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Individual Risk of Fetal Loss Following Routine Second Trimester Amniocentesis: A Controlled Study of 20 460 Cases
Abstract
The aim of this study was to evaluate the impact of maternal risk factors on excess fetal loss related to amniocentesis.
We compared fetal outcome and details of risk factors for fetal loss in 20,460 patients undergoing amniocenteses between April 1997 and March 2005 to 11,017 controls given ultrasound during the same period in our tertiary level prenatal unit. The risk factors were recorded before the procedure. Spontaneous fetal loss was defined as spontaneous miscarriage and intrauterine fetal demise at any gestational age.
The excess rate of spontaneous loss attributed to the amniocentesis procedure averaged 0.49 % (CI: 0.26 - 0.72) for all pregnancies under routine care (1.31 % 268/20,460 versus 0.82 % 90/11,017). The fetal loss rate was increased in the intervention group for the following isolated risk factors: vaginal bleeding before procedure (19/647, 2.9 % CI: 1.6 - 4.2 %); vaginal bleeding at date of procedure (3/33, 9.1 % CI: - 0.7 - 18.9 %); a history of 3 or more spontaneous abortions (6/257, 2.3 % CI: 0.5 - 4.2 %); body mass index > 40 (5/160, 3.1 % CI: 0.4 - 5.8 %) and cigarette consumption > 10/day (13/671, 1.94 % CI: 0.9 - 3.0). If none of these risk factors was present, the abortion rate in the intervention group was 1.18 % (219/18,617) and 0.63 % (61/9,677) in the control group. Maternal age > 40 at birth did not alter the rate of loss in the intervention group, but did in the control group (1.4 % 38/2,717 and 1.69 % 7/414).
After routine amniocentesis patients have an additional procedure-related risk of spontaneous pregnancy loss equivalent to 0.5 %. The absence of risk factors in the patient's history does not reduce this additional risk.
... 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][15][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. ...
... Both 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. ...
... 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. ...
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.
... All three of these techniques for foetal cell extraction allow more foetal DNA be harvested than is possible with NIPT and are followed with standard OI genetic testing analysis (targeted NGS panel, Sanger sequencing, WES). The risk of pregnancy loss if invasive methods are used is estimated to be between approximately 0.5-2% [161]. As with ultrasound, prenatal genetic testing attempts to differ between OI 2 and 3 may be unsuccessful, which can have dramatic consequences for prospective parents and their families. ...
... The amniocentesis analysis is also useful where intrauterine infections need to be analysed [164]. Due to the invasiveness of the procedure, an approximately 0.5-1% risk of miscarriage exists [161]. ...
Background:
Osteogenesis Imperfecta (OI) is a rare genetic disorder involving bone fragility. OI patients typically suffer from numerous fractures, skeletal deformities, shortness of stature and hearing loss. The disorder is characterised by genetic and clinical heterogeneity. Pathogenic variants in more than 20 different genes can lead to OI, and phenotypes can range from mild to lethal forms. As a genetic disorder which undoubtedly affects quality of life, OI significantly alters the reproductive confidence of families at risk. The current review describes a selection of the latest reproductive approaches which may be suitable for prospective parents faced with a risk of OI. The aim of the review is to alleviate suffering in relation to family planning around OI, by enabling prospective parents to make informed and independent decisions.
Main body:
The current review provides a comprehensive overview of possible reproductive options for people with OI and for unaffected carriers of OI pathogenic genetic variants. The review considers reproductive options across all phases of family planning, including pre-pregnancy, fertilisation, pregnancy, and post-pregnancy. Special attention is given to the more modern techniques of assisted reproduction, such as preconception carrier screening, preimplantation genetic testing for monogenic diseases and non-invasive prenatal testing. The review outlines the methodologies of the different reproductive approaches available to OI families and highlights their advantages and disadvantages. These are presented as a decision tree, which takes into account the autosomal dominant and autosomal recessive nature of the OI variants, and the OI-related risks of people without OI. The complex process of decision-making around OI reproductive options is also discussed from an ethical perspective.
Conclusion:
The rapid development of molecular techniques has led to the availability of a wide variety of reproductive options for prospective parents faced with a risk of OI. However, such options may raise ethical concerns in terms of methodologies, choice management and good clinical practice in reproductive care, which are yet to be fully addressed.
... 15,27 In the same way maternal age and abnormal maternal serum a fetoprotein measurements increase the risk for pregnancy loss. 19,[28][29][30][31] Vaginal bleeding during current pregnancy increase the risk of spontaneous abortion and pregnancy loss after amniocentesis in most of the series. 29 In our recent series, we also found that bleeding during first and early second trimester of current pregnancy increase the risk of pregnancy loss after amniocentesis by two to three times. ...
... 19,[28][29][30][31] Vaginal bleeding during current pregnancy increase the risk of spontaneous abortion and pregnancy loss after amniocentesis in most of the series. 29 In our recent series, we also found that bleeding during first and early second trimester of current pregnancy increase the risk of pregnancy loss after amniocentesis by two to three times. ...
In this article, we will review the history and the evolution of the technique of amniocentesis and the indications of the most common invasive diagnostic and therapeutic procedure. Moreover, the most common complications of amniocentesis will be presented. Finally, we will try to establish if the use of concurrent ultrasound had any effect on the prevalence on these complications.
How to cite this article
Theodora M, Antsaklis P, Antsaklis A. Invasive Prenatal Diagnosis: Amniocentesis. Donald School J Ultrasound Obstet Gynecol 2015;9(3):307-313.
... Although various factors are involved in the pathogenesis of preterm labor and PPROM, infection and inammation play an important role in the onset of preterm labor. The most accurate detection of infection 9 occurs with amniocentesis, which is an invasive procedure. Thus, there is a need to research easier diagnostic methods. ...
Prematurity is dened as a birth that occurs before 37 completed weeks (less than 259 days) of gestation. It is associated considerable risk of morbidity and mortality, particularly among extremely preterm infants. It complicates 5-8% of pregnancies in most developed and developing countries and incidence is still increasing worldwide. This study was aimed to estimate the importance of complete blood count parameters like neutrophils, neutrophil to lymphocyte parameters, platelet to lymphocyte parameters for predicting the timing of birth in threatened preterm labour cases. This prospective observational study was conducted in Department of OBG, Vijayanagar Institute of Medical Sciences, Ballari, between 01st August 2023 to 31 st January 2024. Gestational week at delivery showed weak negative correlations with LMR (Lymphocyte- to-Monocyte Ratio) (r* = -0.211, p = 0.03*) and CRP (C-Reactive Protein) (r* = -0.06, p = 0.56), indicating that higher LMR and lower CRP levels may be associated with longer gestational periods. The correlations for WBC (White Blood Cell count) and NLR (Neutrophil-to- Lymphocyte Ratio) were not signicant (NS). As a result, only WBC was found to be a valuable parameter in predicting preterm labor and PPROM, as the CBC test is a cheap and routinely applied test. Although increased LMR levels were demonstrated to be associated with preterm birth and threatened preterm labor, respectively, to be able to extrapolate these ndings into clinical daily practice, further studies are needed
... Although various factors are involved in the pathogenesis of preterm labor and PPROM, infection and inflammation play an important role in the onset of preterm labor. The most accurate detection of infection occurs with amniocentesis, which is an invasive procedure [18]. Thus, there is a need to research easier diagnostic methods. ...
b> Purpose: The purpose of this study was to investigate a possible relationship between systemic inflammatory markers such as neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte monocyte ratio (LMR), threatened preterm labor (TPL), and preterm premature rupture of membranes (PPROM), using complete blood cell count (CBC) parameters. Method: The study was carried out prospectively with patients admitted to our university hospital due to preterm labor and at risk of PPROM. The cases were divided into three groups according to their pregnancy status. Group 1 consisted of 90 patients with PPROM between 24th and 36th gestational weeks; group 2, 115 patients diagnosed with TPL between 24th and 36th gestational weeks; group 3, 101 patients over 36 weeks of gestation (control) who were not in labor. In addition to the demographic data of the patients, CBC parameters (white blood cell (WBC), Hg, Hct, Plt, lymphocyte, monocyte, mean platelet volume, PLR, LMR, and NLR) and C-reactive protein (CRP) values were examined and compared in each of the three groups. Results: CRP and WBC values of group 1 (PPROM) were higher than group 2 (TPL) and group 3 (control) ( p < 0.05 for both). Pearson correlation between the gestational age and PLR and NLR values was significant ( r and p values for PLR and NLR, respectively, r = −0.18, p < 0.001; r = −0.23, p < 0.001). However, there was no significant difference between the groups regarding PLR, NLR, LMR, platelet, monocytes, and lymphocyte counts. Conclusions: Only WBC was a valuable parameter in predicting preterm labor and PPROM. Although there was no significant difference between the groups in PLR and NLR, a negative correlation was found with gestational age at delivery. CRP value is still a helpful parameter in PPROM and TPL prediction.
... As noted earlier, inflammation plays a crucial role in triggering preterm delivery, and the best tool for identifying the potential source of the inflammation/infection is amniocentesis. Nevertheless, amniocentesis has been shown to be associated with a 0.5% risk of fetal loss [33], highlighting the need for less invasive predictive methods. The optimal predictive test should ideally be easily accessible, reproducible, and easy to perform throughout pregnancy to provide enough time for further preventative interventions [34]. ...
Background:
Neutrophil-to-lymphocyte ratio (NLR), as an inflammatory biomarker, has been investigated in several studies for early prediction of preterm delivery. However, their findings seem to be controversial. Thus, this systematic review and meta-analysis was conducted to evaluate the role of NLR in predicting preterm delivery as compared to term controls.
Methods:
PubMed, Web of Science, Embase, Scopus, and Google Scholar were systematically searched from inception up to December 2020. Interstudy heterogeneity was assessed using Cochrane's Q test and the I2 statistic. The random-effects model was employed to pool the weighted mean differences (WMDs) and the corresponding 95% confidence intervals (CIs).
