UNSW Embryology

Prenatal Diagnosis

© Dr Mark Hill (2011)

Acknowledgements

Introduction

This page gives a general introduction to some prenatal diagnostic techniques available at different stages of pregnancy. Some tests measure abnormal protein levels (Alpha-Fetoprotein test), other tests rely on genetic analysis of fetal/placental cells (Amniocentesis/Chorionic Villus Sampling) and still others rely on measuring known parameters of the embryo/fetus/placenta (Ultrasound).

Note that the development of in vitro fertilization techniques now allows cells from early stage blastocysts to be removed and genetically analysed prior to implantation. This has raised some ethical issues relating to what parameters will be in future used in blastocyst selection. See also notes on Ultrasound.

There are additional prenatal diagnostic tests under development based upon new molecular techniques such as Quantitative Fluorescent Polymerase Chain Reaction (QF-PCR), Comparative Genomic Hybridization and fetal cells from maternal blood.

This page also contains a modified version of an information pamphlet "Checking Your Baby's Health Before Birth". There is a separate page for Neonatal Screening

Some Recent Findings

Genetic Testing Franssen MT, Korevaar JC, van der Veen F, Leschot NJ, Bossuyt PM, Goddijn M. Reproductive outcome after chromosome analysis in couples with two or more miscarriages: case-control study. BMJ. 2006 Apr 1;332(7544):759-63. "Couples whose carrier status was ascertained after two or more miscarriages have a low risk of viable offspring with unbalanced chromosomal abnormalities. Their chances of having a healthy child are as high as non-carrier couples, despite a higher risk of miscarriage."

Sharkey FH, Maher E, FitzPatrick DR. [See Related Articles] Chromosome analysis: what and when to request. Arch Dis Child. 2005 Dec;90(12):1264-9. Review.

"Chromosome abnormalities have long been recognised as an important cause of learning disability and multiple malformation syndromes; 0.8% of live born infants have numerical or structural chromosomal anomalies resulting in an abnormal phenotype."

Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ, D'Alton ME [See Related Articles] First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med. 2005 Nov 10;353(19):2001-11.

"First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening.

Check E. Fetal genetic testing: Screen test. Nature. 2005 Dec 8;438(7069):733-4.)

Ultrasound Ruano R. Recent advances in sonographic imaging of fetal thoracic structures. Expert Rev Med Devices. 2005 Mar;2(2):217-22. "Recent ultrasonographic methods applied in the evaluation of fetal thoracic structures and anomalies are presented."

Checking Your Baby's Health Before Birth

Below is a modified version of the NSW State Health Publication Checking your baby's health before birth (a similar online resource is available from South Australia). This pamphlet is an example of the information made available to the general public on the diagnostic testing using Ultrasound, Chorionic Villus Sampling (CVS), Amniocentesis, that can be carried out to check the genetic/physical status of the fetus. The original NSW State Health Publication pamphlet has been modified in layout to fit web format, updated additional content has been added, and additional links to UNSW Embryology resources.

PRENATAL DIAGNOSIS

Every couple wants to have a healthy baby. For most couples, that will come true. However, there are some couples who have a greater chance than others of having a baby with a birth defect.

Special tests are available which are carried out during pregnancy to determine if the baby has a particular problem. These tests are generally referred to as prenatal diagnosis.

Some reasons why you should ask your doctor about prenatal diagnosis:

you have already had a child with a serious disorder
you or your baby's father have a serious disorder which may be passed on to your baby
you have a relative with a serious disorder or the relative has an affected child
you have a family history of a disorder which only affects boys. Women in the family may be "carriers" of the disorder, as with haemophilia
you are planning to have a baby or you are pregnant and you are in your mid-30s or older (not necessarily your first pregnancy)

Can all birth defects be detected by prenatal diagnosis?

No. Although prenatal diagnosis is highly accurate, a normal test result cannot show up every possible problem with the baby.

How is prenatal testing done?

There is an increasing number of tests available to detect birth defects. Ask your doctor or genetic counsellor.

Ultrasound

Ultrasound of 12 week Fetus

The ultrasound scan is a picture of the baby in the uterus (womb). The doctor rubs a jellylike substance on the mother's abdomen before pressing an instrument like a microphone against her skin. Sound waves pass through this instrument into the uterus, through the amniotic fluid and bounce harmlessly off the baby. A computer changes these sound waves into a picture on a television screen so that the outline of the baby is clearly seen.

The ultrasound scan tells your doctor the age of the pregnancy and if you are carrying more than one baby. It can also be used to detect certain things wrong with the baby. This test is harmless to the mother and the baby.

(More? Ultrasound Movies)

Chorionic Villus Sampling (CVS)

This test must be done in the 10th to 12th week after the first day of the mother's last menstrual period. Thus, it is important to see your doctor as soon as you realise that you are pregnant.

The test is done by looking at cells taken from the placenta. No anaesthetic is required, and a test result is usually available in two to three weeks.

