniocentesis is not clear and certainly multifactorial. To our knowledge, there is one study reporting the impact of previous miscarriages on FLR showing that women with three or more spontaneous abortions had higher risk of fetal loss after amniocentesis [14] and another study [19] showing that there is no correlation between history of three or more miscarriages and risk of fetal loss. It should be mentioned at this point that, to our knowledge, there is no other study evaluating the impact of previous terminations of pregnancies on amniocentesis related fetal loss. Blood-stained amniotic fluid is known to be related with intra-amniotic bleeding, even in cases without history of vaginal bleeding. When amniotic fluid is found to be bloodstained at amniocentesis indicating an old intra-amniotic hemorrhage, the risk of fetal loss is almost 6 times higher. On the contrary, in cases where amniotic fluid was mixed with fresh blood (e.g. in cases of placenta perforation) the fetal loss was not higher than cases when the amniotic fluid was clear. Probably, in cases where blood-stained amniotic fluid was reported, the underlying risk factor is hemorrhage during the current pregnancy. Finally, the presence of uterine fibroids was identified as an independent predictive factor for fetal loss. Women who had intramural fibroids 420 mm had almost 3 times greater risk to miscarry after amniocentesis. On the other hand, women who had surgery to remove the fibroids before their pregnancy did not have any added risk for fetal loss. The same was true for any history of uterine surgery. This information may be used when counseling women since they can be assured that normalization of the uterine corpus has a protective role. Our results concerning the presence of fibromas are different than the result of the study of Salvador et al. [20]. Corrado et al. [19] have shown in their study that myomas are risk factors for second trimester fetal loss even when women have not underwent amniocentesis. In our study, the indication for the amniocentesis as well as the gestational age at the procedure did not appear to have any effect on the FLR. Most studies have shown that women who underwent amniocentesis because of an abnormal screening test or due to findings such as major ultrasonographic markers had a higher risk of losing their babies than women who had the test because of age or anxiety [21,22]. This is understandable since we know that women whose fetuses have abnormal biochemical or ultrasound markers have a greater risk of aneuploidies and spontaneous abortion. Nevertheless, in our cases, this indication-related increase was not found.
How to counsel pregnant women after amniocentesis?
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Our study is a retrospective observational one and understandably has limitations. Therefore, the exact contribution of each risk factor studied to the FLR after amniocentesis cannot be determined. However, it is highly unlikely to perform a prospective randomized trial of amniocentesis compared to no amniocentesis groups to evaluate the procedure-related risk for fetal loss due to ethical considerations. It is obvious that the next best way to evaluate the risk for fetal loss after amniocentesis is to examine the largest group of patients possible in a non-randomized sample drawn from an unselected population. The large number of our study population gives strength to our study. Another limitation of our study is the 6.5% loss of pregnancy outcomes. In order to eliminate any possible statistical bias, we correlated the characteristics of our study group (6752 pregnancies) with the group with unknown outcome (468 pregnancies) and we did not find any significant differences in age, indication for amniocentesis or pregnancy characteristics. Thus, we believe that this loss of follow-up does not affect the results of our study. The present study intended to evaluate the impact of different factors on the risk of pregnancy loss after amniocentesis. It is reasonable that fetal loss risk after invasive diagnostic procedures should be individualized since adverse outcome may occur secondary to different conditions in pregnancy. We have shown that various risk factors can alter the odds for fetal loss after amniocentesis and we have presented the specific odd ratios for specific risk factors, derived from a large study group of 6752 women.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Von Schatz F. Gine besondere art von einseitiger polyhydramnie mit anderseitiger oligohydramnie bie eineiigen zwillingen. Arch Gynecol 1882;19:329–69. 2. Beris DCA. Composition of liquor amnii in haemolytic disease of newborn. Lancet 1950;2:443. 3. Fuchs F, Riis P. Antenatal sex determination. Nature 1956;177:330. 4. Steele MW, Breg WR. Chromosome analysis of human amniotic fluid cells. Lancet 1966;383. 5. Medical Research Council. An assessment of the hazards of amniocentesis. Br J Obstet Gynecol 1978;85:1–41. 6. NICHD. National Registry for amniocentesis study group: mid trimester amniocentesis for prenatal diagnosis: safety and accuracy. J Am Med Assoc 1976;236:1471–6. 7. Simpson NE, Dallaire L, Miller JR, et al. Prenatal diagnosis of genetic disease in Canada: report of a collaborative study. Can Med Assoc J 1976;115:739–48. 8. Tabor A, Philip J, Madsen M, et al. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986;1: 1287–93. 9. Mujezinovic F, Alfirevic Z. Procedure-related complications of amniocentesis and chorionic villous sampling a systematic review. Obstet Gynecol 2007;110:687–94. 10. Seeds JW. Diagnostic mid trimester amniocentesis: how safe? Am J Obstet Gynecol 2004;191:608–16. 11. Ennleman KA, Malone FD, Sallivan L, et al. Pregnancy loss rates after midtrimester amniocentesis. Obstet Gynecol 2006;108: 1067–72. 12. Akolekar R, Beta J, Picciarelli G, et al. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2015;45:16–26.
