Screening and Scanning

Introduction
Parents today consider the first antenatal scan as a normal and significant step in pregnancy, usually regarded as a milestone, a confirmation, an uplifting event when the parents-to-be have their first sight of the new baby. For many women, a better understanding of the nature of pregnancy screening can prepare them for some very difficult choices if the screening results are unfavourable.

However, since the majority of pregnancies are normal, an understanding of the process and the options that are available simply serves to give women an informed choice within the time frame as their pregnancy progresses and, ultimately, to help them decide whether they want to be screened or not.

It is understood that some women might consider themselves ‘high risk’ yet would want to continue with the pregnancy at whatever cost, and would not want to proceed with any interventions or suffer the increased anxiety which screening undoubtedly causes among couples affected.

Antenatal Screening looks at more than just testing for the likelihood of fetal/embryo abnormalities and defects before birth such as Down’s syndrome, chromosome abnormalities, genetic diseases and other rarer conditions such as spina bifida and cleft palate. It also identifies infectious diseases and blood disorders which might affect the pregnancy. Screening can also be used for antenatal sex determination¹,dating the pregnancy, the possibility of multiple births and measuring the size of the baby.

Nice guideline 62 Screening includes a guide for Healthcare Professionals to
manage appropriate referrals of high-risk women in pregnancy.²

The aim of this article is to give an overview of the more common screening and scanning available to act as a broad guide to the issues that these seek to identify as an aid to improved support for pregnant women.

It is important to assess every individual woman’s knowledge and understanding of her pregnancy development and the screening tests available to her and whether more information is required. Language and cultural or religious beliefs are factors that Midwives need to take into consideration.

Down’s syndrome is the most common cause of severe learning disability in children. It arises from an extra copy of chromosome 21 in the cells of the fetus. In the absence of prenatal screening, about 1 in 500 babies born would be affected. Edwards’ syndrome is a rare and usually fatal abnormality (birth prevalence about 1 in 7000) which arises from an extra copy of chromosome number 18 in the cells of the foetus.^3,4

Screening divides women into a higher risk group (screen-positive) and a lower risk group (screen-negative). For Down’s syndrome the result is screen-positive if the AFP level is 2.5 MoMs or higher. Mothers will then be offered a diagnostic test such as amniocentesis or CVS, both of which carry a risk of miscarriage. However, most women with a screen- positive result will not have affected pregnancies.

Time frame of screening tests available to pregnant women⁵
Obstetricians and Midwives find it useful to diagnose higher risk pregnancies early so that further testing can be offered to the parents with consultant obstetric management
and specially trained sonographers, Midwives and counselling services available in referral fetal medicine units in the UK. In pregnancies in which Down’s syndrome or other serious abnormalities are diagnosed, the woman will be offered the option of a termination of pregnancy.

There are three main purposes of early diagnosis:
1) To enable medical or surgical treatment of a condition before or after birth.
2) To enable parents to make an informed choice to either continue with the pregnancy or opt for termination of the foetus with a diagnosed condition.
3) To enable parents to prepare psychologically, socially and financially for a baby that will have a disability or a recognised health problem, and also to alert them of a probability of a miscarriage or stillbirth⁶.

Because of an increased risk of miscarriage and possible fetal damage associated with CVS and amniocentesis sampling, the majority of women prefer non-invasive screening to evaluate the risk assessment before considering or consenting to further testing.

First trimester screening tests give a combined risk score based on maternal factors, which include: blood tests for PAPP-A and beta-hCG (two serum markers which correlate with chromosomal abnormalities); weight; age; ethnic group; single or multiple pregnancies; smoking status supported with NT measurement; and gestational age to scan.

There has been a higher interest by women and Midwives in results from the ratio of PAPP-A serum marker and its significance within the first trimester screening, which many mothers and health care providers find confusing and hard to understand.

Physiology
PAPP-A is produced by the placental trophoblasts, especially by the extravillous cytotrophoblasts. It is a ‘protease’ for insulin-like growth factor (IGF) binding proteins 4 and 5. This means it has the ability to help release IGF from these binding proteins so that it is free to interact with its cell receptor. IGF is thought to play an important role in trophoblast invasion and hence the early development and vascularisation of the placenta and the placental bed. These early events in the formation of the placenta are critical to pregnancy outcome and, when abnormal, are associated with: miscarriage; intrauterine growth restriction (IUGR) and the possibility of foetal death in utero; premature delivery; and even cesarean section for indications of foetal or maternal compromise. It has been postulated that low levels of PAPP-A, resulting in less release of IGF, could be an indicator in these poor pregnancy outcomes.⁷


Recent studies would support this association between low PAPP-A levels in first trimester and risk for poor pregnancy outcome. The lower the PAPP-A, the smaller the babies at any gestational age.^8,9

Several other studies confirm the association of the other ‘pregnancy complications’ noted above with low levels of PAPP-A. For example, as a spin-off of the results in the First and Second Trimester Evaluation of Risk (FASTER) trial, it was found that women with PAPP-A at or below the 5th percentile “were significantly more likely to experience foetal loss at less than or equal to 24 weeks, low birth weight, preeclampsia, gestational hypertension, preterm birth (P < .001) and stillbirth, preterm premature rupture of membranes, and placental abruption (P < .02).”

More intensive antenatal fetal surveillance is recommended so that chances of delivering a healthy baby, regardless of the gestational age, are improved.¹⁰

The risk score in antenatal screening represents the chance that the baby has a birth defect. The most common threshold for high risk is a combined score of 1:200 for Down’s syndrome (Tristomy 21); Patau’s syndrome (Trisomy 13); Edward’s syndrome (Trisomy 18.) Therefore a risk score of 1:300 would therefore be considered as low risk. First trimester combined tests have a detection rate of 82-87% and a false positive rate of 5%-10%.