Results:
Out of a total of 4369 recodes, fifteen articles including 3327 participants were enrolled. The meta-analysis finding using the random-effects model produced a pooled estimate suggesting a significantly higher NLR (WMD = 1.23, 95% CI: 0.40-2.07) in women with preterm delivery (P = 0.01). We found significant heterogeneity across the included studies (P < 0.001, I2 = 92.33%). However, interstudy heterogeneity exists mainly due to differences in the definition of preterm delivery (I2 = 0.0%). In the metaregression analysis, there was no significant effect of publication year (B = -0.288, P = 0.088), total sample size (B = -0.002, P = 0.276), and the mean age of cases (B = -0.06, P = 0.692) on the association between NLR and preterm delivery.
Conclusion:
The results of this meta-analysis revealed that the NLR value is higher in patients with preterm delivery. The NLR could be a useful biomarker for predicting preterm delivery; however, further prospective case-control studies are required to produce stronger evidence.
... Additionally, although controversial, some studies have identified some risk factors for fetal loss after amniocentesis in singleton pregnancies, such as maternal age, perforation of the placenta, vaginal bleeding, previous abortions, and abnormal color of the amniotic fluid. [7][8][9][10][11] No studies have explored such risk factors in pregnant women with twins. ...
Objective:
To assess and compare fetal loss rates before 28 weeks of singleton and twin pregnancies after mid-trimester amniocentesis.
Method:
This historic cohort study included 13 773 women with singletons and 426 women with twins undergoing mid-trimester amniocentesis from 1/2015 to 3/2017. Pregnancies resulting in termination or selective reduction before 28 weeks were excluded, as well as twin gestations undergoing single-puncture amniocentesis. Fetal loss rates were compared between singleton and twins taking into account maternal characteristics, amniocentesis procedure, and fetal chromosomal abnormalities.
Results:
The rates of fetal chromosomal abnormalities were similar in singleton and twin gestations (1.13% vs 0.70%, P = 0.253). No difference was found in maternal or fetal characteristics, or amniocentesis procedure between the two groups. The fetal loss rate was significantly higher in twin compared with singleton pregnancies (1.91% vs 0.24%, P < 0.001, RR = 8.25 [95% CI: 4.51 to 15.09]). The fetal loss rate between monochorionic twins and dichorionic twins was similar (1.80% vs 1.78%, P = 1.000).
Conclusions:
Twin pregnancies have higher risk of fetal loss after mid-trimester amniocentesis, which cannot be explained by differences in rates of fetal chromosomal abnormalities, maternal characteristic, or amniocentesis technique. This article is protected by copyright. All rights reserved.
... Although various factors are suspected in the pathogenesis of preterm labour and PPROM, infection or inflammation plays an important role in the initiation of preterm labour, and the best method is amniocentesis for the detection source of the intrauterine infection. However, amniocentesis is related to a risk of foetal loss of approximately 0.5% (Kozlowskı et al. 2008). Therefore, there is a much more need to use a non-invasive method rather than invasive methods. ...
The aim of the study was to investigate peripheral blood platelets, neutrophils and lymphocytes counts in women with preterm premature rupture of membranes (PPROM) and threatened preterm labour (TPL) compared with gestation-matched controls in order to learn how they change. This study was conducted on 60 women with PPROM, 50 women with TPL and 47 healthy pregnant women. Laboratory parameters (including complete blood count, C-reactive protein (CRP)) of all the participants were recorded. The neutrophil-to-lymphocyte ratio (NLR) values were significantly higher in PPROM group than TPL group and healthy control group (6.1 ± 3.9, 4.4 ± 1.7, 4.4 ± 2.2, p = .007, p = .018, respectively). At a cut-off level of 5.14, NLR accurately predicted occurrence of neonatal sepsis (AUC = 0.717 (95% confidence interval 0.610–0.824), p = .001) with sensitivity and specificity rates of 69.7% and 72.0%, respectively. In the management of the patients with PPROM, NLR can be used as a more cost-effective method than other blood parameters that require the use of a kit.
• IMPACT STATEMENT
• What is already known on this subject? There is only one study in the literature evaluating blood count parameters (such as platelet-to-lymphocyte ratio (PLR), NLR) in PPROM pregnancies. That study demonstrated PLR and NLR were both higher in the PPROM group.
• What do the results of this study add? The present study demonstrates that only NLR is higher in the PPROM group. Furthermore, we have also demonstrated distinctively that NLR can predict occurrence of neonatal sepsis.
• What are the implications of these findings for clinical practice and/or further research? High values of NLR may be useful for predicting adverse outcomes in PPROM and TPL patients as a cost-effective method. Further studies are needed to determine whether these parameters can be used to predict if a pregnant woman who is at risk of preterm labour will result in adverse perinatal outcome.
... However, the use of plasma levels of CRH as a predictor for preterm labour is controversial (Pawelec et al. 2013). In the amniotic model, increased concentrations of macrophage migration inhibitor, pro-infl ammatory cytokines and glucocorticoids play important roles in both term and preterm labour (Kozlowski et al. 2008). Infection plays an important role in the initiation of preterm labour, and the best source of intrauterine infection is amniotic fl uid. ...
Objective:
Noninvasive and simple markers are needed for the prediction of preterm delivery in women at risk for preterm labour. The aim of this study was to determine the value of platelet indices in the prediction of preterm delivery.
Design:
A retrospective study.
Setting:
Routine antenatal care in Zonguldak Bülent Ecevit University between 2008 and 2011.
Sample:
Ninety patients who delivered between 28 and 37 weeks of gestational age and 128 patients who delivered at term.
Methods:
Plateletcrit and other haematological markers, cervical dilatation and effacement, and the neutrophil-to-lymphocyte ratio as an inflammation marker.
Main outcome measure:
The role of platelet indices in predicting the preterm delivery.
Results:
The platelet count, plateletcrit, white blood cell count, red cell distribution width, and neutrophil count were significantly higher in the preterm delivery group. Receiver operating characteristic curve analysis showed that the plateletcrit cut-off value for predicting spontaneous preterm labour was 0.201%, with a sensitivity of 95.6% and specificity of 87.5%; the cut-off value for the platelet count was 234 ? 103/mm3 with a sensitivity of 81.0% and specificity of 71.0%.
Conclusion:
Plateletcrit is a low-cost, widely available, and noninvasive marker that might be used for the prediction of preterm delivery in patients with a history of preterm labour.
... In the amniotic model, increased concentrations of macrophage migration inhibitor, pro-infl ammatory cytokines and glucocorticoids play important roles in both term and preterm labour (Kozlowski et al. 2008). Infection plays an important role in the initiation of preterm labour, and the best source of intrauterine infection is amniotic fl uid. ...
... Allerdings ergab die einzige randomisierte Studie von 1986, durchgeführt unter kontinuierlicher Ultraschallsicht mit einer 20G-Nadel zwischen 16 und 18 SSW bei Schwangeren im Alter zwischen 24 und 35 Jahren, ein eingriffsbedingtes Abortrisiko von 1,0 % [38]. Neuere retrospektive, nicht randomisierten Untersuchungen an großen Gruppen mit AZ im Vergleich mit Kontrollgruppen ohne AZ berichten über Abortraten von 0,13 % [39], 0,06 % [40], 0,46 % [41], 0,49 % [42] und 1 % [43]. Weitere Studien mit ähnlichem Design geben das eingriffsbedingte Abortrisiko mit 0,46 bzw. ...
... Any reduction of such detection rates would be unacceptable. However, as every invasive diagnostic test is associated with a risk of miscarriage which is about 0.5 % higher than the natural miscarriage rate, the assessment of foetal DNA from a maternal blood sample would be preferable as it is not associated with an additional risk of miscarriage [19,20]. It would be easier if the assessment of foetal DNA was considered a screening test for trisomy 21. ...
Over the last few years, first trimester screening between 11+ and 13+ weeks of gestation has become one of the most important ultrasound examinations in pregnancy, as it allows physicians to predict several pregnancy complications including pre-eclampsia or pre-term birth. Screening for trisomies 21/18 and 13 using maternal and gestational age, foetal nuchal translucency, and maternal serum biochemistry was formerly the main reason for first trimester screening. However, today this is only one part of the overall examination. In the near future, the analysis of foetal DNA obtained from maternal blood will be used to supplement first trimester screening for aneuploidy or even replace current screening methods. In this review we show how prenatal medicine specialists can use foetal DNA analysis.
... Allerdings ergab die einzige randomisierte Studie von 1986, durchgeführt unter kontinuierlicher Ultraschallsicht mit einer 20G-Nadel zwischen 16 und 18 SSW bei Schwangeren im Alter zwischen 24 und 35 Jahren, ein eingriffsbedingtes Abortrisiko von 1,0 % [38]. Neuere retrospektive, nicht randomisierten Untersuchungen an großen Gruppen mit AZ im Vergleich mit Kontrollgruppen ohne AZ berichten über Abortraten von 0,13 % [39], 0,06 % [40], 0,46 % [41], 0,49 % [42] und 1 % [43]. Weitere Studien mit ähnlichem Design geben das eingriffsbedingte Abortrisiko mit 0,46 bzw. ...
... To decrease the incidence of these monogenetic diseases, prenatal diagnosis is wildly used as the most efficient approach in clinical practices. But traditional sampling approaches for prenatal diagnosis such as amniocentesis and chorionic villus sampling (CVS) are invasive and therefore might increase the risk of miscarriage [3]. ...
The discovery of cell free fetal DNA (cff-DNA) in maternal plasma has brought new insight for noninvasive prenatal diagnosis. Combining with the rapidly developed massively parallel sequencing technology, noninvasive prenatal detection of chromosome aneuploidy and single base variation has been successfully validated. However, few studies discussed the possibility of noninvasive pathogenic CNVs detection.
A novel algorithm for noninvasive prenatal detection of fetal pathogenic CNVs was firstly tested in 5 pairs of parents with heterozygote α-thalassemia of Southeast Asian (SEA) deletion using target region capture sequencing for maternal plasma. Capture probes were designed for α-globin (HBA) and β-globin (HBB) gene, as well as 4,525 SNPs selected from 22 automatic chromosomes. Mixed adaptors with 384 different barcodes were employed to construct maternal plasma DNA library for massively parallel sequencing. The signal of fetal CNVs was calculated using the relative copy ratio (RCR) of maternal plasma combined with the analysis of R-score and L-score by comparing with normal control. With mean of 101.93× maternal plasma sequencing depth for the target region, the RCR value combined with further R-score and L-score analysis showed a possible homozygous deletion in the HBA gene region for one fetus, heterozygous deletion for two fetus and normal for the other two fetus, which was consistent with that of invasive prenatal diagnosis.