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13. Papantoniou N, Daskalakis G, Tzotis J, et al. Risk factors predisposing to fetal loss following a second trimester amniocentesis. BJOG 2001;108:1053–6. 14. Kozlowski P, Knippel A, Stressig R. Individual risk of fetal loss following routine second trimester amniocentesis: a controlled study of 20,460 cases. Ultraschall Med 2008;29:165–72. 15. Mazza V, Pati M, Bertucci E, et al. Age-specific risk of fetal loss post second trimester amniocentesis: analysis of 5043 cases. Prenat Diagn 2007;27:180–3. 16. Tabor A, Vestergaard CHF, Lidegaard O. Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study. Ultrasound Obstet Gynecol 2009;34:19–24. 17. Andersen AM, Wohlfahrt J, Christens P, et al. Maternal ge and fetal loss. Population based restister linkage study. Br Med J 2000;320: 1708–12.
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18. Hoesli IM, Walter Gabel I, Tercanli S, Holzgreve W. Spontaneous fetal loss rates in a non sellected population. Am J Med Genet 2001; 100:106–10. 19. Corrado F, Cannata ML, La Galia T, et al. Pregnancy outcome following mid-trimester amniocentesis. J Obstet Gynecol 2012;32: 117–19. 20. Salvador E, Bienstock J, Blakemore KJ, Pressman E. Leiomyomata uteri, genetic amniocentesis, and the risk of second-trimester spontaneous abortion. Am J Obstet Gynecol 2002;186:913–15. 21. Konn CW, Leung TN, Leung TY, et al. Risk factors for procedure related fetal losses after mod trimester genetic amniocentesis. Prenat Diagn 2006;20:925–30. 22. Odibo AO, Gray DL, Dicke JM, et al. Revisiting the fetal loss rate after second trimester genetic amniocentesis: a single center’s 16-year experience. Obstet Gynecol 2008;111:589–95.
ORIGINAL ARTICLE
Fetal loss following second trimester amniocentesis. Who is at greater risk? How to counsel pregnant women?
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 05/08/15 For personal use only.
Marianna Theodora, Aris Antsaklis, Panos Antsaklis, Konstantinos Blanas, Georgios Daskalakis, Michael Sindos, Spiros Mesogitis, and Nikolaos Papantoniou 1st Department of Obstetrics Gynecology, University of Athens, Athens, Greece
Abstract
Keywords
Objective: The purpose of this retrospective observational cohort study was to determine the impact of certain risk factors on fetal loss, after mid-trimester amniocentesis. Material and methods: Six thousand seven-hundred and fifty-two (6752) consecutive amniocenteses with known pregnancy outcome performed during a 7-year period (2004– 2010) were included in this study. Different maternal-, fetal- and procedure-related factors were evaluated in this study. Results: During this 7-year period, 6752 cases who underwent amniocentesis, with complete data available were evaluated for the outcome and risk factors mentioned. Total fetal loss rate (FLR) up to the 24th week was 1.19%. Risk factors associated with increased risk of fetal loss after amniocentesis were maternal age (OR:2.0), vaginal spotting (OR:2.2) and serious bleeding (OR:3.5) during pregnancy, history of 2nd trimester termination of pregnancy (OR:4.0), history of more than three spontaneous (OR:3.0) or surgical first trimester abortions (OR:2.1), fibromas (OR:3.0) and stained amniotic fluid (OR:6.1). Conclusions: Amniocentesis is a safe-invasive procedure for prenatal diagnosis with total FLR of 1.19% in our institution during the study period. The present study has emphasized the significance of certain risk factors for adverse outcome and therefore the need to individualize the risk.
