Amniocentesis and chorionic villus sampling for prenatal diagnosis

Zarko Alfirevic; Kate Navaratnam; Faris Mujezinovic

doi:10.1002/14651858.CD003252.pub2

Cochrane Database of Systematic Reviews

Amniocentesis y toma de muestras de vellosidades coriónicas para el diagnóstico prenatal

Información

DOI:

https://doi.org/10.1002/14651858.CD003252.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

04 septiembre 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Embarazo y parto

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Cifras del artículo

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Contraer

Autores

Zarko Alfirevic

Correspondencia a: Department of Women's and Children's Health, The University of Liverpool, Liverpool, UK

[email protected]
Kate Navaratnam

Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
Faris Mujezinovic

University Clinical Department of Gynecology and Perinatology, University Clinical Center Maribor, Maribor, Slovenia

Contributions of authors

Z Alfirevic developed the protocol, interpreted the data, and wrote the original review. F Mujezinovic extracted the data and co‐wrote the original review. K Navaratnam completed the GRADE assessments for included studies and updated the review.

Sources of support

Internal sources

The University of Liverpool, UK.

External sources

No sources of support supplied

Declarations of interest

Zarko Alfirevic: Zarko Alfirevic is Director of the Harris Wellbeing Preterm Birth Centre, which is grant funded by the charity Wellbeing of Women. This grant is administered by the University of Liverpool, and Zarko Alfirevic is not paid directly. He is the principal investigator or co‐investigator on several grants from public funders, including National Institute of Health Research, British Medical Association, European Commission, and WHO. He has received research support in the past from Perkin Elmer and Alere for research related to pre‐eclampsia and preterm birth prevention. These grants were administered by his employers and ZA did not benefit directly. ZA is also a Co‐coordinating Editor of Cochrane Pregnancy and Childbirth.

Kate Navaratnam: none known.

Faris Mujezinovic: none known.

Acknowledgements

We are grateful to Sarah Ayers from the National Perinatal Epidemiology Unit in Oxford for providing unpublished data from the MRC 1991 and Ammala 1993 (MRC Finland) trials and to Frank Vandenbussche and Helen Nagel for useful additional information and unpublished data from Leiden 1998. Earlier drafts of this review were improved following useful comments by Amy Durban (USA) and Gill Gyte (UK) who were our consumer referees, Professor Martin Whittle who was one of the peer reviewers, and Simon Gates, statistical adviser to the Cochrane Pregnancy and Childbirth Group.

We would like to thank Sara Brigham who extracted data and co‐wrote the first version of this review and Karin Sundberg, who was an author on previous versions of this review.

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Version history

Published

Title

Stage

Authors

Version

2017 Sep 04

Amniocentesis and chorionic villus sampling for prenatal diagnosis

Review

Zarko Alfirevic, Kate Navaratnam, Faris Mujezinovic

https://doi.org/10.1002/14651858.CD003252.pub2

2003 Jul 21

Amniocentesis and chorionic villus sampling for prenatal diagnosis

Review

Zarko Alfirevic, Faris Mujezinovic, Karin Sundberg

https://doi.org/10.1002/14651858.CD003252

Differences between protocol and review

Methods updated to the current standard methods text for Cochrane Pregnancy and Childbirth. Searches of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) were added.

Five 'Summary of findings' tables were incorporated. Primary and secondary outcomes were specified.

The following outcomes were not pre‐specified in the protocol:

Results given in less than 7 days (not pre‐specified)
Results given in less than 14 days (not pre‐specified)
Results given in less than 21 days (not pre‐specified)
Results given after 21 days (not pre‐specified)
Not wanting another baby at 22 weeks' gestation (not pre‐specified)

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Female; Humans; Pregnancy;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias domain presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias domain for each included study.

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Analysis 1.1

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 1 All known pregnancy loss (including termination of pregnancy).

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Analysis 1.2

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 2 Spontaneous miscarriage.

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Analysis 1.3

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 3 Non‐compliance with allocated procedure.

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Analysis 1.4

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 4 Multiple insertions.

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Analysis 1.5

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 5 Second test performed.

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Analysis 1.6

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 6 Laboratory failure.

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Analysis 1.7

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 7 All non‐mosaic abnormalities.

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Analysis 1.8

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 8 Vaginal bleeding after test.

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Analysis 1.9

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 9 Amniotic leakage after test.

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Analysis 1.10

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 10 Termination of pregnancy (all).

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Analysis 1.11

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 11 Perinatal deaths.

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Analysis 1.12

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 12 Stillbirths.

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Analysis 1.13

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 13 Neonatal deaths.

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Analysis 1.14

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 14 All recorded deaths after viability.

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Analysis 1.15

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 15 Anomalies (all recorded).

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Analysis 1.16

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 16 Talipes.

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Analysis 1.17

Comparison 1 Second trimester amniocentesis (AC) versus control (no testing), Outcome 17 Neonatal respiratory distress syndrome.

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Analysis 2.1

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 1 All known pregnancy loss (including termination of pregnancy).

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Analysis 2.2

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 2 Spontaneous miscarriage.

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Analysis 2.3

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 3 Spontaneous miscarriage after test.

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Analysis 2.4

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 4 Non‐compliance with allocated procedure.

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Analysis 2.5

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 5 Sampling failure.

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Analysis 2.6

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 6 Multiple insertions.

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Analysis 2.7

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 7 Second test performed.

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Analysis 2.8

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 8 Laboratory failure.

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Analysis 2.9

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 9 All non‐mosaic abnormalities.

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Analysis 2.10

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 10 True mosaics.