When the test is carried out by an obstetrician experienced in the technique, the risk of miscarriage related to the test is about 2 per cent (occurring in 1 in 50 pregnancies).

(More? Prenatal Diagnosis - Chorionic Villus Sampling (CVS))

Amniocentesis

This test is done in the 14th to 18th week of pregnancy. A small amount of the amniotic fluid is taken from the uterus and then sent to a laboratory to be studied. Cells from the developing baby are found in the amniotic fluid.

No anaesthetic is required, and a result is usually obtained in about three to four weeks. When the test is carried out by an obstetrician experienced in the technique, the risk of a miscarriage related to the test is about 1 per cent (occurring in 1 in 100 pregnancies).

(More? Prenatal Diagnosis - Amniocentesis)

Cordocentesis

(percutaneous umbilical blood sampling, PUBS, fetal blood sampling, umbilical vein sampling) This chromosome analysis test is done at in the 18th week or later of high-risk pregnancies. The technique may be used when either alternative tests (amniocentesis, CVS, ultrasound) are either inconclusive or not achievable (severe oligohydramnios).

The risk of a miscarriage related to the test is about 3 per cent (occurring in 3 in 100 pregnancies).

Coelocentesis

Is a technique of sampling of extracoelomic fluid usually for an early prenatal diagnostic technique.

Fetal Fibronectin

As a prenatal diagnostic test, a positive fetal fibronectin test result can indicate a higher risk of preterm delivery, but may also has false positive results. The negative result is more reliable as an indicator of reduced risk of preterm birth.

(fFN) is an extracellular matrix glycoprotein produced by fetal cells. Fetal fibronectin appears to act as an adhesive between the interface of the chorion and the decidua (fetal membrane and uterine lining).

(More? Normal Development - Birth | Birth - Premature)

Links: March of Dimes - Fetal Fibronectin (fFN): A Test for Preterm Delivery

Magnetic Resonance Imaging

Magnetic Resonance Imaging (MRI) can be used in fetuses at 18 weeks gestational age or later and has been used mainly in brain and spinal diagnosis. (More? Prenatal Diagnosis - Magnetic Resonance Imaging)

References:

Griffiths PD, Paley MN, Widjaja E, Taylor C, Whitby EH. In utero magnetic resonance imaging for brain and spinal abnormalities in fetuses. BMJ. 2005 Sep 10;331(7516):562-5.
Kok RD, de Vries MM, Heerschap A, van den Berg PP. Absence of harmful effects of magnetic resonance exposure at 1.5 T in utero during the third trimester of pregnancy: a follow-up study. Magn Reson Imaging. 2004 Jul;22(6):851-4.

Gene Tests

A new site developed by NIH "GeneTests" provides medical genetics information resources available at no cost to all interested persons. It contains educational information, a directory of genetic testing laboratories and links to other databases such as OMIM.

Links: GeneTests |

Ethics of Testing

Major developmental abnormalities detected early enough can be resolved far more easily than those discovered late in a pregnancy.

What are the ethical questions that are raised by prenatal testing? Future individual rights or parents rights? But what about diseases, like Huntington's, where a diagnostic test can be made but there are no current treatments for the postnatal (95% of cases adult onset) disease?

Guidelines for the molecular genetics predictive test in Huntington's disease

Recommendation 2.1 "the test is available only to individuals who have reached the age of majority."
Recommendation 7.2 "the couple requesting antenatal testing must be clearly informed that if they intend to complete the pregnancy if the fetus is a carrier of the gene defect, there is no valid reason for performing the test."

(excerpt from: IHA and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease.)

References:

Clarke A. The genetic testing of children. Working Party of the Clinical Genetics Society (UK) J Med Genet. 1994 Oct;31(10):785-97.
No authors listed Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet. 1995 Nov;57(5):1233-41.
No authors listed International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease. J Med Genet. 1994 Jul;31(7):555-9.
BMJ - Prenatal genetic testing for parents who won't terminate

Comparative Genomic Hybridization

This new test under development is based upon microarray-based comparative genomic hybridization (array CGH).

All fetal cells should have complete copies of maternal and paternal genomes. The test compares regions of fetal DNA that deviate from this "pattern" due to either too much or too little DNA, alterations reflect regions of the genome that are either copied or deleted. These genetic changes may therefore cause disease. (More? Prenatal Diagnosis - Comparative Genomic Hybridization)

What happens if the results of the test show a birth defect?

Most often, the baby will not have the disorder for which the test was done. In those few cases where the test does show a birth defect, the parents will need to have all the necessary information to help them make a choice about continuing the pregnancy. All aspects should be fully discussed with your doctor.

Genetic counselling will provide current information about the disorder and support during this time. Ask your doctor for a referral or contact your local genetic counselling service for an appointment.

How can I find out more about prenatal diagnosis?