Amniocentesis, fetal loss, risk factors
Introduction Amniocentesis is the oldest invasive procedure in prenatal medicine. It was first used in the end of the nineteenth century for evacuation of excessive amniotic fluid in pregnancies complicated by hydramnion [1]. Since the beginning of the 1950s, it was used to determine the amniotic composition in cases of Rhesus isoimmunization [2]. Amniocentesis was used for diagnostic reasons in the 1950s, as a method for sex determination by the identification of Barr bodies in the noncultured amniocytes [3]. Ten years later, the karyotype of the embryo was determined through a culture of fetal cells derived from the amniotic fluid [4]. Since then, amniocentesis has been established as a basic invasive method for the prenatal diagnosis of various pregnancy-related conditions, such as fetal karyotyping, diagnosis of metabolic or enzymatic diseases, assessment of the severity hemolytic disease, establishment of lung maturity and diagnosis of fetal infections. Although amniocentesis has been applied in prenatal diagnosis for half a century, its potential risk for adverse Address for correspondence: Dr Marianna Theodora, PhD, 1st Department of Obstetrics Gynecology, University of Athens, Vas Sofias 80, Athens 11527, Greece. E-mail: [email protected]
History Received 17 July 2014 Revised 30 November 2014 Accepted 22 January 2015 Published online 9 March 2015
perinatal outcome has not been established. The actual risk of fetal loss accounted to the procedure is yet not clear. Initial evaluation of procedure-related fetal loss rate (FLR) in the 1970s was 0.3–1.5% [5–7]. In the mid-1980s, the only prospective randomized trial showed a risk of 1% [8]. In the past decade, two metanalyses showed a risk of 0.6% [9,10], whereas significantly lower risk (0.03%) has been reported [11]. The diversity in defining the actual risk rate for miscarriage is due to the lack of data coming from randomized trials, as well as the diversity of the methodology and populations studied. It is known that miscarriage does not occur only in association with amniocentesis. Thus, it is essential to take into consideration the background loss rate which is associated with the gestational age, parity and any other underlying risk factors such as pathological conditions of the mother and the fetus as well. It is known that gestational age is an important determinant of the observed FLR, and that the earlier the pregnancy, the greater is the pre-procedure risk of miscarriage. Similarly, we hypothesized that other factors such as bleeding during current pregnancy, history of spontaneous or induced abortions, fibromas and discolored amniotic fluid may be responsible for a higher risk of fetal loss even without any invasive procedure.
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The goal of the present retrospective study was to evaluate the overall fetal loss risk after amniocentesis performed in a tertiary university centre with experienced physicians in a 7-year period and to determine the impact of certain risk factors on the perinatal outcome. To our knowledge, this is one of the few studies with significant number of cases that evaluates these parameters and provides useful information when counseling pregnant women, considering prenatal diagnosis.
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Material and methods Six-thousand seven-hundred and fifty-two (6752) cases of pregnant women who sought prenatal diagnosis for various reasons during the years 2004–2010 were included in this study. Indications for amniocentesis in this group arose from maternal age, 1st and 2nd trimester screening for aneuploidies, positive sonographic markers for aneuploidies and maternal infection with Toxoplasma gondii or Cytomegalovirus. Known metabolic and genetic diseases comprised another group of indications mainly in younger women in our series. Finally, maternal anxiety was the indication for a significant number of procedures. Women with multiple pregnancies were excluded from our study. A thorough medical, family and obstetric history was obtained from the woman and her partner before the procedure. Indication was noted as well as all screening tests previously performed during this pregnancy. Amniocentesis was postponed if bleeding had occurred within 2 weeks prior to the procedure. Women with history of vaginal bleeding during the 1st or early 2nd trimester regardless of the severity of bleeding, but not active bleeding were allowed to have an amniocentesis. A complete anatomical survey of the fetus was carried out before amniocentesis. Terminations due to congenital malformations were not included. The placental site was recorded and transplacental puncture was avoided when feasible. A 22-gauge, 8-cm spinal needle was used in all cases. The procedure was carried out under continuous ultrasonic guidance by means of high definition ultrasound apparatus, equipped with a 3.5-MHz curved linear transducer, by experienced physicians. The invasive procedure itself and related risks were thoroughly explained to the couple and written consent was obtained in all cases. Additionally, couples were informed that we are interested in the outcome of the pregnancy and we provided them with an outcome data form, to be completed by the obstetrician and posted to our department. We also informed them that we would contact them in case that the data form was not received or additional information was needed. Total FLR up to 24th week and its relation to certain risk factors were estimated, using the statistical model of multiple logistic regression analysis. Advanced maternal age, vaginal spotting and/or bleeding during pregnancy, previous history of first or second trimester abortions, fibroids, uterine scars, placental location, blood-stained amniotic fluid and number of needle insertions were risk factors evaluated in this study.