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Analysis 2.11

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 11 Maternal contamination.

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Analysis 2.12

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 12 Known false negative after birth.

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Analysis 2.13

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 13 Reporting time.

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Analysis 2.14

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 14 Amniotic leakage after test.

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Analysis 2.15

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 15 Termination of pregnancy (all).

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Analysis 2.16

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 16 Stillbirths.

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Analysis 2.17

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 17 Neonatal deaths.

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Analysis 2.18

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 18 All recorded deaths after viability.

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Analysis 2.19

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 19 Anomalies (all recorded).

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Analysis 2.20

Comparison 2 Early versus second trimester amniocentesis (AC), Outcome 20 Talipes.

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Analysis 3.1

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 1 All known pregnancy loss (including termination of pregnancy).

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Analysis 3.2

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 2 Spontaneous miscarriage.

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Analysis 3.3

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 3 Spontaneous miscarriage after test.

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Analysis 3.4

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 4 Non‐compliance with allocated procedure.

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Analysis 3.5

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 5 Sampling failure.

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Analysis 3.6

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 6 Multiple insertions.

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Analysis 3.7

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 7 Second test performed.

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Analysis 3.8

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 8 Laboratory failure.

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Analysis 3.9

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 9 All non‐mosaic abnormalities.

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Analysis 3.10

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 10 True mosaics.

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Analysis 3.11

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 11 Confined mosaics.

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Analysis 3.12

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 12 Maternal contamination.

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Analysis 3.13

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 13 Known false positive after birth.

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Analysis 3.14

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 14 Known false negative after birth.

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Analysis 3.15

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 15 Results given in less than 7 days (not pre‐specified).

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Analysis 3.16

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 16 Results given in less than 14 days (not pre‐specified).

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Analysis 3.17

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 17 Results given in less than 21 days (not pre‐specified).

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Analysis 3.18

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 18 Result given after 21 days (not pre‐specified).

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Analysis 3.19

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 19 Vaginal bleeding after test.

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Analysis 3.20

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 20 Amniotic leakage after test.

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Analysis 3.21

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 21 Vaginal bleeding after 20 weeks.

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Analysis 3.22

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 22 Pre‐labour ruptured membranes before 28 weeks.

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Analysis 3.23

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 23 Antenatal hospital admission.

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Analysis 3.24

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 24 Delivery before 37 weeks.

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Analysis 3.25

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 25 Delivery before 33 weeks.

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Analysis 3.26

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 26 Termination of pregnancy (all).

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Analysis 3.27

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 27 Perinatal deaths.

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Analysis 3.28

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 28 Stillbirths.

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Analysis 3.29

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 29 Neonatal deaths.

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Analysis 3.30

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 30 All recorded deaths after viability.

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Analysis 3.31

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 31 Congenital anomalies (all recorded).

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Analysis 3.32

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 32 Haemangioma.

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Analysis 3.33

Comparison 3 Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC), Outcome 33 Limb reduction defects.

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Analysis 4.1

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 1 All known pregnancy loss (including termination of pregnancy).

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Analysis 4.2

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 2 Spontaneous miscarriage.

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Analysis 4.3

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 3 Spontaneous miscarriage after test.

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Analysis 4.4

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 4 Non‐compliance with allocated procedure.

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Analysis 4.5

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 5 Sampling failure.

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Analysis 4.6

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 6 Multiple insertions.

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Analysis 4.7

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 7 Second test performed.

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Analysis 4.8

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 8 Laboratory failure.

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Analysis 4.9

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 9 All non‐mosaic abnormalities.

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Analysis 4.10

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 10 True mosaics.

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Analysis 4.11

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 11 Confined mosaics.

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Analysis 4.12

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 12 Amniotic leakage after test.

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Analysis 4.13

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 13 Vaginal bleeding after test.

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Analysis 4.14

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 14 Termination of pregnancy (all).

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Analysis 4.15

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 15 Perinatal deaths.

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Analysis 4.16

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 16 Stillbirths.

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Analysis 4.17

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 17 Neonatal deaths.

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Analysis 4.18

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 18 Anomalies (all recorded).

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Analysis 4.19

Comparison 4 Transcervical versus transabdominal chorionic villus sampling (CVS), Outcome 19 Talipes.

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Analysis 5.1

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 1 All known pregnancy loss (including termination of pregnancy).

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Analysis 5.2

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 2 Spontaneous miscarriage.

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Analysis 5.3

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 3 Spontaneous miscarriage after test.

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Analysis 5.4

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 4 Non‐compliance with allocated procedure.

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Analysis 5.5

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 5 Sampling failure.

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Analysis 5.6

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 6 Multiple insertions.

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Analysis 5.7

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 7 Second test performed.

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Analysis 5.8

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 8 Laboratory failure.

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Analysis 5.9

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 9 All non‐mosaic abnormalities.

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Analysis 5.10

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 10 True mosaics.

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Analysis 5.11

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 11 Confined mosaics.

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Analysis 5.12

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 12 Maternal contamination.

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Analysis 5.13

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 13 Known false positive after birth.

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Analysis 5.14

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 14 Knonw false negative after birth.

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Analysis 5.15

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 15 Reporting time.

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Analysis 5.16

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 16 Vaginal bleeding after 20 weeks.

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Analysis 5.17

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 17 Amniotic leakage after test.

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Analysis 5.18

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 18 Vaginal bleeding after test.

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Analysis 5.19

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 19 Pre‐labour ruptured membranes before 28 weeks.

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Analysis 5.20

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 20 Delivery before 37 weeks.