The ideal time to learn about prenatal diagnosis is before a planned pregnancy. In some cases, tests need to be done before a pregnancy to check whether the parents are "carriers" of a disorder which may affect their baby.

NSW Centres

Further information can be obtained front the following centres. They specialise in prenatal diagnosis and related genetic counselling (original pamphlet listed centres 1997 with some updates)

Camperdown	Royal Prince Alfred Hospital Fetal Medicine Unit Missenden Road, Camperdown, NSW 2050 Ph: (02) 9515 6042 Fax: (02) 9515 6579 or (02) 9515 3811
Kogarah	St George Hospital Clinical Genetic Service Level 1, Prichard Wing, Gray Street, Kogarah, NSW 2217 Ph: (02) 9113 3635 Fax: (02) 9113 3694
Liverpool	Liverpool Hospital Fetal Maternal Unit Locked Bag 7103, Liverpool BC NSW 1871 Ph: (02) 9828 5631 Fax: (02) 9828 5570
Newcastle	John Hunter Hospital Maternal and Fetal Medicine Locked Bag 1, Hunter Region Mail Centre Newcastle, NSW 2310 Ph: (02) 4921 4694 Fax: (02) 4921 3133
Penrith	Nepean Hospital Perinatal Ultrasound Level 3 South Block, Derby Street, Penrith, NSW 2751 Ph: (02) 4734 2578 Fax: (02) 4737 3206
Randwick	Royal Hospital for Women Maternal/Fetal Medicine, Barker Street, Randwick, NSW 2031 Ph: (02) 9382 6098 Fax: (02) 9382 6706
St Leonards	Royal North Shore Hospital Maternal Fetal Medicine Unit Pacific Highway, St Leonards, NSW 2065 Ph: (02) 9926 7099 Fax: (02) 9926 5590
Westmead	Westmead Hospital Fetal Medicine Unit, Locked Bag 4001, Westmead, NSW 2145 Ph: (02) 9845 6802 Fax: (02) 9891 1216

Australian Capital Territory (ACT) - Specialised Prenatal Services

Canberra

The Canberra Hospital
The Clinical Genetics Dept
PO Box 11, Woden, ACT 2605
Ph: (02) 6244 2133
Fax: (02) 6244 4625

For information on services in other areas:

Genetic Education Program, Tel: 9438 7324

Written in association with the NSW Genetic Education Program

PO. Box 317, St Leonards, NSW 2065. Tel: (02) 9438 7324.

References

Checking your baby's health before birth. State Health Publication Number (PA) 94-090

The Australian NHMRC

1988 recommendations for neonates be assessed for follow-up care under the following conditions.

(Note: there is no current NHMRC health guideline)

Birthweight less than 1500g or gestational age less than 32 weeks
Small-for-gestational-age neonates
Perinatal asphyxia
Apgar score less than 3 at 5 minutes
clinical evidence of neurological dysfunction
delay in onset of spontaneous respiration for more than 5 minutes and requiring mechanical ventilation
Clinical evidence of central nervous system abnormalities ie., seizures, hypotonia
Hyperbilirubinaemia of greater than 350umol/l in full term neonates
Genetic, dysmorphic or metabolic disorders or a family history of serious genetic disorder
Perinatal or serious neonatal infection including children of mothers who are HIV positive
Psychosocial problems eg., infants of drug-addicted or alcoholic mothers.

Glossary

A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers

Terms

false negative rate - The proportion of pregnancies that will test negative given that the congenital anomaly is present.

false positive rate - The proportion of pregnancies that will test positive given that the congenital anomaly is absent.

negative predictive value - The probability that a congenital anomaly is absent given that the prenatal screening test is negative.

positive predictive value - The probability that a congenital anomaly is present given that the prenatal screening test is positive.

pre-implantation genetic diagnosis - (PGD) a screening procedure for embryos produced through in vitro fertilisation (IVF) for genetic diseases that would generate developmental abnormalities or serious postnatal diseases.

prenatal screening sensitivity - (detection rate) The probability of testing positive on a prenatal screening test if the congenital anomaly is present.

prenatal screening specificity - The probability of testing negative on a prenatal screening test if the congenital anomaly is absent.

WWW Links

Medline - Prenatal Testing

Finally

Each section of the notes covering early development and specific systems contain references to specific abnormalities (on Page 2 of each notes section). The best source for Australian statistical data is the Australian Institute of Health and Welfare National Perinatal Statistics Unit, UNSW which publishes "Congenital Malformations Australia" every 2 years. Be aware that some congenital abnormalities, by their nature, affect multiple systems. In the USA, the Center for Disease Control (CDC) keeps and publishes relevant statistical information. A very difficult issue in abnormal development are the many different Ethical implications.

This current page is a link to Normal and Abnormal Development and Population Data.

Where to Next?

Look at types of Abnormal Development that can occur during development.

Alternatively, look at normal development. Development Notes

Quick Links

This quick link is to the abnormal development page for each system.