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Statistical analysis Qualitative variables are presented with absolute and relative frequencies, while quantitative variables are presented with mean and standard deviation (SD). To test the effect of the factors under investigation on fetal loss, univariate logistic regression analyses were used and data were modeled using backward stepwise logistic regression analysis with variable removal set at p ¼ 0.1 and variable entry set at p ¼ 0.05. Odds ratios with 95% confidence intervals (CI) were computed from the results of the logistic regression analyses. Hypothesized interactions of variables in the models were not significant. All p values reported are two-tailed. Statistical significance was set at 0.05 and analyses were conducted using SPSS statistical software (version 13.0, SPSS Inc., Chicago, IL).
Results Seven-thousand two-hundred and twenty (7220) amniocenteses were performed in our center during the seven years period. The outcome of the pregnancy was known in 6752 cases (93.5%). These procedures were performed between 16 + 0 and 19 + 6 weeks of gestation (Table 1). Fetal loss rate was evaluated as the number of miscarriages or intrauterine deaths up to 24 weeks of pregnancy. Terminations of pregnancy due to oligohygramnios and preterm premature rupture of membranes were also included. On the contrary, terminations due to fetal congenital malformations and/or pathology of the fetus were excluded. Mean maternal age was 35.6 years (SD ¼ 4.4 years) and 82.3% of the women (5557/6752) were older than 34 years. Three or more miscarriages during the 1st trimester were recorded in 8.5% (574/6752) of the pregnancies studied. Second trimester termination of pregnancy was noted in 2.5% (169/6752), while first trimester terminations were noted in 25.5% (1722/6752). Spotting and serious hemorrhage during the current pregnancy, was observed in 13.6% (918/6752) and 3.7% (250/6752), respectively. Anterior placenta was observed in 48.4% (3268/6752) of our cases and placental puncture has been avoided in 92% (3006/3268) of these cases. Other characteristics regarding our study population are presented in Table 1. Total FLR up to 24th week was 1.19% (95% CI: 0.92– 1.45). FLR according to all factors under investigation and their impact on adverse pregnancy outcome are presented in Table 2. Fetal loss was significantly greater for women older than 34 years old (1.3%, 72/5557) compared to women younger than 34 years (0.6%, 7/1195). Women with spotting or serious hemorrhage during the current pregnancy had significantly greater fetal loss in univariate analysis compared to those without hemorrhage (2.0% and 3.3%, versus 1.0%, respectively). In our series, FLR after amniocentesis was seriously affected by history of miscarriages and surgical abortions. It is noteworthy that the FLR was 4.0% (5/129) for women with three or more surgical abortions which is significantly greater from the 1% (50/5030) fetal loss observed in women without previous surgical abortions. In a similar way, univariate analysis revealed that three or more 1st trimester
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Table 1. Sample characteristics (N ¼ 6752).
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Table 2. Fetal loss rate (%) and associations derived by univariate logistic regression analysis.