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Analysis 5.21

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 21 Delivery before 33 weeks.

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Analysis 5.22

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 22 Termination of pregnancy (all).

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Analysis 5.23

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 23 Perinatal deaths.

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Analysis 5.24

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 24 Stillbirths.

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Analysis 5.25

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 25 Neonatal deaths.

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Analysis 5.26

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 26 All recorded deaths after viability.

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Analysis 5.27

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 27 Anomalies (all recorded).

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Analysis 5.28

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 28 Talipes equinovarus.

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Analysis 5.29

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 29 Haemangioma.

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Analysis 5.30

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 30 Neonatal respiratory distress syndrome.

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Analysis 5.31

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 31 Birthweight below 10th centile.

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Analysis 5.32

Comparison 5 Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS), Outcome 32 Birthweight below 5th centile.

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Analysis 6.1

Comparison 6 Ultrasound versus no ultrasound before second trimester amniocentesis, Outcome 1 All known pregnancy loss (including termination of pregnancy).

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Analysis 6.2

Comparison 6 Ultrasound versus no ultrasound before second trimester amniocentesis, Outcome 2 Spontaneous miscarriage.

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Analysis 6.3

Comparison 6 Ultrasound versus no ultrasound before second trimester amniocentesis, Outcome 3 Spontaneous miscarriage after test.

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Analysis 6.4

Comparison 6 Ultrasound versus no ultrasound before second trimester amniocentesis, Outcome 4 Sampling failure.

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Analysis 6.5

Comparison 6 Ultrasound versus no ultrasound before second trimester amniocentesis, Outcome 5 Multiple insertions.

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Analysis 6.6

Comparison 6 Ultrasound versus no ultrasound before second trimester amniocentesis, Outcome 6 Bloody tap (not pre‐specified).

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Summary of findings for the main comparison. Second trimester amniocentesis compared to control for prenatal diagnosis

Second trimester amniocentesis compared to control for prenatal diagnosis
Patient or population: prenatal diagnosis Setting: hospitals in Denmark Intervention: second trimester amniocentesis Comparison: control
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with control	Risk with second trimester amniocentesis (AC)
All known pregnancy loss (including termination of pregnancy)	Study population		RR 1.41 (0.99 to 2.00)	4606 (1 RCT)	⊕⊕⊕⊝ MODERATE¹
	23 per 1000	32 per 1000 (22 to 45)
Spontaneous miscarriage	Study population		RR 1.60 (1.02 to 2.52)	4606 (1 RCT)	⊕⊕⊕⊕ HIGH
	13 per 1000	21 per 1000 (13 to 33)
Sampling failure	‐	‐	‐	‐	‐	No trial reported this outcome
Laboratory failure	Study population		RR 27.02 (1.61 to 454.31)	4606 (1 RCT)	⊕⊕⊕⊕ HIGH	There were no events in the control group and only 13 in the AC group, so it was not possible to calculate the anticipated absolute effect.
	0 per 1000	0 per 1000 (0 to 0)
Known false negative after birth	‐	‐	‐	‐	‐	No trial reported this outcome
Delivery before 33 weeks	‐	‐	‐	‐	‐	No trial reported this outcome
Anomalies (all recorded)	Study population		RR 0.93 (0.62 to 1.39)	4507 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹
	22 per 1000	20 per 1000 (13 to 30)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Wide confidence intervals crossing the line of no effect (‐1)

Summary of findings for the main comparison. Second trimester amniocentesis compared to control for prenatal diagnosis

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Summary of findings 2. Early compared to second trimester amniocentesis for prenatal diagnosis

Early compared to second trimester amniocentesis for prenatal diagnosis
Patient or population: prenatal diagnosis Setting: hospitals in Canada Intervention: early amniocentesis Comparison: second trimester amniocentesis
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with second trimester amniocentesis (AC)	Risk with early AC
All known pregnancy loss (including termination of pregnancy)	Study population		RR 1.29 (1.03 to 1.61)	4334 (1 RCT)	⊕⊕⊕⊕ HIGH ¹
	59 per 1000	76 per 1000 (61 to 95)
Spontaneous miscarriage	Study population		RR 1.41 (1.00 to 1.98)	4334 (1 RCT)	⊕⊕⊕⊝ MODERATE ^{1, 2}
	25 per 1000	36 per 1000 (25 to 50)
Sampling failure	Study population		RR 4.53 (0.53 to 38.56)	629 (1 RCT)	⊕⊕⊕⊝ MODERATE ^{1, 2}
	3 per 1000	15 per 1000 (2 to 129)
Laboratory failure	Study population		RR 9.76 (3.49 to 27.26)	4368 (1 RCT)	⊕⊕⊕⊕ HIGH ¹
	2 per 1000	18 per 1000 (6 to 50)
Known false negative after birth	Study population		RR 3.00 (0.12 to 73.67)	4368 (1 RCT)	⊕⊕⊕⊝ MODERATE ^{1, 2}	There were no events in the 2nd trimester AC group and only one in the early AC group, so it was not possible to calculate the anticipated absolute effect
	0 per 1000	0 per 1000 (0 to 0)
Known false negative after birth ‐ Incorrect sex determination	Study population		RR 5.00 (0.24 to 104.18)	4368 (1 RCT)	⊕⊕⊕⊝ MODERATE ^{1, 2}	There were no events in the 2nd trimester AC group and only 2 in the early AC group, so it was not possible to calculate the anticipated absolute effect.
	0 per 1000	0 per 1000 (0 to 0)
Delivery before 33 weeks	‐	‐	‐	‐		No trial reported this outcome
Anomalies (all recorded)	Study population		RR 1.73 (1.26 to 2.38)	4334 (1 RCT)	⊕⊕⊕⊕ HIGH ²
	27 per 1000	46 per 1000 (34 to 64)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ One study, contributing 100% data, had unclear allocation concealment for one trial site, and satisfactory concealment for the other trial site (not downgraded) 2 Wide 95% confidence interval, crossing the line of no effect (‐1)