Our study showed the feasibility to detect pathogenic CNVs using target region capture sequencing, which might greatly extend the scope of noninvasive prenatal diagnosis.
... There are 4% neonates born with a congenital disease completely or partially due to genetic defect, and these diseases can be categorized into three groups: chromosomal aberrations, monogenic diseases and polygenic diseases (1). Theoretically, the first two kinds of genetic diseases can be directly diagnosed with the fetal sample before birth; however, we have to face a hard nut that all the invasive prenatal diagnosis procedures bear a risk of fetal loss ranging from 0.25% to 1% depending on the particular approach used, while the current general non-invasive tests are just for screening rather than direct analysis of fetal DNA (2)(3)(4)(5)(6)(7)(8). Ever since the fetal cells were found with haemoglobin F in maternal blood in 1964 (9), several research groups had turned to the study of fetal nucleated cells in maternal blood, but the application of this approach to clinical practice is yet to be optimized. ...
The discovery of circulating fetal nucleic acids is a great step on the way of developing non-invasive prenatal diagnosis (NIPD) for genetic disorders. Here, we briefly discuss the current applications of circulating fetal nucleic acids in genetic testing for different kinds of hereditary diseases with an emphasis on using circulating cell-free fetal DNA in diagnosis of monogenic disorders. As the genetic skin disorders impair the quality of life at different levels, we next discuss some ethical issues in NIPD for genetic skin diseases of various severities and in particular, the responsibility of doctors and parents, respectively, in the prenatal genetic testing.
... When couples who are carriers of a genetic disorder wish to conceive they have the option to either not perform prenatal genetic testing and to accept the possibility of an affected child or to perform an invasive test (chorionic villus sampling or amniocentesis) in order to determine the genetic status of the embryo. Both of these invasive methods are accompanied by a small risk of abortion due to the procedure [28]. Furthermore, at present, these tests cannot be performed earlier than 10-11 weeks of gestation, therefore a significant period of time remains between the date the pregnancy is detected until the results of genetic testing are received causing increased anxiety and uncertainty in respect to the future of the pregnancy. ...
Preimplantation genetic diagnosis (PGD) allows birth of unaffected children for couples at risk for a genetic disorder. We present the strategy and outcome of PGD for four lysosomal storage disorders (LSD): Tay-Sachs disease (TSD), Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (HS), and subsequent development of stem cell lines. For each disease, we developed a family-specific fluorescent multiplex single-cell PCR protocol that included the familial mutation and informative markers surrounding the mutation. Embryo biopsy and PGD analysis were performed on either oocytes (polar bodies one and two) or on single blastomeres from a six-cell embryo. We treated twenty families carrying mutations in these lysosomal storage disorders, including 3 couples requiring simultaneous analysis for two disorders (TSD/GD, TSD/balanced Robertsonian translocation 45XYder(21;14), and HS/oculocutaneus albinism). These analyses led to an overall pregnancy rate/embryo transfer of 38% and the birth of 20 unaffected children from 17 families. We have found that PGD for lysosomal disorders is a safe and effective method to prevent birth of affected children. In addition, by using mutant embryos for the derivation of stem cell lines, we have successfully established GD and HS hESC lines for use as valuable models in LSD research.
... Prenatal diagnosis (PD) of single-gene disorders through the use of invasive techniques is an accepted part of clinical practice and is performed when there is a family history of a particular disease or, less frequently, ultrasonographic findings. Conventional prenatal diagnosis requires invasive obstetric procedures (chorion biopsy or amniocentesis) that entail a risk of fetal loss which is estimated at 0.5-1% depending on the method used (Kozlowski et al., 2008;Mujezinovic and Alfirevic, 2007). ...
Prenatal diagnosis (PD) is available for pregnancies at risk of monogenic disorders. However, PD requires the use of invasive obstetric techniques for fetal-sample collection and therefore, involves a risk of fetal loss. Circulating fetal DNA in the maternal bloodstream is being used to perform non-invasive prenatal diagnosis (NIPD). NIPD is a challenging discipline because of the biological features of the maternal blood sample. Maternal blood is an unequal mixture of small (and fragmented) amounts of fetal DNA within a wide background of maternal DNA. For this reason, initial NIPD studies have been based on the analysis of specific paternally inherited fetal tracts not present in the maternal genome so as to ensure their fetal origin. Following this strategy, different NIPD studies have been carried out, such as fetal-sex assessment for pregnancies at risk of X-linked disorders, RhD determination, and analysis of single-gene disorders with a paternal origin. The study of the paternal mutation can be used for fetal diagnosis of dominant disorders or to more accurately assess the risk of an affected child in case of recessive diseases. Huntington's disease, cystic fibrosis, or achondroplasia are some examples of diseases studied using NIPD. New technologies are opening NIPD to the analysis of maternally inherited fetal tracts. NIPD of trisomy 21 is the latest study derived from the use of next-generation sequencing (NGS).
... This seems counterintuitive as screening tests are non-invasive and do not involve any risk of direct harm to the mother or baby. Research on amniocentesis has focused mainly on the risk of miscarriage, 24,25 anxiety 26,27 and knowledge. Little research has been directed at identifying womenÕs information and support needs surrounding the decision to accept or decline amniocentesis. ...
Our aim was to clarify and categorize information and decision support needs of pregnant women deciding about amniocentesis.
Prenatal screening for Down's syndrome (implemented in routine practice) generates a quantifiable risk of chromosome abnormality. To increase certainty, chromosomal material needs to be obtained through amniocentesis or other diagnostic test. Amniocentesis carries risks of pregnancy loss.
Semi-structured interviews were conducted with health professionals and pregnant women who had considered amniocentesis. The data were qualitatively analysed using a two-step thematic content analysis.
A sample of 17 health professionals and 17 pregnant women were interviewed. Professionals demonstrated little consensus regarding the miscarriage rate, the potential consequences of amniocentesis testing and the uncertainty associated with the tests. Furthermore, methods employed to communicate risks varied between professionals. Pregnant women reported heightened stress and anxiety. Twelve out of 17 women described the decision as complex and difficult to make while five participants were satisfied with the information and support provided. Women would have liked more information about the risks involved, the results, the consequences of an amniocentesis and associated emotional difficulties. Women highlighted the need for personalized information, presented in multiple ways, while remaining simple and unbiased.
There is variation in the provision of information related to amniocentesis testing. The majority of pregnant women reported difficulties making a decision and identified dimensions of information and decision support where improvements were needed.
Sickle Cell Disease (SCD) is one of the most prevalent autosomal recessive disease, affecting over 600,000 newborns globally each year. In Spain, the Spanish Registry of Hemoglobinopathies (REHem) has registered 1142 cases. Despite improvements in treatments, prophylaxis, and vaccines, it remains a chronic condition requiring lifelong care. Allogeneic transplantation is the only cure, contingent upon the availability of an HLA-compatible donor. SCD is considered a rare disease in some population, resulting from a mutation of a single nucleotide in codon 6 GAG>GTG (HBB: c.20A>T) of the β-globin gene, producing hemoglobin S (HbS), altering the shape of red blood cells and obstructing circulation, leading to severe complications in multiple organs. Heterozygous individuals (βS/βA) have the ‘sickle cell trait,’ typically asymptomatic. Homozygotes experience symptomatic disease, with chronic and acute infarctions in organs and tissues, episodes of intense pain, cerebral infarctions, splenomegaly, massive hemolytic episodes, and acute chest syndrome, causing a risk of premature death increasing the threat of premature mortality. Prenatal diagnosis provides expecting couples with information about the fetus’s genetic health, enabling informed decision-making. Although conventional techniques are invasive and carry risks, Non-Invasive Prenatal Diagnosis (NIPD) has been developed using cell free fetal DNA (cffDNA) in maternal blood to determine the fetus’s genotype. However, the co-presence of maternal DNA and cffDNA, along with the low concentration of the latter, has been a challenge in non-invasive studies. We present the results of a pilot study where the use of digital PCR (dPCR) has been established for NIPD of SCD, a highly sensitive technique allowing the detection of mutations in low-frequency samples, presenting itself as a safe alternative for SCD diagnosis.
Diagnostic puncture (amniocentesis, chorionic villus sampling, and fetal blood sampling) is an essential part of prenatal diagnostics and the only established and sufficiently scientifically evaluated possibility of diagnosing genetic diseases from pregnancy-specific cells. The number of diagnostic punctures in Germany, as in other countries, has fallen significantly. This is largely due to the introduction of first-trimester screening with further detailed ultrasound examination of the fetus and the analysis of cf-DNA (cell-free DNA) from maternal blood (noninvasive prenatal test - NIPT). On the other hand, knowledge about the incidence and appearance of genetic diseases has increased. The development of modern molecular genetic techniques (microarray and exome analysis) makes a differentiated investigation of these diseases increasingly possible. The requirements for education and counseling regarding these complex correlations have thus increased. The studies performed in recent years make it clear that diagnostic puncture performed in expert centers is associated with a low risk of complications. In particular, the procedure-related miscarriage risk hardly differs from the background risk for spontaneous abortion. In 2013, the Section of Gynecology and Obstetrics of the German Society for Ultrasound in Medicine (DEGUM) published recommendations on diagnostic puncture in prenatal medicine 1. The developments described above and new findings in recent years make it necessary to revise and reformulate these recommendations. The aim of this review is to compile important and current facts regarding prenatal medical puncture (including technique, complications, genetic examinations). It is intended to provide basic, comprehensive, and up-to-date information on diagnostic puncture in prenatal medicine. It replaces the publication from 2013 1.