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N (%) Age (years) 534 34 Gestational age at the procedure (weeks) 16 + 0–16 + 6 17 + 0–17 + 6 18 + 0–18 + 6 19 + 0–19 + 9 History of uterine scars No Yes Hemorrhage during this pregnancy No Minor (spotting) Serious No of needle insertions 1 2 Number of surgical abortions None 1–2 3 TOP (415 weeks) No Yes Number of miscarriages in the 1st trimester None 1–2 3 Miscarriages after the 2nd trimester No Yes Indication Maternal age Maternal request High risk for aneuploidies screening test Single genes genetic disorders Other Placenta location Anterior Posterior Uterine fibroids No Yes Stained amniotic fluid No Yes
1195 (17.7) 5557 (82.3)
Fetal loss %
6587 (97.5) 165 (2.5)
Age (years) 534 0.6 34 1.3 History of uterine surgery No 1.1 Yes 1.4 Hemorrhage during pregnancy No 1.0 Minor (spotting) 2.0 Serious 3.3 Number of needle insertions One 1.2 Two 0.6 Number of surgical abortions None 1.0 1–2 1.5 3 4.0 TOP (415 weeks) No 1.1 Yes 3.0 Number of miscarriages in 1st trimester None 1.0 1–2 1.3 3 2.1 Miscarriages after the 2nd trimester No 1.2 Yes 1.6 Indication for amniocentesis Maternal age 1.3 Maternal request 1.6 High-risk result in aneuploidy0.7 screening tests Single gene genetic disorders 0.4 Placenta location Anterior 1.3 Posterior 1.1 Uterine fibroids No 1.1 Yes 3.0 Stained amniotic fluid No 1.1 Yes 6.1
6703 (99.3) 49 (0.7)
OR, odds ratio; CI, 95% confidence interval. *Indicates reference category.
1329 2893 1932 598
(19.7) (42.8) (28.6) (8.9)
5481 (80.7) 1271 (19.3) 5584 (82.7) 918 (13.6) 250 (3.7) 6570 (97.3) 182 (2.7) 5030 (74.5) 1593 (23.6) 129 (1.9) 6583 (97.5) 169 (2.5) 4071 (60.3) 2107 (31.2) 574 (8.5) 6629 (98.1) 123 (1.9) 5054 519 458 701 20
(74.9) (7.7) (6.8) (10.4) (0.3)
3268 (48.4) 3484 (51.6)
miscarriages were associated with increased fetal loss estimated at 2.1% (12/574). Finally, history of terminations of pregnancy in gestational ages of415 weeks was associated with 3.0% (5/169) fetal loss before 24 weeks. The crude odds ratios for the aforementioned factors were 4.07, 2.69 and 2.15, respectively (Table 2). The presence of intramural fibromas also increased the risk of fetal loss after amniocentesis. Women who had fibromas had 3.0% FLR, whereas in cases where myomas were not seen the FLR was 1.1%. One of the most important factors for increased risk of pregnancy loss was stained amniotic fluid. In particular, when old blood-stained amniotic fluid was aspirated during the procedure the risk of pregnancy loss prior to the 24th week was 6.0% (3/49) compared with 1.1% (74/6730) in cases, where the amniotic fluid was clear or fresh blood-stained. Other factors, however, do not seem to have a negative effect on pregnancy outcome. More specifically, gestational
OR (95% CI)
p value
1.0* 2.20 (1.01–4.79)
0.047
1.0 1.25 (0.74–2.13)
0.402
1.0 2.12 (1.24–3.64) 3.51 (1.65–7.47)
0.006 0.001
1.0 0.46 (0.06–3.31)
0.439
1.0 1.46 (0.89–2.4) 4.07 (1.6–10.4)
0.135 0.003
1.0 2.69 (1.07–6.76)
0.035
1.0 1.26 (0.77–2.07) 2.15 (1.12–4.12)
0.365 0.021
1.0 1.39 (0.34–5.71)
0.651
1.0 1.22 (0.58–2.56) 0.52 (0.16–1.65)
0.600 0.265
0.33 (0.1–1.07)
0.065
1.0 0.84 (0.54–1.32)
0.458
1.0 2.71 (1.08–6.80)
0.034
1.0 5.61 (1.71–18.42) 0.005
age at the procedure, history of uterine surgery (previous caesarean section, fibromas excision), indication for amniocentesis, placental location and number of needle insertions did not increase the risk of fetal loss after amniocentesis in our series. Finally, we evaluated if there was any difference in the total fetal loss after amniocentesis over different time periods since the total period of our study covers 7 years and operators’ experience is determinative for pregnancy outcome [10,12]. The total fetal loss after amniocentesis, before 24 weeks was stable in this 7-year period at the rate of 1%. This is due to the extensive experience of the operators in our department. When backward stepwise logistic regression analysis was conducted with fetal loss as the dependent variable, it was found that maternal age 434 years, spotting or serious bleeding, three of more surgical abortions, fibroids and
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Table 3. Odds ratios and 95% confidence intervals derived from multiple logistic regression analysis with fetal loss as the dependent variable.