Summary of findings 2. Early compared to second trimester amniocentesis for prenatal diagnosis

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Summary of findings 3. Transabdominal chorionic villus sampling compared to second trimester amniocentesis for prenatal diagnosis

Chorionic villus sampling compared to second trimester amniocentesis for prenatal diagnosis
Patient or population: prenatal diagnosis Setting: hospital in Denmark Intervention: chorionic villus sampling Comparison: second trimester amniocentesis
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with second trimester amniocentesis	Risk with chorionic villus sampling
All known pregnancy loss (including termination of pregnancy)	Study population		RR 0.90 (0.66 to 1.23)	2234 (1 RCT)	⊕⊕⊝⊝ LOW^{1, 2}
	70 per 1000	63 per 1000 (46 to 86)
Spontaneous miscarriage	Study population		RR 0.77 (0.49 to 1.21)	2069 (1 RCT)	⊕⊕⊝⊝ LOW^{1, 2}
	39 per 1000	30 per 1000 (19 to 47)
Sampling failure	‐	‐	‐	‐	‐	No trial reported this outcome
Laboratory failure	‐	‐	‐	‐	‐	No trial reported this outcome
Known false negative after birth	‐	‐	‐	‐	‐	No trial reported this outcome
Delivery before 33 weeks	‐	‐	‐	‐	‐	No trial reported this outcome
Perinatal deaths (stillbirths and neonatal deaths in the first week of life)	Study population		RR 1.18 (0.40 to 3.51)	2069 (1 RCT)	⊕⊕⊝⊝ LOW^{1, 2}
	6 per 1000	7 per 1000 (2 to 21)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Wide 95% confidence intervals that cross the line of no effect (‐1) ² One study, contributing 100% data, with unclear method of randomisation (‐1)

Summary of findings 3. Transabdominal chorionic villus sampling compared to second trimester amniocentesis for prenatal diagnosis

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Summary of findings 4. Transcervical compared to transabdominal chorionic villus sampling for prenatal diagnosis

Transcervical compared to transabdominal chorionic villus samplingfor prenatal diagnosis
Patient or population: prenatal diagnosis Setting: Denmark, Italy, United States Intervention: transcervical chorionic villus sampling Comparison: transabdominal chorionic villus sampling
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with transabdominal chorionic villus sampling	Risk with transcervical chorionic villus sampling
All known pregnancy loss (including termination of pregnancy)	Study population		RR 1.16 (0.81 to 1.65)	7978 (5 RCTs)	⊕⊝⊝⊝ VERY LOW^{1, 2, 3}
	74 per 1000	86 per 1000 (60 to 123)
Spontaneous miscarriage	Study population		RR 1.68 (0.79 to 3.58)	3384 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1, 2, 4}
	45 per 1000	76 per 1000 (36 to 162)
Sampling failure	Study population		RR 1.79 (1.13 to 2.82)	5231 (4 RCTs)	⊕⊕⊕⊝ MODERATE ⁴
	11 per 1000	20 per 1000 (12 to 31)
Laboratory failure	Study population		RR 2.23 (0.69 to 7.22)	1194 (1 RCT)	⊕⊕⊝⊝ LOW ^{1, 5}
	7 per 1000	15 per 1000 (5 to 49)
Known false negative after birth	‐	‐	‐	‐	‐	No trial reported this outcome
Delivery before 33 weeks	‐	‐	‐	‐	‐	No trial reported this outcome
Anomalies (all recorded)	Study population		RR 0.68 (0.41 to 1.12)	3622 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1, 6}
	20 per 1000	14 per 1000 (8 to 22)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Wide 95% confidence intervals crossing the line of no effect (‐1) ² Statistical heterogeneity I² > 60% ³ Four of five contributing studies did not specify randomisation method. All studies had design limitations. In one study, the proportion of cases where the operator deviated from the allocated procedure increased during the study (‐1) ⁴ Three of four studies, contributing > 95% weight, did not specify randomisation method. All studies had design limitations. In one study, the proportion of cases where the operator deviated from the allocated procedure increased during the study (‐1). ⁵ One study contributing data had design limitations ‐ the proportion of cases where the operator deviated from the allocated procedure increased during the study (‐1). ⁶ One of two contributing studies did not specify randomisation method. All studies had design limitations. In one study, the proportion of cases where the operator deviated from the allocated procedure increased during the study (‐1).