Hearing loss is the most common neurosensory deficit. It results from a variety of heritable and acquired causes and is linked to multiple deleterious effects on a child's development that can be ameliorated by prompt identification and individualized therapies. Diagnosing hearing loss in newborns is challenging, especially in mild or progressive cases, and its management requires a multidisciplinary team of healthcare providers comprising audiologists, pediatricians, otolaryngologists and genetic counselors. While physiologic newborn hearing screening has resulted in earlier diagnosis of hearing loss than ever before, a growing body of knowledge supports the concurrent implementation of genetic and cytomegalovirus testing to offset the limitations inherent to a singular screening modality. In this review, we discuss the contemporary role of screening for hearing loss in newborns as well as future directions in its diagnosis and treatment.
Objective: To compare the fetal loss rate associated with second-trimester amniocentesis between the procedures with penetration and nonpenetration of the placenta, as a primary outcome and to compare the rates of adverse pregnancy outcomes including preterm birth, fetal growth restriction and low birth weight, as secondary outcomes.
Method: A retrospective cohort study was conducted on women undergoing second-trimester amniocentesis. Our prospective database of amniocentesis, from January 1989 to December 2018, was accessed to retrieve the records meeting the inclusion criteria consisting of singleton pregnancies, gestational age of 16–22 weeks, and known obstetric outcomes. The patients were categorized into two groups: placental penetration and nonpenetration. The rates of fetal loss, including abortion (<24 weeks of gestation) and fetal death in utero (>24 weeks of gestation), and other adverse pregnancy outcomes were compared between the two groups.
Results: A total of 21,566 procedures were performed during the study period. Of them, 8601 were excluded due to chromosomal/structural abnormalities, various underlying medical diseases and incomplete data or unavailability of final outcomes. Finally, 12,965 cases were available for analysis including 4692 (36.2%) in the group of placental penetration and 8273 (63.8%) in the group of nonpenetration. The abortion rate after amniocentesis trended to be increased in the placental penetration group (0.6 versus 0.4%, p = .064; RR: 1.60, 95%CI 0.97-2.64). Likewise, the fetal loss rate trended to be increased in the placental penetration group (1.0 versus 0.7%, p = .121; RR: 1.35 95%CI 0.92–1.98). Interestingly, preterm birth rate was significantly increased in the placental penetration group (13.8 versus 12.6%, p = .043; RR: 1.10 95%CI 1.00–1.20).
Conclusion: Fetal loss rate was slightly increased, but not statistically significant, among the procedures with placental penetration. However, penetration of the placenta was slightly but significantly associated with an increase in rates of preterm birth.
Objectives
This study was used to demonstrate the feasibility of haplotype-based noninvasive prenatal diagnosis for Hemophilia A.
Methods
Two families affected by Hemophilia A participated in our study. Maternal haplotypes associated with pathogenic mutation was built using targeted region genotypes of mother and the proband. Combined with maternal pathogenic haplotype, a Hidden Markov Model was constructed to deduce fetal haplotype using high-coverage targeted sequencing of maternal plasma. The presence of pathogenic haplotype in male indicated affected fetus, in female indicated carrier. Prenatal diagnosis was confirmed with amniocentesis by long distance PCR.
Results
The haplotype-based noninvasive prenatal diagnosis was successfully performed in Hemophilia A. One fetus was identified to be normal, another fetus was identified as carrier, and the results were confirmed by amniocentesis .
Conclusion
Our research demonstrated the feasibility of noninvasive prenatal diagnosis for Hemophilia A by haplotype-based approach.
Die pränatale Chromosomendiagnostik ist in zahlreichen Labors als Routineverfahren etabliert. Zur Durchführung der pränatalen Analysen ist ein invasives Verfahren erforderlich. Die Amniozentese im II. Trimester stellt das weltweit am häufigsten eingesetzte Punktionsverfahren dar. Der optimale Zeitpunkt für die Durchführung der Amniozentese liegt nach 15+0 SSW. Die Chorionzottenbiopsie (CVS) steht als alternative Punktionsart für das I. Trimester zur Verfügung. Die eingriffsbedingen Verlustraten nach transabdominaler CVS und Amniozentese im II. Trimester sind mit ca. 0,2 % vergleichbar. Mit zunehmender Verbreitung und Akzeptanz der sonographischen und biochemischen Diagnostik sowie des Screenings mittels zellfreier DNA-Tests ist allerdings in vielen Ländern ein Trend zu einem Rückgang an invasiven Eingriffen insgesamt zu beobachten.
Vor mehr als 40 Jahren erschienen die ersten Berichte über eine erfolgreiche Chromosomendiagnostik aus angezüchteten Fruchtwasserzellen. Seit Beginn der siebziger Jahre wurde die pränatale Chromosomendiagnostik in zahlreichen Labors als Routineverfahren etabliert und stellt auch heute noch den Hauptanteil der durchgeführten pränatalen Analysen dar (Kap. 27, Genetik). Dabei ist die Amniozentese im II. Trimenon das weltweit am häufigsten eingesetzte Punktionsverfahren. Üblicherweise liegen die Ergebnisse erst nach der 16. SSW vor, sodass die Chorionzottenbiopsie (″chorionic villous sampling″, CVS) als alternative Punktionsart für das I. Trimenon entwickelt wurde.
During the last two decades prenatal genetic screening and diagnosis has become the cornerstone of medical care for family planning to prevent genetic disease. Carrier screening programs for genetic disorders that are prevalent in various populations identify couples and pregnancies at risk of having an affected child. These couples can proceed with a choice of invasive prenatal diagnosis tests of the fetus (chorionic villous sampling and amniocentesis), or non-invasive prenatal testing of free fetal DNA circulation in the maternal blood which has emerged within the last few years and is currently available for fetal sexing for X Linked disorders. Despite the advances in prenatal diagnosis, couples found to have a fetus affected with a genetic disorder may need to face the dilemma of pregnancy termination. Preimplantation genetic diagnosis (PGD) is an alternative to preempt risk of having a child affected with a life altering genetic disorder. This technique allows biopsy and genetic diagnosis of embryos obtained from in vitro fertilization by analysis of the genetic material from one or a few embryonic cells. Only unaffected embryos are returned to the mother to establish the pregnancy. We present our experience using PGD for four Lysosomal storage disorders: Tay Sachs, Gaucher type 1, Hunter and Fabry disease with some of the couples being carriers of more than one genetic disorder. PGD is applicable to most disorders for which the gene and the familial mutation are known and should be presented to couples as an alternative to invasive prenatal testing.
Objective:
The aim of this study was to compare transabdominal chorionic villus sampling, transcervical chorionic villus sampling and amniocentesis with respect to their total fetal loss rates.
Methods:
We retrospectively evaluated procedures of invasive prenatal testing performed during a 14-year period (2001-2014) including 936 amniocentesis procedures and 1051 chorionic villus samplings, of which 405 cases were executed transabdominally and 646 transcervically. Only singleton pregnancies before 24 weeks and 0 days of gestation where the pregnancy outcome was known were included. Fetal loss was defined as an abortion occurring either before 24 weeks and 0 days of gestation or <2 weeks after the procedure.
Results:
The total fetal loss rates were determined to be 1.73% for transabdominal chorionic villus sampling, 2.01% for transcervical chorionic villus sampling and 1.18% for amniocentesis. No statistically noticeable differences between the total fetal loss rates of all three procedures were found (P=0.399).
Conclusion:
Our study has shown that chorionic villus sampling (either transabdominal or transcervical) and amniocentesis are equal methods for invasive prenatal testing with respect to their abortion risk.
The expanding knowledge in human genetics has led to practical applications at an increasing rate — especially in genetic counseling and genetic screening. Conventional and invasive diagnostic procedures have been complemented or entirely replaced by genetic-testing. DNA tests allow us to predict diseases and to modify risk figures. With increasing numbers of both diagnostic and predictive genetic tests available, genetic counseling is becoming more important in virtually all fields of clinical practice. The traditional areas of genetic counseling included pediatrics (assessment of children with developmental delay and dysmorphic features) and obstetrics (prenatal diagnosis). However, as the genetic basis of more and more diseases is unraveled, genetic counseling is now increasingly requested from other disciplines, including neurology, oncology, ophthalmology.
We present in this study our 10years experience in prenatal diagnosis of cystic fibrosis performed in the Tunisian population.
Based on family history, 40 Tunisian couples were selected for prenatal diagnosis. Fetal DNA was isolated from amniotic fluid collected by transabdominal amniocentesis or from chronic villi by transcervical chorionic villus sampling. The genetic analysis for cystic fibrosis mutations was performed by denaturant gradient gel electrophoresis and denaturing high-pressure liquid phase chromatography. We performed microsatellites analysis by capillary electrophoresis in order to verify the absence of maternal cell contamination.
Thirteen fetuses were affected, 21 were heterozygous carriers and 15 were healthy with two normal alleles of CFTR gene. Ten couples opted for therapeutic abortion. The microsatellites genotyping showed the absence of contamination of the fetal DNA by maternal DNA in 93.75%.