Age (years) 534 34 Hemorrhage during pregnancy No Minor (spotting) Serious Number of surgical abortions None 1–2 3 Number of miscarriages in 1st trimester None 1–2 3 Uterine fibroid No Yes Stained amniotic fluid No Yes
OR (95% CI)
p value
1.0* 2.19 (1.00–4.77)
0.049
1.0 1.96 (1.14–3.38) 2.74 (1.23–6.11)
0.015 0.014
1.0 1.32 (0.8–2.18) 3.44 (1.32–8.94)
0.280 0.011
1.0 1.25 (0.75–2.06) 1.93 (1.00–3.73)
0.391 0.050
1.0 2.52 (1.01–6.40)
0.048
1.0 3.74 (1.05–13.29)
0.041
OR, odds ratio; CI, 95% confidence interval. *Indicates reference category.
stained amniotic fluid, were risk factors with statistical significance (Table 3). More specifically, maternal age was independently associated with fetal loss, with odds ratio equal to 2.19 (95% CI: 1.00–4.77). Hemorrhage during pregnancy was another independent predictor for fetal loss indicating that women with spotting or serious bleeding had 1.96 and 2.74 times greater odds for fetal loss. Also, the likelihood for fetal loss was 3.44 times greater for women with more than three surgical abortions. The same pattern was found for women with three or more miscarriages in the 1st trimester, with 1.93 times greater odds for fetal loss compared to those with no miscarriages. Multiple regression analysis showed that uterine fibroids and stained amniotic fluid were risk factors that could predict independently fetal loss and the adjusted odds ratios for the aforementioned factors were 2.52 and 3.74.
Discussion Amniocentesis is the most common invasive procedure for prenatal diagnosis. It has been performed for almost half a century and carries a small additional risk for miscarriage, above the background risk estimated for pregnancies without invasive procedures. The actual risk of fetal loss, however, is still blare and different databases report procedure-related miscarriage ranging from 1% in the mid-1980s [8] down to 0.035% recently [11]. The etiology for this differentiation is mainly the absence of prospective randomized trials. Additional reasons for the diversity of results are the diversity of methodology and populations studied. It is accepted that miscarriage does not occur only in association with amniocentesis. When estimating the fetal loss after a procedure, it is essential to take into consideration the background loss rate which is associated with gestational
age, parity and other underlying risk factors such as pathological conditions of the mother and the fetus. In general, the background risk is overestimated because fetuses with chromosomal and other anomalies (with and without following termination of pregnancy) are not usually excluded from the control group of the studies. The present study provides a significant study group of 6752 cases performed in a tertiary centre by experienced operators, with standard procedure protocols and detailed information regarding pregnancy outcomes. A limitation of the present study is its non-randomized design. Despite this limitation, our study provides the best possible contemporary information about relative risk of fetal loss after amniocentesis, attributed to common risk factors which complicate pregnancies. In our study, total fetal loss up to 24th week was 1.19%. This result is in accordance with other recent studies. Though earlier studies [5–7] have shown higher risk for fetal loss both in amniocentesis and no amniocentesis groups, more recent studies reported that the total risk for miscarriage in women who had amniocentesis ranged from 1% [11] up to 1.6% [8]. Accordingly, a systematic review [9] has shown that pooled relative risks for total fetal loss before 28 weeks was estimated at 1.46%. A recent meta-analysis (2000–2014) showed that the procedure-related risk of miscarriage before 24th week following amniocentesis is 0.81% [12]. Our study determined the relative risk of various maternal and pregnancy factors which are alleged to correlate with increased FLR such as maternal age, fibroids, history of vaginal bleeding, history of induced or spontaneous abortion, indication for the amniocentesis and stained amniotic fluid. Additionally, various factors related to the procedure itself such as location and puncture of the placenta, number of punctures in the same procedure, bloody amniotic fluid and operators’ experience have been studied in order to determine the possible added risk. In the present study, we found that women older than 34 years had greater risk of miscarriage than younger women. In particular, pregnant women aged from 34 to 36 years had 3.7 times greater odds for fetal loss when compared to women