Summary of findings 4. Transcervical compared to transabdominal chorionic villus sampling for prenatal diagnosis

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Summary of findings 5. Early amniocentesis compared to transabdominal chorionic villus sampling for prenatal diagnosis

Early amniocentesis compared to transabdominal chorionic villus samplingfor prenatal diagnosis
Patient or population: prenatal diagnosis Setting: Canada, Denmark, the Netherlands, United Kingdom, United States Intervention: early amniocentesis Comparison: transabdominal chorionic villus sampling
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with transabdominal chorionic villus sampling	Risk with early amniocentesis
All known pregnancy loss (including termination of pregnancy)	Study population		RR 1.15 (0.86 to 1.54)	5491 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1, 2}
	30 per 1000	35 per 1000 (26 to 47)
Spontaneous miscarriage	Study population		RR 1.73 (1.15 to 2.60)	5491 (4 RCTs)	⊕⊕⊕⊝ MODERATE ¹
	13 per 1000	23 per 1000 (15 to 34)
Sampling failure	Study population		RR 0.58 (0.24 to 1.38)	5566 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1, 2}
	8 per 1000	5 per 1000 (2 to 11)
Laboratory failure	Study population		RR 0.74 (0.34 to 1.63)	5566 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1, 2}
	6 per 1000	4 per 1000 (2 to 9)
Known false negative after birth	Study population		Not estimable	555 (1 RCT)	⊕⊕⊝⊝ LOW ^{3, 4}
	0 per 1000	0 per 1000 (0 to 0)
Delivery before 33 weeks	Study population		RR 0.50 (0.09 to 2.73)	1121 (1 RCT)	⊕⊕⊝⊝ LOW ^{2, 3}
	7 per 1000	4 per 1000 (1 to 19)
Anomalies (all recorded)	Study population		RR 1.14 (0.57 to 2.30)	5305 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1, 2, 5}
	25 per 1000	29 per 1000 (14 to 58)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Three of four studies, contributing > 50% weight of analysis, did not specify randomisation method (‐1). ² Wide 95% confidence intervals crossing the line of no effect (‐1) ³ Randomisation method not specified (‐1) ⁴ One study with 555 women and no events therefore not possible to estimate risk (‐1) ⁵ Statistical heterogeneity I²>60% (‐1)

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Table 1. Systematic reviews of observational studies (chorionic villus sampling)

Systematic review (by first author)	Single or multiple pregnancies	Pregnancy loss rates reported % (95% CI)	Pooled procedure‐related pregnancy losses % (95% CI)
Agarwal 2012	Twins	Total 3.84% (2.48 to 5.47) < 20 weeks 2.75% (1.28 to 4.75) < 28 weeks 3.44% (1.67 to 5.81)	‐
Akolekar 2015	Singletons	< 24 weeks 2.18% (1.61 to 2.82)	0.22% (‐0.71 to 1.16)
Mujezinovic 2007	Singletons	Total 2.0% (1.0 to 1.7) < 24 weeks 1.3% (0.5 to 2.3)	< 14 days 0.7% (0.3 to 1.4)

Table 1. Systematic reviews of observational studies (chorionic villus sampling)

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Table 2. Systematic reviews of observational studies (amniocentesis)

Systematic review (by first author)	Single or multiple pregnancies	Pregnancy loss rates reported % (95% CI)	Pooled procedure‐related pregnancy losses % (95% CI)
Agarwal 2012	Twins	Total 3.07% (1.83 to 4.61) < 20 weeks 2.25% (1.23 to 3.57) < 24 weeks 2.54% (1.43 to 3.96) < 28 weeks 1.70% (0.37 to 3.97)	‐
Akolekar 2015	Singletons	< 24 weeks 0.81% (0.58 to 1.08)	0.11% (‐0.04 to 0.26)
Mujezinovic 2007	Singletons	Total 1.9% (1.4 to 2.5) < 24 weeks 0.9% (0.60 to 1.30)	< 14 days 0.6 (0.5‐0.7)
Vink 2012	Twins	Monochorionic 7.7% vs 1.4% (amniocentesis vs control)	< 24 weeks 3.5% (2.6 to 4.7)

Table 2. Systematic reviews of observational studies (amniocentesis)

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Comparison 1. Second trimester amniocentesis (AC) versus control (no testing)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All known pregnancy loss (including termination of pregnancy) Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.99, 2.00]

2 Spontaneous miscarriage Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	1.60 [1.02, 2.52]

3 Non‐compliance with allocated procedure Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	1.73 [1.03, 2.91]

4 Multiple insertions Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	91.08 [5.61, 1477.53]

5 Second test performed Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	41.04 [2.48, 678.07]

6 Laboratory failure Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	27.02 [1.61, 454.31]

7 All non‐mosaic abnormalities Show forest plot	1	4593	Risk Ratio (M‐H, Random, 95% CI)	30.85 [1.85, 515.31]

8 Vaginal bleeding after test Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.66, 1.37]

9 Amniotic leakage after test Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	3.90 [1.95, 7.80]

10 Termination of pregnancy (all) Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	2.50 [0.97, 6.44]

11 Perinatal deaths Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.28, 1.38]

12 Stillbirths Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.36, 1.93]

13 Neonatal deaths Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 2.06]

14 All recorded deaths after viability Show forest plot	1	4606	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.28, 1.38]

15 Anomalies (all recorded) Show forest plot	1	4507	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.62, 1.39]

16 Talipes Show forest plot	1	4507	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.37, 1.22]

17 Neonatal respiratory distress syndrome Show forest plot	1	4507	Risk Ratio (M‐H, Random, 95% CI)	2.11 [1.06, 4.19]

Comparison 1. Second trimester amniocentesis (AC) versus control (no testing)

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Comparison 2. Early versus second trimester amniocentesis (AC)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All known pregnancy loss (including termination of pregnancy) Show forest plot	1	4334	Risk Ratio (M‐H, Random, 95% CI)	1.29 [1.03, 1.61]

2 Spontaneous miscarriage Show forest plot	1	4334	Risk Ratio (M‐H, Random, 95% CI)	1.41 [1.00, 1.98]

3 Spontaneous miscarriage after test Show forest plot	1	4334	Risk Ratio (M‐H, Random, 95% CI)	3.22 [1.88, 5.53]

4 Non‐compliance with allocated procedure Show forest plot	1	4368	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.57, 0.75]