Our diagnostic strategy provides rapid and reliable prenatal diagnosis at risk families of cystic fibrosis.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Greater maternal body mass index (BMI) before or during early pregnancy is associated with an increased risk of fetal death, stillbirth, perinatal death, neonatal death, and infant death. This systematic review and meta-analysis of cohort studies was conducted to determine the strength of these associations, the shape of the dose-response relationship, potential confounding, and potential sources of heterogeneity. PubMed and EMBASE databases were searched for cohort studies that reported on maternal BMI before or in early pregnancy and risk of fetal death, miscarriage, stillbirth, and neonatal, perinatal, and infant death. Articles that provided adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) for 3 or more categories of BMI (<18.5 or <20, <25, 30–<35, 35–<40, and 40–<45 kg/m2) were eligible. Summary RRs per 5 BMI units for the association between maternal BMI and fetal and infant death were calculated using the random effects model. Absolute risks were reported per 10,000 pregnancies for BMIs of 20, 25, and 30 kg/m2. Thirty-eight studies were included in the dose-response analysis. Seven studies investigated the association between BMI and fetal death. The summary RR was 1.21 (95% CI, 1.09–1.35). For BMIs of 20, 25, and 30 kg/m2, absolute risks were 76 (reference standard), 82 (95% CI, 76–88), and 102 (95% CI, 93–112), respectively. Five of these studies reported on BMI and miscarriages; the summary RR was 1.16 (95% CI, 1.07–1.26). Eighteen studies investigated BMI and stillbirth; the summary RR was 1.24 (95% CI, 1.18–1.30). For BMIs of 20, 25, and 30 kg/m2, absolute risks were 40 (reference standard), 48 (95% CI, 46–51), and 59 (95% CI, 55–63), respectively. Studies that reported results for antepartum and intrapartum stillbirths had summary RRs of 1.28 (95% CI, 1.15–1.43) and 0.90 (95% CI, 0.76–1.06), respectively. Eleven studies assessed BMI and perinatal death; the summary RR was 1.16 (95% CI, 1.00–1.35). For BMIs of 20, 25, and 30 kg/m2, absolute risks were 66 (reference standard), 73 (95% CI, 67–81), and 86 (95% CI, 76–98), respectively. Twelve studies analyzed BMI and neonatal death; the summary RR was 1.15 (95% CI, 1.07–1.23). For BMIs of 20, 25, and 30 kg/m2, absolute risks were 20 (reference standard), 21 (95% CI, 19–23), and 24 (95% CI, 22–27), respectively. For early and postneonatal deaths, the summary RRs were 1.31 (95% CI, 1.22–1.41) and 1.14 (95% CI, 1.06–1.22). Four studies analyzed maternal BMI and infant death; the summary RR was 1.18 (95% CI, 1.09–1.28). For BMIs of 20, 25, and 30 kg/m2, absolute risks were 33 (reference standard), 37 (95% CI, 34–39), and 43 (95% CI, 40–47), respectively. Even small increases in maternal BMI were associated with increased risks of adverse pregnancy outcomes. Weight management guidelines for women who plan pregnancies should consider these findings to reduce the incidence of adverse outcomes.
The purpose of this retrospective controlled study is to estimate the risk for fetal loss and preterm delivery attributed to second trimester amniocentesis from a single tertiary center.
The study group consists of 12,413 singleton pregnancies with consecutive amniocenteses, performed in a single tertiary center during a 15-year period (1996–2010) with known pregnancy outcome. The control group consisted of 6993 pregnancies with negative second trimester screening for aneuploidies during the same period who did not have any invasive test. The two groups were compared in terms of fetal loss rate up to 24 weeks and premature deliveries.
Total fetal loss up to 24 weeks in the study group, excluding terminations of pregnancy, was estimated at 1.25% (1.05%–1.45%, confidence interval [CI]: 95%). In the control group the loss rate was 0.65% giving a procedure related fetal loss rate of 0.6% which was not found to be a statistically significant difference. Delivery before the 28
The present study has shown that the risk of miscarriage that can be attributed to amniocentesis in our institution is 0.6%, and this is not statistically significant when compared with cases without any invasive procedure during pregnancy. Similarly, the risk for preterm labor was not statistically significant when compared with controls.
Importance
Evidence suggests that maternal obesity increases the risk of fetal death, stillbirth, and infant death; however, the optimal body mass index (BMI) for prevention is not known.Objective
To conduct a systematic review and meta-analysis of cohort studies of maternal BMI and risk of fetal death, stillbirth, and infant death.Data Sources
The PubMed and Embase databases were searched from inception to January 23, 2014.Study Selection
Cohort studies reporting adjusted relative risk (RR) estimates for fetal death, stillbirth, or infant death by at least 3 categories of maternal BMI were included.Data Extraction
Data were extracted by 1 reviewer and checked by the remaining reviewers for accuracy. Summary RRs were estimated using a random-effects model.Main Outcomes and Measures
Fetal death, stillbirth, and neonatal, perinatal, and infant death.Results
Thirty eight studies (44 publications) with more than 10 147 fetal deaths, more than 16 274 stillbirths, more than 4311 perinatal deaths, 11 294 neonatal deaths, and 4983 infant deaths were included. The summary RR per 5-unit increase in maternal BMI for fetal death was 1.21 (95% CI, 1.09-1.35; I2 = 77.6%; n = 7 studies); for stillbirth, 1.24 (95% CI, 1.18-1.30; I2 = 80%; n = 18 studies); for perinatal death, 1.16 (95% CI, 1.00-1.35; I2 = 93.7%; n = 11 studies); for neonatal death, 1.15 (95% CI, 1.07-1.23; I2 = 78.5%; n = 12 studies); and for infant death, 1.18 (95% CI, 1.09-1.28; I2 = 79%; n = 4 studies). The test for nonlinearity was significant in all analyses but was most pronounced for fetal death. For women with a BMI of 20 (reference standard for all outcomes), 25, and 30, absolute risks per 10 000 pregnancies for fetal death were 76, 82 (95% CI, 76-88), and 102 (95% CI, 93-112); for stillbirth, 40, 48 (95% CI, 46-51), and 59 (95% CI, 55-63); for perinatal death, 66, 73 (95% CI, 67-81), and 86 (95% CI, 76-98); for neonatal death, 20, 21 (95% CI, 19-23), and 24 (95% CI, 22-27); and for infant death, 33, 37 (95% CI, 34-39), and 43 (95% CI, 40-47), respectively.Conclusions and Relevance
Even modest increases in maternal BMI were associated with increased risk of fetal death, stillbirth, and neonatal, perinatal, and infant death. Weight management guidelines for women who plan pregnancies should take these findings into consideration to reduce the burden of fetal death, stillbirth, and infant death.
Purpose:
The purpose of this study was to classify pregnancy loss and fetal loss as well as the influence of maternal risk factors in multiple pregnancies.
Methods and materials:
Details of the procedure and pregnancy outcome of all patients were extracted from the clinical audit database of two tertiary centers. The files were collected in the time from January 1993 to May 2011. The procedure-related pregnancy and fetal loss rate was classified as all unplanned abortions without important fetal abnormalities or obstetric complications within 14 days after AC and CVS.
Results:
We had a total number of 288 multiple pregnancies with a total of 637 fetuses. After the exclusion of 112 pregnancies with abnormal karyotype or fetal abnormalities detected by ultrasound as well as cases of selective feticide, repeated invasive procedures and monochorionic-monoamniotic pregnancies, 176 pregnancies and 380 fetuses were left for final analysis. Overall 132 amniocenteses and 44 chorionic villous sampling procedures were performed. The total pregnancy loss rate was 8.0 % (14/176), 6.1 % (n = 8) for amniocentesis and 13.6 % (n = 6) for CVS. The procedure-related pregnancy loss rate was 3.4 %, 2.3 % after amniocentesis (3 cases) and 6.8 % after CVS (3 cases). There was no statistical significance between the two procedures (p = 0.15).
Conclusion:
The procedure-related loss rate of 3.4 % can be compared to the rates in the literature. The higher loss rates in multiple pregnancies than in singleton pregnancies have to be discussed when counseling parents.
Objective. The purpose of our study was to reconsider the complete diagnostic protocol in some selected cases, highly suspected after first trimester anatomical and biochemical evaluation. Method. We used the three-year data from a first trimester morphologic and genetic prospective study conducted in three university clinics. We considered the first trimester (11-14 gestational weeks) morphological and biochemical findings in the affected singleton pregnancies. The diagnostic of the chromosomal abnormalities was made using quantitative fluorescence polymerase chain reaction (QF-PCR) and multiplex ligation-dependent probe amplification (MLPA) techniques after chorionic villous sampling (CVS) and the genetic results were confirmed by karyotyping. Results. In the vast majority of the cases multiple first trimester morphological markers were found in association to chromosomopaties (90.9%). In almost half of the cases (45.4%) more than six anatomical features were found abnormal and also the biochemical risk was increased. In these cases, the genetic techniques were concordant with the ultrasound morphological presumptive diagnosis. In all these patients we noted a high degree of anxiety related to the time needed for completion of genetic assessment. Conclusions. We consider that an alternative approach in certain socio-economic settings is termination of pregnancy (TOP) followed by genetic diagnostic in cases with ultrasound evaluation revealing typical morphological / functional features for genetic syndromes and altered serum biochemistry.
Purpose:
To assess the total and procedure-related fetal loss rate and associated risk factors following amniocentesis (AC), chorionic villus sampling (CVS) and fetal blood sampling (FBS).
Materials and methods:
We performed a retrospective analysis of patients with invasive diagnostics from 1993 to 2011 in two tertiary referral centers. We aimed to classify pregnancy loss after an invasive procedure and included the time after the invasive procedure and the result of targeted ultrasound/karyotype analysis in the analysis. Fetal losses occurring within two weeks after an invasive procedure were classified as procedure-related.
Results:
After excluding 1553 pregnancies with abnormal karyotype, fetal malformations and multiple insertions, 6256 cases were retrieved for final analysis. The total fetal loss rate was 1.5 %. The procedure-related fetal loss rate was 0.4 % for AC, 1.1 % for CVS and 0.4 % for FBS. Maternal vaginal bleeding in the first trimester was significantly associated with an increased procedure-related fetal loss rate (p= 0.008). The number of invasive procedures declined during the study period with increasing numbers of CVS in the first trimester.
Conclusion:
In our population the procedure-related fetal loss rate was 0.4 % after AC and 1.1 % and 0.4 % after CVS and FBS, respectively. Different gestational ages at the time of invasive procedures might account in part for those differences. Vaginal bleeding during the first trimester is associated with increased procedure-related fetal loss. Overall, declining numbers of invasive procedures are the result of changing attitudes toward invasive procedures and more sophisticated noninvasive prenatal screening programs over the last 20 years.
Introduction:
Since the presence of circulating cell-free fetal DNA (ccffDNA) in maternal peripheral blood was demonstrated in 1997, great efforts have been done in order to use this source of fetal material for noninvasive prenatal diagnosis. The advantage that it represents is avoiding the obstetric invasive procedures required for conventional prenatal diagnosis.
Areas covered:
Efforts are mainly focused on finding the most accurate way to diagnose the most common fetal aneuploidies, paying special attention to trisomy 21. Recent advances in technology offer new diagnostic tools with high degrees of sensitivity thus generating great expectations for this type of diagnosis. However, there are other reasons why pregnant women undergo conventional prenatal diagnosis. Being at risk of transmitting a monogenic disorder is one of them. And although the percentage of those pregnancies may represent a small percentage of the diagnosis performed in the first trimester, these numbers should not be underestimated.