younger than 34 years. Accordingly, the odds ratio for women aged from 36.5 to 38 years and women over 38 are 4.79 and 2.08, respectively, when compared with women 534 years old. This increased risk for fetal loss with increased maternal age is in agreement with a previous study from our centre [13]. Other studies found no difference in FLR related to maternal age [14–16]. However, our experience with significant number of procedures shows that maternal age is a significant factor that should be taken under consideration when consulting women. This has been shown by other studies in which advanced maternal age was a risk for second trimester miscarriages not only due to chromosomal abnormalities but due to hormonal and anatomical reasons as well [17,18]. Another known risk factor for adverse outcome after invasive diagnostic procedures is previous bleeding. Serious bleeding has been reported as a risk factor for pregnancy loss even without an invasive procedure. In our centre active bleeding, 2 weeks before the procedure is a contraindication for the procedure while history of bleeding is not. Both
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DOI: 10.3109/14767058.2015.1012061
spotting and serious bleeding during first and early second trimester were found to be independent risk factors for fetal loss after amniocentesis in our study. This has also been reported in other studies [14,19]. Women reporting history of three or more miscarriages or induced abortions were identified as having greater odds of fetal loss after undergoing amniocentesis. It is noteworthy that women with induced abortions have almost 4 times greater risk of losing their baby after amniocentesis than women without history of abortions. It is known that women with recurrent miscarriages are in greater risk of fetal loss in every pregnancy. The reason why women with recurrent abortions have higher ratio of miscarriage after amniocentesis is not clear and certainly multifactorial. To our knowledge, there is one study reporting the impact of previous miscarriages on FLR showing that women with three or more spontaneous abortions had higher risk of fetal loss after amniocentesis [14] and another study [19] showing that there is no correlation between history of three or more miscarriages and risk of fetal loss. It should be mentioned at this point that, to our knowledge, there is no other study evaluating the impact of previous terminations of pregnancies on amniocentesis related fetal loss. Blood-stained amniotic fluid is known to be related with intra-amniotic bleeding, even in cases without history of vaginal bleeding. When amniotic fluid is found to be bloodstained at amniocentesis indicating an old intra-amniotic hemorrhage, the risk of fetal loss is almost 6 times higher. On the contrary, in cases where amniotic fluid was mixed with fresh blood (e.g. in cases of placenta perforation) the fetal loss was not higher than cases when the amniotic fluid was clear. Probably, in cases where blood-stained amniotic fluid was reported, the underlying risk factor is hemorrhage during the current pregnancy. Finally, the presence of uterine fibroids was identified as an independent predictive factor for fetal loss. Women who had intramural fibroids 420 mm had almost 3 times greater risk to miscarry after amniocentesis. On the other hand, women who had surgery to remove the fibroids before their pregnancy did not have any added risk for fetal loss. The same was true for any history of uterine surgery. This information may be used when counseling women since they can be assured that normalization of the uterine corpus has a protective role. Our results concerning the presence of fibromas are different than the result of the study of Salvador et al. [20]. Corrado et al. [19] have shown in their study that myomas are risk factors for second trimester fetal loss even when women have not underwent amniocentesis. In our study, the indication for the amniocentesis as well as the gestational age at the procedure did not appear to have any effect on the FLR. Most studies have shown that women who underwent amniocentesis because of an abnormal screening test or due to findings such as major ultrasonographic markers had a higher risk of losing their babies than women who had the test because of age or anxiety [21,22]. This is understandable since we know that women whose fetuses have abnormal biochemical or ultrasound markers have a greater risk of aneuploidies and spontaneous abortion. Nevertheless, in our cases, this indication-related increase was not found.