5 Sampling failure Show forest plot	1	629	Risk Ratio (M‐H, Random, 95% CI)	4.53 [0.53, 38.56]

6 Multiple insertions Show forest plot	1	4368	Risk Ratio (M‐H, Random, 95% CI)	2.79 [1.92, 4.04]

7 Second test performed Show forest plot	1	4107	Risk Ratio (M‐H, Random, 95% CI)	8.72 [3.47, 21.91]

8 Laboratory failure Show forest plot	1	4368	Risk Ratio (M‐H, Random, 95% CI)	9.76 [3.49, 27.26]

9 All non‐mosaic abnormalities Show forest plot	1	4368	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.75, 1.66]

10 True mosaics Show forest plot	1	4368	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.25, 4.00]

11 Maternal contamination Show forest plot	1	4368	Risk Ratio (M‐H, Random, 95% CI)	2.00 [0.37, 10.92]

12 Known false negative after birth Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

12.1 False negative chromosomal results (excluding sex determination)	1	4368	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.12, 73.67]
12.2 Incorrect sex determination	1	4368	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.24, 104.18]
13 Reporting time Show forest plot	1	4107	Mean Difference (IV, Random, 95% CI)	1.20 [0.89, 1.51]

14 Amniotic leakage after test Show forest plot	1	4368	Risk Ratio (M‐H, Random, 95% CI)	2.05 [1.43, 2.94]

15 Termination of pregnancy (all) Show forest plot	1	4334	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.89, 1.77]

16 Stillbirths Show forest plot	1	4334	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.34, 1.59]

17 Neonatal deaths Show forest plot	1	4334	Risk Ratio (M‐H, Random, 95% CI)	4.98 [0.58, 42.56]

18 All recorded deaths after viability Show forest plot	1	4334	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.50, 1.99]

19 Anomalies (all recorded) Show forest plot	1	4334	Risk Ratio (M‐H, Random, 95% CI)	1.73 [1.26, 2.38]

20 Talipes Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

20.1 Talipes equinovarus	1	4334	Risk Ratio (M‐H, Random, 95% CI)	14.43 [3.45, 60.41]

Comparison 2. Early versus second trimester amniocentesis (AC)

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Comparison 3. Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All known pregnancy loss (including termination of pregnancy) Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Transcervical CVS versus amniocentesis	4	6527	Risk Ratio (M‐H, Random, 95% CI)	1.40 [1.09, 1.81]
1.2 Transabdominal CVS versus amniocentesis	1	2234	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.66, 1.23]
1.3 CVS (any route) versus amniocentesis	2	6503	Risk Ratio (M‐H, Random, 95% CI)	1.43 [1.22, 1.67]
2 Spontaneous miscarriage Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Transcervical CVS versus amniocentesis	3	5506	Risk Ratio (M‐H, Random, 95% CI)	1.50 [1.07, 2.11]
2.2 Transabdominal CVS versus amniocentesis	1	2069	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.49, 1.21]
2.3 CVS (any route) versus amniocentesis	2	6280	Risk Ratio (M‐H, Random, 95% CI)	1.51 [1.23, 1.85]
3 Spontaneous miscarriage after test Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Transcervical CVS versus amniocentesis	2	1579	Risk Ratio (M‐H, Random, 95% CI)	1.77 [0.28, 11.00]
3.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	3.46 [2.21, 5.42]
4 Non‐compliance with allocated procedure Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Transcervical CVS versus amniocentesis	3	4595	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.14, 1.87]
4.2 CVS (any route) versus amniocentesis	1	3197	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.52, 0.83]
5 Sampling failure Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Transervical CVS versus amniocentesis	1	797	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.26, 1.19]
5.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	3.09 [1.98, 4.82]
6 Multiple insertions Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Transcervical CVS versus amniocentesis	1	794	Risk Ratio (M‐H, Random, 95% CI)	3.93 [2.72, 5.68]
6.2 CVS (any route) versus amniocentesis	1	2917	Risk Ratio (M‐H, Random, 95% CI)	4.85 [3.92, 6.01]
7 Second test performed Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 Transcervical CVS versus amniocentesis	3	4256	Risk Ratio (M‐H, Random, 95% CI)	19.63 [1.24, 309.90]
7.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	2.83 [1.94, 4.13]
8 Laboratory failure Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8.1 Transcervical CVS versus amniocentesis	2	2792	Risk Ratio (M‐H, Random, 95% CI)	22.62 [3.07, 166.89]
8.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.29, 2.06]
9 All non‐mosaic abnormalities Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9.1 Transcervical CVS versus amniocentesis	2	2667	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.73, 1.72]
10 True mosaics Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10.1 Transcervical CVS versus amniocentesis	1	672	Risk Ratio (M‐H, Random, 95% CI)	3.42 [0.14, 83.63]
11 Confined mosaics Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

11.1 Transcervical CVS versus amniocentesis	1	1995	Risk Ratio (M‐H, Random, 95% CI)	5.66 [1.97, 16.24]
12 Maternal contamination Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

12.1 Transcervical CVS versus amniocentesis	1	1991	Risk Ratio (M‐H, Random, 95% CI)	12.30 [3.81, 39.67]
12.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	8.90 [0.48, 165.26]
13 Known false positive after birth Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

13.1 Transcervical CVS versus amniocentesis	2	2627	Risk Ratio (M‐H, Random, 95% CI)	4.40 [0.46, 42.38]
13.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.06, 15.80]
14 Known false negative after birth Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