Some women will request invasive tests even if they have a low risk result due to their own history or background.They are often referred to the FMU (fetal medicine unit) by their Community Midwives at booking.

Reporting of results
The screening results are usually ready within 48 hours of receipt of the blood sample and will be sent to the antenatal clinic or doctor who ordered the test. All low risk results are sent to women within the guidelines directly, to be held in the patient’s notes.

Screen-positive results are telephoned and faxed directly from the testing centres to the antenatal clinic or doctor. Upon receipt, patients are usually contacted directly by telephone or visited by their Community Midwife and offered appointments for the next available fetal medicine clinic where the findings are discussed with specialist obstetricians and senior midwives offering counselling and support to the parents. Further invasive investigation is discussed.

In 2009 there were 706,248 live births in England and Wales. Of these, 114,288 were to women aged 35-39, and 26,976 to women over 40, compared to 14,252 births in 1999 to women ages 40 and over¹¹.

The increased rate of maternal age for primigravida women and the social factors influencing why this is on the increase is significant in the role of NTS screening programs and the related rise in referrals to fetal medicine units within the UK and Europe¹².

The attached chart shows the increased possibility of a Down’s syndrome baby, factor-related to maternal age.


Diagnostic tests

Amniocentesis
An amniocentesis is performed at about 15 to 16 weeks of pregnancy. Under ultrasound guidance, a sample of amniotic fluid is collected using a needle inserted through the abdominal wall. Cells from the sample can be used to diagnose Down’s syndrome. The risk of miscarriage due to the procedure is about 1%, but varies between units. Down’s syndrome is diagnosed using a technique called quantitative fluorescence polymerase chain reaction (QF-PCR). This provides a rapid diagnosis, usually within 48 hours of the amniocentesis being performed. It also detects trisomy 18,13 and sometimes sex chromosome abnormalities. To diagnose other conditions, the cells must grow before they can be examined and so the final results can take up to 2-3 weeks.

Chorionic Villus Sampling (CVS)
Occasionally this test may be offered as an alternative to amniocentesis. CVS involves taking a sample of placental tissue by inserting a needle through the abdominal wall or a fine instrument through the cervix. As with amniocentesis, QF-PCR is used to provide a rapid diagnosis for Down’s syndrome, trisomy18 and 13 and sometimes sex chromosome abnormalities. At this stage of pregnancy, the risk of miscarriage due to the procedure is thought to be about the same as the risk following an amniocentesis. With CVS there is roughly a 1% chance that the test will not provide a conclusive result and the miscarriage risk is 1-2%. In these circumstances an amniocentesis will need to be performed to provide a definite diagnosis.

Detailed ultrasound scan
Nearly all cases of anencephaly and open spina bifida can be detected by this method at the 20-week scan.

Both false positives and negative results will have a large impact on a couple when they are told the result, or when the child is born. Diagnostic tests, such as amniocentesis, are considered to be very accurate for the defects they check for, though even these tests are not perfect, with a reported 0.2% error rate, often due to rare abnormalities (such as mosaic Down’s syndrome where only some of the foetal/placental cells carry the genetic abnormality).

A higher maternal serum AFP level indicates a greater risk for anencephaly and open spina bifida. This screening is 80% and 90% sensitive for spina bifida and anencephaly, respectively.¹³

Conclusion
Regardless of all the information available, screening and any further diagnostic tests, undoubtedly have many benefits in helping women prepare for the impending birth of their child if it is affected with a genetic birth defect or a complicated pregnancy. Parents, families and health care professionals are able to direct resources appropriately to educate families of the difficulties ahead. It also gives the women and their partner the option to terminate the pregnancy should they so wish fully aware of the probable outcomes to them.
It is important to realise it is the women’s choice and to respect and support them impartially with whatever they decide to do and to be very aware of the long term affects of this process on couples and families within our profession.

References

1. Wald NJ et al. Corrections to SURUSS report. J Med Screen 2006;51:52
2. Nice guidelines (2009) 62 National institute of clinical excellence www.nice.org.uk
3. www.screening. nhs.uk
4. Report of the RCOG Working party on biochemical markers and the detection of Down’s syndrome. RCOG press. July 1998.
5. Selikowitz M. Down’s syndrome: The facts. Oxford University Press, 1996.
Wald NJ, Cuckle HS. Biochemical Screening. In: Prenatal Diagnosis
6. Ed Brock D et al. Churchill Livingstone: 563-577, 1992. Wald NJ: Biochemical detection of neural tube defects and Down’s syndrome.
7. Wald NJ et al. Prenatal Screening for Down’s syndrome using inhibin-A as a serum marker. Prenatal diagnosis 16:143- 153(1996).
8. Turnbull’s Obstetrics 2nd Edition. Ed. Chamberlain G. Churchill Livingstone: 195-209, 1995.
9. Chandra S et al. Unexplained elevated maternal serum alpha-fetoprotein and/or human chorionic gonadotropin and the risk of adverse outcomes. Am J Obstet Gynecol. 2003 Sep;189(3):775-81. [abstract]
10.Wald NJ et al. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess 2003;7:i-iv,1-88. pISSN: 13665278 and in J Med Screen 2003;10:56-104.
11. National statistics online Live births in England and Wales
www.statistics.gov.uk/cci/nugget.asp?id=369
12. Morris JK et al. Comparison of models of maternal age-specific risk for Down syndrome live births.Prenat Diagn. 2003 Mar;23(3):252-8
13. Antenatal Screening for Down’s Syndrome and Open Neural Tube Defects 2009
www.wolfson.qmul.ac.uk/epm/screening/routine.html