Expert opinion:
Management of pregnancies at risk of an X-linked Mendelian disorder has changed thanks to the noninvasive fetal sex assessment. As for other Mendelian disorders, until recently, their study was limited to those cases paternally inherited. Nevertheless, the new emerging technologies are also opening the scope to maternally inherited disorders.
Simple, more sensitive markers to predict spontaneous preterm delivery in preterm labour are needed. The aim of this study is to compare the clinical effectiveness of various serum inflammatory markers and cervix length for prediction of spontaneous preterm delivery.
We retrospectively reviewed medical records of 175 patients hospitalized for preterm labour (102 with preterm delivery and 73 with term delivery). For all study subjects, haematological markers and cervix length were recorded on admission. Because neutrophil to lymphocyte ratio (NLR) showed the potential as a diagnostic marker, we designed a combined marker by dividing cervix length by NLR. The diagnostic and prognostic accuracy of the combined marker was analysed using multivariate analyses.
The levels of combined marker (P < 0·001), neutrophil (P < 0·001), lymphocyte (P = 0·02), NLR (P < 0·001), C-reactive protein (P = 0·016) and the cervix length (P < 0·001) in preterm delivery group were significantly different from those of term delivery group. Compared to cervix length or systemic inflammatory markers alone, combined marker showed higher sensitivity (64·2%) and specificity (88·3%) for prediction of preterm delivery. On Cox multivariate analysis, combined marker positive (< 0·29) and short cervix length (< 1·7 cm) were independent poor prognostic factors and combined marker positive was the most powerful prognostic marker for spontaneous preterm delivery (hazard ratio = 5·60, P < 0·001). Conclusions: Combined marker could be used as a simple and sensitive parameter for identifying women at risk of spontaneous preterm delivery.
To investigate the impact of the a priori attitude, nondirective counselling and targeted second trimester ultrasound examination on the decision process concerning invasive prenatal diagnosis in the second trimester.
A prospective study including 696 high-risk pregnancies at 15 to 18 weeks' gestation, performed from 2005-2007. Attitudes towards invasive prenatal testing were explored before and after genetic counselling and targeted ultrasound examination in a tertiary referral centre.
Initially, 311 (44.7%) women intended to have an invasive testing (group 1), 150 women (21.5%) were against an invasive procedure (group 2), and 235 women (33.8%) wanted to make their final decision depending on the sonographic result (group 3). The total rate of amniocentesis was 87.1%, 5.3% and 13.6%, respectively. Overall, the a priori decision was sparsely influenced by the ultrasound examination. Only 12.9% (40/311) and 5.3% (8/150) of the primarily determined women (group 1, 2) changed their opinion. However, in the initially undecided group, 86.7% declined an amniocentesis after a normal ultrasound scan.
The referral indication and the a priori opinion are the strongest influencing factors with regard to invasive testing and the ultrasound scan has a low impact in those preselected patients. However, ultrasound has an important reassuring aspect in women willing to use ultrasound as assistance in the process of decision making.
Data from the first phase (1974-1979) of this New York City case-control study showed that 1) cigarette smoking during pregnancy was associated positively with chromosomally normal spontaneous abortion and 2) both past and current smoking were associated inversely with trisomic loss in women under age 30 years and positively in older women. The authors used data from two subsequent study phases (1979-1982 and 1982-1986) to test the stability of these associations over time and the homogeneity between payment groups (private vs. public). Spontaneous abortions (cases) were classified as chromosomally normal (n = 1,388), trisomic (n = 557), or other chromosomally aberrant (n = 409). Controls (n = 4,165) were women who had registered for prenatal care before 22 weeks' gestation and delivered at 28 weeks or later. For chromosomally normal loss, later data gave modest support to prior observations. In the total sample, current smoking (defined as smoking during the month of the last menstrual period) of 14 or more cigarettes per day was increased among chromosomally normal cases in comparison with controls (adjusted odds ratio (OR) = 1.3, 95% confidence interval (CI) 1.1-1.7) and in comparison with other aberrant cases (adjusted OR = 1.2, 95% CI 0.8-1.8). Stronger associations in public patients than in private patients (adjusted odds ratios of 1.4-1.5 versus 0.8-0.9, respectively) might indicate either a mediating effect of social disadvantage or a chance fluctuation. For trisomic loss, later data did not support prior observations. Associations between trisomy and past or current smoking did not vary significantly with age in either payment group; assuming no effect modification of age, adjusted odds ratios for smoking in relation to trisomy were 0.9-1.0.
Hypochondroplasia (HCH) is an autosomal dominant skeletal dysplasia characterized by short extremities, short stature and lumbar lordosis, usually exhibiting a phenotype similar to but milder than achondroplasia (ACH). Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are present in a significant proportion of HCH patients. Reports of prenatal diagnosis of HCH are very rare and the phenotype/genotype correlation in these patients is poor. Here we present two sporadic cases with second trimester ultrasound findings consistent with a diagnosis of a non-lethal skeletal dysplasia. Ultrasound evaluation after 23 weeks of gestation showed a decreased rate of development of the femora (femur length <fifth centile), while biparietal diameter, abdominal circumference, and foot length were within normal limits. Femur length/foot and femur length/abdominal circumference ratios were <0.87 and <0.18, respectively. Prenatal cytogenetic and molecular genetic analysis was performed. Karyotype was normal and FGFR3 G380R mutation characteristic of ACH was excluded in both fetuses. Molecular genetic analysis carried out retrospectively revealed that both fetuses were heterozygous for the C1620A mutation resulting in N540K substitution in FGFR3, the most common mutation in HCH. We conclude that the combination of ultrasound and molecular genetic approach is helpful for establishing an accurate diagnosis of HCH in utero and subsequently for appropriate genetic counseling and perinatal management.
Studienziel: Die retrospektive, komplikationsbezogene Analyse aller invasiven pränataldiagnostischen Eingriffe im Dienste der Qualitätssicherung und der exakten Patientenaufklärung. Methode: In einem zweijährigen Beobachtungszeitraum wurden an einer pränataldiagnostischen Spezialabteilung 2256 ultraschallgeleitete invasive Eingriffe durchgeführt. Unter Zuhilfenahme einer Computerdatenbank werden 2066 Patientinnen nachverfolgt. Die Erfassung der Komplikationen wird im Zeitraum von 14 Tagen nach dem Eingriff durchgeführt. Ergebnisse: Abhängig von der Art des Eingriffes liegt bei Einlingsschwangerschaften die Rate an schweren Komplikationen (Abortus, IUFT) zwischen 0,44 % und 0,99 % (AC 0,74 %, PP 0,44 %, CVS 0,99 %, CC 0,75 %). Die Komplikationsrate nach AC beträgt 1,49 % bei Ausbildungsassistenten, gegenüber 0,58 % bei Fachärzten. Bei Mehrlingsschwangerschaften (AC) beträgt die Rate an schweren Komplikationen 1,99 %. Schlussfolgerung: Im Aufklärungsgespräch über die Indikationsstellung zur invasiven pränatalen Diagnostik ist für die Patientin vor allem die Komplikationsrate an der betreuenden Abteilung von Interesse. Nicht zuletzt aufgrund der größeren Erfahrung sollten kompliziertere invasive Eingriffe einem Zentrum für pränatale Diagnostik vorbehalten bleiben.
Women who are the most difficult to trace after amniocentesis or chorion villus sampling are often those who have had an adverse pregnancy outcome. To calculate total fetal loss figures for use in prenatal counselling we have followed in a multicentre study 100% of women who had undergone these procedures. Early spontaneous loss (within three weeks of the procedure) and total spontaneous loss were much lower after amniocentesis (0.2% and 1.3%, respectively) than after chorion villus sampling (1.2% and 2.9%). Four spontaneous fetal losses among the 20 pregnancies that were the most difficult to follow-up increased the loss rate by 0.5% for chorion villus sampling. Risk of early fetal loss after chorion villus sampling was related to experience of the operator (relative risk [RR] 4.3, p = 0.003), and total fetal loss was lower in pregnancies tested at 10 weeks' or more gestational age compared with those tested before 10 weeks' (RR 0.4, p = 0.01). A table showing the frequency of each of the seven possible outcomes after amniocentesis and chorion villus sampling is useful in counselling those considering one or other test.