14.1 Transcervical CVS versus amniocentesis	2	2627	Risk Ratio (M‐H, Random, 95% CI)	7.84 [0.41, 151.61]
14.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	2.97 [0.12, 72.81]
15 Results given in less than 7 days (not pre‐specified) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

15.1 CVS (any route) versus amniocentesis	1	3099	Risk Ratio (M‐H, Random, 95% CI)	23.52 [12.54, 44.10]
16 Results given in less than 14 days (not pre‐specified) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

16.1 CVS (any route) versus amniocentesis	1	3099	Risk Ratio (M‐H, Random, 95% CI)	3.96 [3.17, 4.95]
17 Results given in less than 21 days (not pre‐specified) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

17.1 CVS (any route) versus amniocentesis	1	3099	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.63, 0.82]
18 Result given after 21 days (not pre‐specified) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

18.1 CVS (any route) versus amniocentesis	1	3099	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.28, 0.39]
19 Vaginal bleeding after test Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

19.1 Transcervical CVS versus amniocentesis	2	3193	Risk Ratio (M‐H, Random, 95% CI)	11.48 [2.58, 51.08]
20 Amniotic leakage after test Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

20.1 Transabdominal CVS vs amniocentesis	1	1485	Risk Ratio (M‐H, Random, 95% CI)	2.53 [0.81, 7.92]
20.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.18, 1.64]
21 Vaginal bleeding after 20 weeks Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

21.1 Transcervical CVS versus amniocentesis	1	797	Risk Ratio (M‐H, Random, 95% CI)	1.44 [0.62, 3.33]
21.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.69, 1.42]
22 Pre‐labour ruptured membranes before 28 weeks Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

22.1 Transcervical CVS versus amniocentesis	1	722	Risk Ratio (M‐H, Random, 95% CI)	4.97 [1.45, 17.03]
22.2 CVS (any route) versus amniocentesis	1	2765	Risk Ratio (M‐H, Random, 95% CI)	1.60 [0.80, 3.17]
23 Antenatal hospital admission Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

23.1 Transcervical CVS versus amniocentesis	1	780	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.81, 2.68]
23.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.75, 1.08]
24 Delivery before 37 weeks Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

24.1 Transcervical CVS versus amniocentesis	2	2506	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.67, 2.47]
24.2 CVS (any route) versus amniocentesis	1	3189	Risk Ratio (M‐H, Random, 95% CI)	1.33 [1.13, 1.57]
25 Delivery before 33 weeks Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

25.1 Transcervical CVS versus amniocentesis	1	768	Risk Ratio (M‐H, Random, 95% CI)	2.16 [0.94, 4.94]
26 Termination of pregnancy (all) Show forest plot	3		Risk Difference (M‐H, Random, 95% CI)	Subtotals only

26.1 Transcervical CVS versus amniocentesis	2	3454	Risk Difference (M‐H, Random, 95% CI)	‐0.00 [‐0.01, 0.01]
26.2 CVS (any route) versus amniocentesis	1	3201	Risk Difference (M‐H, Random, 95% CI)	0.01 [‐0.00, 0.02]
27 Perinatal deaths Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

27.1 Transcervical CVS versus amniocentesis	3	5521	Risk Ratio (M‐H, Random, 95% CI)	1.79 [0.42, 7.69]
27.2 Transabdominal CVS versus amniocentesis	1	2069	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.40, 3.51]
27.3 CVS (any route) versus amniocentesis	2	6280	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.64, 2.24]
28 Stillbirths Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

28.1 Transcervical CVS versus amniocentesis	2	3454	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.02, 45.31]
28.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.35, 2.81]
29 Neonatal deaths Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

29.1 Transcervical CVS versus amniocentesis	3	4251	Risk Ratio (M‐H, Random, 95% CI)	1.63 [0.38, 7.05]
29.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	2.64 [0.70, 9.93]
30 All recorded deaths after viability Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

30.1 Transcervical CVS versus amniocentesis	2	1579	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.02, 25.93]
30.2 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	1.44 [0.67, 3.09]
31 Congenital anomalies (all recorded) Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

31.1 Transcervical CVS versus amniocentesis	2	1408	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.25, 1.59]
31.2 CVS (any route) versus amniocentesis	2	3338	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.66, 0.89]
32 Haemangioma Show forest plot	1	182	Risk Ratio (M‐H, Random, 95% CI)	1.35 [0.81, 2.24]

33 Limb reduction defects Show forest plot	1	3201	Risk Ratio (M‐H, Random, 95% CI)	4.95 [0.24, 102.97]

33.1 CVS (any route) versus amniocentesis	1	3201	Risk Ratio (M‐H, Random, 95% CI)	4.95 [0.24, 102.97]

Comparison 3. Chorionic villus sampling (CVS) versus second trimester amniocentesis (AC)

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Comparison 4. Transcervical versus transabdominal chorionic villus sampling (CVS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All known pregnancy loss (including termination of pregnancy) Show forest plot	5	7978	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.81, 1.65]

2 Spontaneous miscarriage Show forest plot	4	3384	Risk Ratio (M‐H, Random, 95% CI)	1.68 [0.79, 3.58]

3 Spontaneous miscarriage after test Show forest plot	3	1347	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.75, 2.04]