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Our study is a retrospective observational one and understandably has limitations. Therefore, the exact contribution of each risk factor studied to the FLR after amniocentesis cannot be determined. However, it is highly unlikely to perform a prospective randomized trial of amniocentesis compared to no amniocentesis groups to evaluate the procedure-related risk for fetal loss due to ethical considerations. It is obvious that the next best way to evaluate the risk for fetal loss after amniocentesis is to examine the largest group of patients possible in a non-randomized sample drawn from an unselected population. The large number of our study population gives strength to our study. Another limitation of our study is the 6.5% loss of pregnancy outcomes. In order to eliminate any possible statistical bias, we correlated the characteristics of our study group (6752 pregnancies) with the group with unknown outcome (468 pregnancies) and we did not find any significant differences in age, indication for amniocentesis or pregnancy characteristics. Thus, we believe that this loss of follow-up does not affect the results of our study. The present study intended to evaluate the impact of different factors on the risk of pregnancy loss after amniocentesis. It is reasonable that fetal loss risk after invasive diagnostic procedures should be individualized since adverse outcome may occur secondary to different conditions in pregnancy. We have shown that various risk factors can alter the odds for fetal loss after amniocentesis and we have presented the specific odd ratios for specific risk factors, derived from a large study group of 6752 women.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Von Schatz F. Gine besondere art von einseitiger polyhydramnie mit anderseitiger oligohydramnie bie eineiigen zwillingen. Arch Gynecol 1882;19:329–69. 2. Beris DCA. Composition of liquor amnii in haemolytic disease of newborn. Lancet 1950;2:443. 3. Fuchs F, Riis P. Antenatal sex determination. Nature 1956;177:330. 4. Steele MW, Breg WR. Chromosome analysis of human amniotic fluid cells. Lancet 1966;383. 5. Medical Research Council. An assessment of the hazards of amniocentesis. Br J Obstet Gynecol 1978;85:1–41. 6. NICHD. National Registry for amniocentesis study group: mid trimester amniocentesis for prenatal diagnosis: safety and accuracy. J Am Med Assoc 1976;236:1471–6. 7. Simpson NE, Dallaire L, Miller JR, et al. Prenatal diagnosis of genetic disease in Canada: report of a collaborative study. Can Med Assoc J 1976;115:739–48. 8. Tabor A, Philip J, Madsen M, et al. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986;1: 1287–93. 9. Mujezinovic F, Alfirevic Z. Procedure-related complications of amniocentesis and chorionic villous sampling a systematic review. Obstet Gynecol 2007;110:687–94. 10. Seeds JW. Diagnostic mid trimester amniocentesis: how safe? Am J Obstet Gynecol 2004;191:608–16. 11. Ennleman KA, Malone FD, Sallivan L, et al. Pregnancy loss rates after midtrimester amniocentesis. Obstet Gynecol 2006;108: 1067–72. 12. Akolekar R, Beta J, Picciarelli G, et al. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2015;45:16–26.
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13. Papantoniou N, Daskalakis G, Tzotis J, et al. Risk factors predisposing to fetal loss following a second trimester amniocentesis. BJOG 2001;108:1053–6. 14. Kozlowski P, Knippel A, Stressig R. Individual risk of fetal loss following routine second trimester amniocentesis: a controlled study of 20,460 cases. Ultraschall Med 2008;29:165–72. 15. Mazza V, Pati M, Bertucci E, et al. Age-specific risk of fetal loss post second trimester amniocentesis: analysis of 5043 cases. Prenat Diagn 2007;27:180–3. 16. Tabor A, Vestergaard CHF, Lidegaard O. Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study. Ultrasound Obstet Gynecol 2009;34:19–24. 17. Andersen AM, Wohlfahrt J, Christens P, et al. Maternal ge and fetal loss. Population based restister linkage study. Br Med J 2000;320: 1708–12.
J Matern Fetal Neonatal Med, Early Online: 1–6
18. Hoesli IM, Walter Gabel I, Tercanli S, Holzgreve W. Spontaneous fetal loss rates in a non sellected population. Am J Med Genet 2001; 100:106–10. 19. Corrado F, Cannata ML, La Galia T, et al. Pregnancy outcome following mid-trimester amniocentesis. J Obstet Gynecol 2012;32: 117–19. 20. Salvador E, Bienstock J, Blakemore KJ, Pressman E. Leiomyomata uteri, genetic amniocentesis, and the risk of second-trimester spontaneous abortion. Am J Obstet Gynecol 2002;186:913–15. 21. Konn CW, Leung TN, Leung TY, et al. Risk factors for procedure related fetal losses after mod trimester genetic amniocentesis. Prenat Diagn 2006;20:925–30. 22. Odibo AO, Gray DL, Dicke JM, et al. Revisiting the fetal loss rate after second trimester genetic amniocentesis: a single center’s 16-year experience. Obstet Gynecol 2008;111:589–95.