The influence of the localization of the placenta and some technical problems associated with the performance of amniocentesis (AC) on the incidence of spontaneous abortion (SA) after AC was evaluated in a prospective study comprising all women (2276) referred for AC at the University Hospital in Odense during a 7-year period. Women with predisposing factors for SA were excluded from this analysis, which comprised 1545 women. Of these, 1289 women had an AC and 256 were judged not to need an AC after ultrasonographic examination. The localization of the placenta per se had no influence on the incidence of SA. However, if the placenta was covering the whole anterior wall so that perforation of the placenta could not be avoided, or if more than one insertion was necessary, or there was macroscopic blood contamination in the amniotic fluid, the risk of SA was increased by a factor 4 to 5. The influence of previous obstetric or gynecologic complications on the incidence of SA was also examined. In this analysis the data from women with first trimester hemorrhage in the present pregnancy were included and the study population therefore consisted of 1594 women. Of these, 1318 had an AC, and 276 had ultrasound scanning only. Patients with one or more previous pregnancies with fetal loss had a significantly greater risk of SA after AC than patients with no previous pregnancies or successfully completed pregnancies. Two subgroups with special problems, namely, women with previous complaint of infertility of at least 2 years' duration and women with first trimester bleeding, also had an increased risk of SA.(ABSTRACT TRUNCATED AT 250 WORDS)
The process of fertilization in humans, is remarkably inefficient. Spontaneous abortion is estimated to be between 15 and 20% of all clinical pregnancies, and the early spontaneous abortion rate is closer to 30-50% of fertilized ova. Not all authors agree on the definition of "recurrent spontaneous abortion" (RSA), so the frequency of repeated pregnancy wastage is difficult to determine; from empirically derived data, it has been estimated to range between 0.4 and 0.8%. Because of the various etiologies of RSA, their association in determining an abortive event, it is difficult to evaluate their exact incidence. Moreover, their is no prospective study on this subject, so it is advisable to distinguish between the admitted causes, the likely factors, and the etiologies to be evaluated. In the first group, the congenital or acquired müllerian anomalies (especially the septate uterus), represent about 25% of the RSA, but a lot of problems concerning the physiopathology are still debated, even if the rate of pregnancies after surgery ranges around 50% in certain series. On the other hand, the genetic factors, identified especially with the banding technique, are undeniable: however, although the rate of chromosomal aberrations in the offspring (Monosomy X, Trisony 16, Triploidy) is very high (50 to 60% of spontaneous abortions in the first trimester of pregnancy), when couples with usual abortions are subjected to karyotypic analysis, genetic anomalies (especially translocations) are been noted in only 6.2% of the women and 2.6% of the men. In the second group, the infective factors (chlamydiae, toxoplasma and mycoplasma) are difficult to analyse since the serology is not sufficient without a real proof of an endometrial colonization. Among the endocrinological causes, the classical luteal phase deficiency remains a subject of controversy (estimated between 3 and 30%) not only for the establishment of the diagnosis, but also for the efficiency of progesterone supplementation. In the third group, the autoimmune diseases, especially systemic lupus erythematosus (SLE) are most likely a cause of fetal wastage, by secreting antibodies that cross-react with the antigenic determinants of the trophoblast. These patients should be screened for lupus like anticoagulant; the therapy with glucocorticoids during pregnancy is still debated. More recently, the immunologic factors have been estimated to play an important role in the etiology of usual abortion: in these cases women share HLA antigens with their partners more frequently than expected.(ABSTRACT TRUNCATED AT 400 WORDS)
Midtrimester amniocentesis was performed on 2,100 consecutive patients over a four-year period. A specially designed ultrasonic aspiration transducer was used to guide the needle into the amniotic cavity under direct vision by following the path of the needle tip ultrasonically as it entered the fluid. This technique has made the aspiration of amniotic fluid relatively simple and safe. We obtained an adequate amount of amniotic fluid in 99.2% of the patients at their initial visits. The incidence of grossly bloody taps was 0.8%, and the total number of bloody amniotic fluid specimens was 2.37%. The rate of primary culture failure was 0.53%. The total fetal loss within eight weeks after amniocentesis was 0.9% as compared with 0.52% in a control population composed of pregnant women between 16 and 24 weeks of gestation. The estimated amniocentesis-related fetal loss was 0.38%.
To assess the risk of fetal loss attributable to second-trimester amniocentesis.
A cohort study was undertaken among singleton pregnant women undergoing genetic amniocentesis and controls matched prospectively on a one-to-one basis, matched strictly for maternal age, parity, and socioeconomic status. Both groups were recruited at 15-24 weeks' gestation and observed until delivery. The fetal loss rates of the groups were compared.
A total of 2256 pairs were recruited to the study. After excluding those pairs lost to follow-up, those with fetal malformation, and those later proven to have major chromosomal abnormalities, 2045 matched pairs were compared by pregnancy outcomes. There were no significant differences in fetal loss rates, premature deliveries, or placental abruptions between the study and control groups (P > .05). However, this study did not have enough statistical power to identify differences of less than 1%.
Second-trimester amniocentesis is probably not associated with a greater fetal loss rate than that of matched controls.
The aim of this retrospective controlled study is to evaluate the impact of predisposing factors on amniocentesis-related fetal loss. It comprises 3910 consecutive cases of women, aged 20-34 years, who had genetic amniocentesis during the years 1992-97 (study group). The control group comprised 5324 women under 35, at low risk for Down syndrome, during the same period. The fetal losses in both groups were analysed, in respect of: (a) maternal historical conditions; and/or (b) bleeding during current pregnancy. The leading indication for amniocentesis in women 20-34 years was maternal anxiety, mainly for marginal age (33-34 years), which accounted for a remarkable 34.4% of the study group. Total fetal loss rate up to the 28th week was 2.1% in the study group versus 1. 5% in controls. A history of previous spontaneous or induced abortions, as well as bleeding during the current pregnancy, was associated with a substantial rise of fetal loss in both groups. In cases with no predisposing factors, the added fetal loss rate was 0.03%. Previous abortions and bleeding during the current pregnancy are associated with the most fetal losses after amniocentesis. In the absence of these, the added fetal loss rate (0.03%) is non-significant.
The epidemiologic characteristics of unexplained stillbirths are largely unknown or unreliable. We define sudden intrauterine unexplained death as a death that occurs antepartum and results in a stillbirth for which there is no explanation despite postmortem examinations, and we present risk factors for this type of stillbirth in singleton gestations. Study Design: Singleton antepartum stillbirths (n = 291) and live births (n = 582) in Oslo were included and compared with national data (n = 2025 and n = 575,572, respectively). Explained stillbirths (n = 165) and live births in Oslo served as controls for the cases of sudden intrauterine unexplained death (n = 76) in multiple logistic regression analyses.
One fourth of stillbirths remain unexplained. The risk of sudden intrauterine unexplained death (1/1000) increased with gestational age, high maternal age, high cigarette use, low education, and overweight or obesity. Primiparity and previous stillbirths or spontaneous abortions were not associated with sudden intrauterine unexplained death.
Risk factors for sudden intrauterine unexplained death are identifiable by basic antenatal care. Adding unexplored stillbirths to the unexplained ones conceals several risk factors and underlines the necessity of a definition that includes thorough postmortem examinations.
We sought to assess changes in indications, technique, successful fluid aspiration, and pregnancy outcomes in a large cohort of genetic amniocenteses performed by a single physician.
Records were reviewed regarding 4600 women who underwent genetic amniocentesis by a single physician between 1972 and 2000. Changes in indications, procedural technique, ease of performance, amniotic fluid reports, and pregnancy loss rates were tabulated and compared over time.
The indications for amniocentesis changed significantly (P < .0001) over time with the increasing use of maternal serum screening studies and fetal assessment by ultrasonography. The ease with which clear amniotic fluid was aspirated increased with experience, improvements in ultrasound technology, and modifications of amniocentesis technique. Procedure-related total pregnancy loss rate was 0.95%, and loss rate within 60 days of the procedure was 0.55%. Increasing operator experience did not improve the pregnancy loss rate significantly.
Successful aspiration of clear amniotic fluid increases with amniocentesis experience. Pregnancy outcome did not change significantly with increasing amniocentesis experience.
The purpose of this study was to determine the impact of leiomyomata uteri on the risk of second-trimester spontaneous abortion and to determine whether genetic amniocentesis further increases this risk.
We retrospectively identified pregnant women with leiomyomata uteri who underwent genetic amniocentesis (cases) at the University of Rochester and the Johns Hopkins Hospital between April 1994 and June 2000. Two control groups were also identified: (1) pregnant women without leiomyomata who had undergone genetic amniocentesis (amnio only) and (2) pregnant women at similar gestational ages with leiomyomata who had not undergone amniocentesis (myoma only). Cases and controls were matched for maternal age and parity. All subjects were then followed up to ascertain pregnancy outcomes.
One hundred twenty-eight women with leiomyomata uteri who underwent genetic amniocentesis were identified and matched with 128 amnio-only controls and 128 myoma-only controls. The incidence of spontaneous abortion was 6.3% among the cases, 0.8% in the amnio-only controls, and 7.0% in the myoma-only controls. The relative risk (95% CI) for spontaneous abortion was 8.0 (1.02-63.04) for cases versus amnio only but was not significantly different from 1.0 for cases versus myoma-only controls.
Women with leiomyomata are at an increased risk for second-trimester spontaneous abortion. Midtrimester amniocentesis does not appear to further increase this risk.
In routine obstetrical practice, prior to offering invasive prenatal diagnosis, it is crucial to weigh the risks attendant on amniocentesis against the individual's risk of aneuploidy. We took advantage of a policy of follow-up of patients undergoing Down syndrome maternal serum screening to compare the rates of fetal loss before 24 weeks and of early premature delivery at 24-28 weeks between women who underwent amniocentesis and women who did not. A total of 54 902 patients entered the study, of whom 4039 (7.35%) were lost to follow-up and 387 were excluded because of a severe fetal abnormality. Of the 50 476 remaining patients, 3472 had an amniocentesis whereas 47 004 had not and served as controls. In the amniocentesis group, the fetal loss rate before 24 weeks was 1.12% (95% CI=1.08-1.15) and the 24-28 weeks premature delivery rate was 0.40% (95% CI=0.39-0.41) which was significantly higher than in controls (0.42% with 95% CI 0.41-0.43 and 0.24% with 95% CI 0.23-0.25, respectively). The 0.86% difference in adverse outcome rates between the amniocentesis and control groups may be attributable to amniocentesis and compares favourably with the positive predictive value of maternal serum markers (1.70%) observed in the present study.
The purpose of this study was to determine whether patients with first-trimester threatened abortion are at increased risk for poor pregnancy outcome.
A large prospective multicenter database was studied. Subjects were divided into three groups: (1) no bleeding, (2) light bleeding, and (3) heavy bleeding. Univariate and multivariable logistic regression analyses were used.
The study comprised 16,506 patients: 14,160 patients without bleeding, 2094 patients with light bleeding, and 252 patients with heavy bleeding. Patients with vaginal bleeding, light or heavy, were more likely to experience a spontaneous loss before 24 weeks of gestation (odds ratio, 2.5 and 4.2, respectively) and cesarean delivery (odds ratio, 1.1 and 1.4, respectively). Light bleeding subjects were more likely to have preeclampsia (odds ratio, 1.5), preterm delivery (odds ratio, 1.3), and placental abruption (odds ratio, 1.6). Heavy vaginal bleeding subjects were more likely to have intrauterine growth restriction (odds ratio, 2.6), preterm delivery (odds ratio, 3.0), preterm premature rupture of membranes (odds ratio, 3.2), and placental abruption (odds ratio, 3.6).
First-trimester vaginal bleeding is an independent risk factor for adverse obstetric outcome that is directly proportional to the amount of bleeding.
Celocentesis is the ultrasound-guided aspiration of fluid from the extra-amniotic cavity at 7-8 weeks of gestation. This paper reports on the clinical application of celocentesis for early prenatal diagnosis.