4 Non‐compliance with allocated procedure Show forest plot	3	5187	Risk Ratio (M‐H, Random, 95% CI)	1.68 [0.59, 4.76]

5 Sampling failure Show forest plot	4	5231	Risk Ratio (M‐H, Random, 95% CI)	1.79 [1.13, 2.82]

6 Multiple insertions Show forest plot	2	1314	Risk Ratio (M‐H, Random, 95% CI)	2.54 [1.47, 4.42]

7 Second test performed Show forest plot	1	1194	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.65, 2.37]

8 Laboratory failure Show forest plot	1	1194	Risk Ratio (M‐H, Random, 95% CI)	2.23 [0.69, 7.22]

9 All non‐mosaic abnormalities Show forest plot	1	2862	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.87, 1.75]

10 True mosaics Show forest plot	1	2862	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.39, 2.17]

11 Confined mosaics Show forest plot	1	2862	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.26, 2.77]

12 Amniotic leakage after test Show forest plot	1	44	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.01, 6.52]

13 Vaginal bleeding after test Show forest plot	3	1358	Risk Ratio (M‐H, Random, 95% CI)	6.93 [0.77, 62.83]

14 Termination of pregnancy (all) Show forest plot	2	1303	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.56, 1.22]

15 Perinatal deaths Show forest plot	1	2037	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.11, 1.68]

16 Stillbirths Show forest plot	2	1227	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.11, 17.53]

17 Neonatal deaths Show forest plot	2	4845	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.14, 2.55]

18 Anomalies (all recorded) Show forest plot	2	3622	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.41, 1.12]

19 Talipes Show forest plot	1	2624	Risk Ratio (M‐H, Random, 95% CI)	3.21 [0.33, 30.80]

Comparison 4. Transcervical versus transabdominal chorionic villus sampling (CVS)

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Comparison 5. Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All known pregnancy loss (including termination of pregnancy) Show forest plot	4	5491	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.86, 1.54]

2 Spontaneous miscarriage Show forest plot	4	5491	Risk Ratio (M‐H, Random, 95% CI)	1.73 [1.15, 2.60]

3 Spontaneous miscarriage after test Show forest plot	4	5489	Risk Ratio (M‐H, Random, 95% CI)	1.71 [1.12, 2.61]

4 Non‐compliance with allocated procedure Show forest plot	4	5566	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.09, 0.72]

5 Sampling failure Show forest plot	4	5566	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.24, 1.38]

6 Multiple insertions Show forest plot	3	4445	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.21, 0.95]

7 Second test performed Show forest plot	4	5566	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.28, 1.43]

8 Laboratory failure Show forest plot	4	5566	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.34, 1.63]

9 All non‐mosaic abnormalities Show forest plot	4	5566	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.47, 1.90]

10 True mosaics Show forest plot	3	5451	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.10, 2.20]

11 Confined mosaics Show forest plot	4	5566	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.27, 2.47]

12 Maternal contamination Show forest plot	2	4330	Risk Ratio (M‐H, Random, 95% CI)	1.92 [0.02, 162.80]

13 Known false positive after birth Show forest plot	2	670	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.02, 8.73]

14 Knonw false negative after birth Show forest plot	1	555	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

15 Reporting time Show forest plot	1	3775	Mean Difference (IV, Random, 95% CI)	4.00 [3.82, 4.18]

16 Vaginal bleeding after 20 weeks Show forest plot	1	3698	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.35, 1.43]

17 Amniotic leakage after test Show forest plot	3	4934	Risk Ratio (M‐H, Random, 95% CI)	3.35 [0.37, 30.09]

18 Vaginal bleeding after test Show forest plot	3	4934	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.42, 1.12]

19 Pre‐labour ruptured membranes before 28 weeks Show forest plot	1	3698	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.27, 0.92]

20 Delivery before 37 weeks Show forest plot	3	1755	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.78, 1.74]

21 Delivery before 33 weeks Show forest plot	1	1121	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.09, 2.73]

22 Termination of pregnancy (all) Show forest plot	4	5489	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.45, 1.25]

23 Perinatal deaths Show forest plot	4	5428	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.53, 2.28]

24 Stillbirths Show forest plot	4	5428	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.52, 2.36]

25 Neonatal deaths Show forest plot	4	5455	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.05, 3.11]

26 All recorded deaths after viability Show forest plot	4	5453	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.43, 3.24]

27 Anomalies (all recorded) Show forest plot	4	5305	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.57, 2.30]

28 Talipes equinovarus Show forest plot	4	5305	Risk Ratio (M‐H, Random, 95% CI)	3.75 [1.42, 9.88]

29 Haemangioma Show forest plot	4	5305	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.26, 2.20]

30 Neonatal respiratory distress syndrome Show forest plot	4	4725	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.21, 3.98]

31 Birthweight below 10th centile Show forest plot	1	3618	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.66, 1.06]

32 Birthweight below 5th centile Show forest plot	2	629	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.05, 9.38]

Comparison 5. Early amniocentesis (AC) versus transabdominal chorionic villus sampling (CVS)

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Comparison 6. Ultrasound versus no ultrasound before second trimester amniocentesis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All known pregnancy loss (including termination of pregnancy) Show forest plot	1	223	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.02]

2 Spontaneous miscarriage Show forest plot	1	223	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.02]

3 Spontaneous miscarriage after test Show forest plot	1	223	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.02]

4 Sampling failure Show forest plot	1	223	Risk Ratio (M‐H, Random, 95% CI)	10.90 [0.61, 194.85]

5 Multiple insertions Show forest plot	1	223	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.41, 1.09]

6 Bloody tap (not pre‐specified) Show forest plot	1	223	Risk Ratio (M‐H, Random, 95% CI)	1.87 [0.87, 4.02]

Comparison 6. Ultrasound versus no ultrasound before second trimester amniocentesis

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Amniocentesis y toma de muestras de vellosidades coriónicas para el diagnóstico prenatal

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