Celocentesis was successfully performed in nine pregnancies and 1-2 mL of fluid were obtained after one needle insertion. The indications were prenatal diagnosis of beta-thalassemia or sickle cell disease (n = 6), Marfan syndrome (n = 1) and paternity testing (n = 2). Molecular biological techniques were used to analyze the celomic fluid and this was successfully carried out in all cases.
In two cases pregnancy termination was performed at the request of the mother because in one case the fetus was found to have sickle cell anemia and in the second case paternity testing demonstrated that the father was not the woman's husband. In both cases the results were confirmed using the placental samples collected after pregnancy termination. In six of the seven pregnancies with desirable results, amniocentesis was performed at 16 weeks and the results were concordant with those obtained from celocentesis. All pregnancies were uneventful and resulted in the delivery of healthy and appropriately grown babies.
Celocentesis may be a viable alternative to the currently used tests of chorionic villus sampling and amniocentesis.
To assess, in a randomized trial, the safety and accuracy of amniocentesis and transabdominal chorionic villus sampling (CVS) performed at 11-14 weeks of gestation, given that this time frame is increasingly relevant to early trisomy screening.
We compared amniocentesis with CVS from 77 to 104 days of gestation in a randomized trial in a predominantly advanced maternal age population. Before randomization, the feasibility of both procedures was confirmed by ultrasonography, and experienced operators performed sampling under ultrasound guidance; conventional cytogenetic analysis was employed. The primary outcome measure was a composite of fetal loss plus preterm delivery before 28 weeks of gestation in cytogenetically normal pregnancies.
We randomized 3,775 women into 2 groups (1,914 to CVS; 1,861 to amniocentesis), which were comparable at baseline. More than 99.6% had the assigned procedure, and 99.9% were followed through delivery. In contrast to previous thinking, in the cytogenetically normal cohort (n = 3,698), no difference in primary study outcome was observed: 2.1% (95% confidence interval 1.5, 2.8) for CVS and 2.3% (95% confidence interval, 1.7, 3.1) for amniocentesis. However, spontaneous losses before 20 weeks and procedure-related, indicated terminations combined were increased in the amniocentesis group (P =.07, relative risk 1.74). We found a 4-fold increase in the rate of talipes equinovarus after amniocentesis (P =.02) overall and in week 13 (P =.03, relative risk = 4.65), but data were insufficient to determine this risk in week 14.
Amniocentesis at 13 weeks carries a significantly increased risk of talipes equinovarus compared with CVS and also suggests an increase in early, unintended pregnancy loss.
I
Genetic mid-trimester amniocentesis is a common invasive procedure. The origin of the commonly quoted 0.5% rate of procedure-related pregnancy loss after amniocentesis is obscure and is in conflict with the only randomized prospective study that reported a procedure-related rate of loss of 1.0%. This review was performed to establish an estimate of procedure-related pregnancy loss after mid-trimester amniocentesis. The impact of placental puncture on the rate of loss and the risk of direct needle injury to the fetus were also examined.
The National Library of Medicine database was used to identify English language reports of >1000 amniocenteses with sufficient detail and follow up data to allow the calculation of the rate of spontaneous pregnancy loss after amniocentesis but before 28 completed weeks. These reports were divided into 2 groups to assess the impact of the ultrasound technique. Group I described only preamniocentesis ultrasound evaluation; group II described primarily concurrent ultrasound needle guidance. Pregnancy loss between the 2 groups was compared. The impact of placental puncture and reported direct fetal trauma were examined. The significance of differences was tested using chi-square analysis, with significance at a probability value of < or =.05.
Twenty-nine reports that totaled 68,119 amniocenteses were examined. In a comparison of all studies in group I with all studies in group II, there was a lower rate of loss after amniocenteses with the use of concurrent guidance (1.4%) compared with the use of preamniocentesis ultrasound evaluation (2.1%) that was significant ( P <.001). Among only the 5 controlled studies that used preamniocentesis ultrasound evaluation, the difference in rate of loss between amniocentesis patients and control subjects was 0.6% ( P =.0042; 95% CI, 0.19, 1.03), which was identical to the difference in the rate of loss of 0.6% between amniocentesis patients and control subjects from the 5 controlled studies that used concurrent ultrasound needle guidance ( P <.0001; 95% CI, 0.31, 0.90). Multiple case reports and small series of presumed fetal needle trauma were reviewed, but most of these attributed causation to the amniocentesis needle based only on circumstantial association. Two cases with direct evidence of fetal needle trauma are discussed. Finally, the rate of loss after placental puncture from among 9 reports that provided this detail was 1.4% and not different from the overall rate of loss that was noted in group II.
This examination of experience with 68,119 amniocenteses from both controlled and uncontrolled studies provides a substantive basis for several conclusions: (1) Contemporary amniocentesis with concurrent ultrasound guidance in controlled studies appears to be associated with a procedure-related rate of excess pregnancy loss of 0.6% (95% CI, 0.31, 0.90). To determine the total rate of loss, this must be added to the reported natural rate of loss without amniocentesis among control patients of 1.08%. (2) The use of concurrent ultrasound guidance appears to reduce the number of punctures and the incidence of bloody fluid. Concurrent ultrasound guidance was associated with a reduced rate of loss when all studies were compared, but not among controlled studies. (3) Direct fetal needle trauma is rare, and rarely proved, but may occur more frequently than is reported because of a failure to diagnose and a failure of the consistent production of sequelae. (4) This experience does not substantiate an increased rate of pregnancy loss if placental puncture is required.
The purpose of this study was to investigate age-specific spontaneous fetal loss rates of pregnancies without known chromosomal or structural abnormalities from mid-second trimester onward.
The study consisted of 264,653 women screened between October 1995 and September 2000 with available pregnancy outcomes. Pregnancies associated with fetal chromosomal or structural abnormalities, insulin dependent diabetes mellitus, and multiple pregnancies were excluded. Spontaneous fetal losses at or after 15 weeks of gestation were identified. Women were grouped according to maternal age at expected date of delivery. Spontaneous fetal loss rates in each group were evaluated after adjusting fetal losses associated with amniocentesis and identifiable ethnic groups.
Fetal loss rates increased in both younger and older women. The lowest rate was seen in women at mid-20s. Compared with Caucasian and Asian women, black women had higher fetal loss rate at nearly every age group.
The results of the study provided a baseline age-specific spontaneous fetal loss rate of pregnancies at a specified gestational window.
This study was undertaken to determine the clinical use of comparative genomic hybridization (CGH) for detection of fetal trisomy 21 from fetal ceIls (nucleated red blood cells; nRBCs) isolated from maternal peripheral venous blood.
Maternal peripheral venous blood samples were collected in sterile tubes containing heparin. After triple density gradient centrifugation, magnetic activated cell sorting using CD45 and CD71 was used to isolate the fetal nRBCs. Fetal nRBCs were successfully isolated from maternal peripheral blood in all cases. After laser-microdissecting fetal nRBCs, degenerate oligonucleotide-primed polymerase chain reaction, and nick translation, DNA size was suitable for hybridization.
By CGH analysis, we diagnosed one normal male, one normal female, and one trisomy 21 male fetus. These results were confirmed by amniocentesis.
Prenatal diagnosis from fetal cells in maternal peripheral blood by CGH shows clinical promise as an alternative or as a supplement to fluorescence in situ hybridization with chromosome-specific probes but further studies are warranted.
The purpose of this study was to investigate whether second-trimester amniocentesis increases fetal loss rate. Two thousand sixty-eight women with singleton gestations who underwent mid-trimester amniocentesis at 15 to 22 weeks gestation and 2068 controls matched one-to-one for maternal age, parity, and the number of prior spontaneous abortions were studied prospectively in a case-control study design. The fetal loss rates and other adverse pregnancy outcomes were compared between the study and control groups using the Pearson chi2 test or Fisher exact test when appropriate. In the amniocentesis group, eight (0.4%) fetal losses occurred within 30 days of the procedure, and in the control group, six (0.3%) losses occurred within 30 days of the inclusion in the study; the difference was not statistically significant ( p = 0.59; OR, 1.34; 95% CI, 0.46 to 3.85). The total fetal loss rates including spontaneous abortions and intrauterine fetal deaths/stillbirths were 2.3 and 2% in the study and control groups, respectively, and the difference was not significant ( p = 0.59; OR, 1.12; 95% CI, 0.74 to 1.71). Amniotic fluid leakage occurred in only two (0.1%) of 2068 study patients. Transplacental needle passage was not associated with an increased risk of pregnancy loss compared with nontransplacental amniocentesis ( p = 0.92; OR, 0.96; 95% CI, 0.47 to 1.95). There was no statistically significant difference in fetal loss rate between women requiring two needle insertions to obtain amniotic fluid and those having only one insertion ( p = 1.00; OR, 0.75; 95% CI, 0.10 to 5.53). The rates of preterm deliveries, small for gestational age infants, preeclampsia/eclampsia, placental abruptions, and cesarean deliveries were also not significantly different between two groups (each p > 0.05). We conclude that second-trimester amniocentesis for prenatal diagnosis is a safe procedure that does not appear to increase fetal loss rate.
Microarray-based comparative genomic hybridization (array-CGH) which detects aneuploidies and submicroscopic deletions and duplications in one assay is now offered for genetic diagnosis in children and adults. Its application to prenatal diagnosis is still limited, but very promising. We predict that array-CGH on fetal DNA obtained through amniocentesis or chorionic villus sampling and in the future possibly through noninvasive collection from the maternal cervix or blood, will transform the practice of prenatal diagnosis.
The power of array-CGH for genetic diagnosis and gene discovery is supported by recent studies. Most arrays for clinical use carry large DNA fragments, but alternative designs containing oligonucleotides will move into the clinic. Some oligonucleotide arrays can simultaneously analyze DNA copy number and single nucleotide polymorphisms, thereby adding potential assessment of uniparental disomy and paternity. Recent array-CGH studies have revealed extensive interindividual copy number variation of genomic segments, unanticipated complexity of apparently balanced translocations, and new phenotypes associated with DNA deletions and duplications. These observations affect counseling for prenatal diagnosis by array-CGH.
We believe that array-CGH will be embraced as a tool for prenatal diagnosis of chromosomal defects, but its introduction into clinical practice should proceed with caution by experienced laboratories.