Screening And Diagnosis In Fetal Medicine Biology Essay

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In Ancient Greece, Spartans killed newborn male babies judged to be unhealthy or weak, by throwing them from a Mount, while pre-Islamic Arabs buried their girls alive. Those ancient people practiced a basic form of postnatal genetic selection, in one case based on physical appearance and in the second case, based on sex. Today, with the advent of technology and genetic progress, those ancient postnatal selections have now been replaced by prenatal screening and diagnosis.

Prenatal screening is aimed at estimating the likelihood of a baby having congenital or chromosomal anomalies during pregnancy (Ettorre et al, 2007). In the 1970s, prenatal screening was mainly used for screening of spina bifida (Chan et al, 1993) and Down's syndrome (Wald et al, 1988). Based on the accuracy of the screening test, the baby will be classified at a risk level and if deemed high enough, parents may be offered to establish a definite diagnosis, which may pose a risk of miscarriage. Once a more definite diagnosis is established, if positive, parents may decide to pursue or terminate the pregnancy, and otherwise, it gives reassurance to the parents. A study by Stoll (2002) carried out in France showed incidence of Down's syndrome decreased by 80% over 21 years from 1979 to 1999 but also an increased rate of termination, while a study by Buckley and Buckley (2008) demonstrates that false positive results lead to unnecessary intervention, anxiety for parents and possible fetal loss.

This process of prenatal screening and diagnosis raises ethical questions as it may seem to offer parents the tools to achieve the "best" possible baby or avoid a baby with a disability, leading to a population perceived as "eugenic".

So let us discuss the advantages and disadvantages of prenatal screening and diagnosis and how it may evolve in the next 10 years.

Advantages of Prenatal Screening

Prenatal screening by definition is aimed at identifying and estimating risks in an unborn baby of chromosomal or genetic abnormalities, and more recently for identification of pregnancies with adverse outcome. The risk can be calculated by a combination of maternal blood test by checking different hormones and by ultrasonography.

Prenatal screening does not pose any risk to the baby or the mother and it can quite accurately detect normality or the lack of it in a baby. 98% of women want first trimester screening (Graaf et al, 2002) as it gives reassurance to parents. A study by Lo et al (2009) has shown that given the choice, women would opt for first trimester screening and would even be willing to pay for test with low positive false rate to be given the "all clear" so that they can enjoy a stress-free pregnancy. The main categories of screening in fetal medicine are biochemical screening to check level of different hormone in maternal blood and ultrasound screening . It is vital to do counselling before any screening test can be considered, as evaluation and consequence of risk assessment for a genetic disorder can have a huge impact on the expecting couple so the difference between screening and diagnosis should be clearly understood and conveyed to the expecting couple.

Aneuploidy (e.g. trisomy 21) is a major cause of genetic disorders which subsequently leads to increased prenatal mortality and morbidity so different methods of prenatal diagnosis of aneuploidy have been used over the last four decades( Nicolaides ,et al 2011).

The ideal screening test would be easy to implement, low cost, with a high detection success rate, and lowest possible false positive rate, allowing early and safe detection. Nicolaides (2011) describes test for aneuploidy in detail and covers biochemical and ultrasound screening for first and second trimester screening, with the focus moving to the first trimester screening (Table 1). They are various tests for serum markers and ultrasound, and although the false-positive rate remains about the same, the detection rate can vary greatly depending on the test chosen. The most useful and reliable test as of today is the combined test of maternal age (MA),with Nuchal translucency (NT)which is measuring fluid behind the fetal neck, measurement of free beta human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein-A (PAPP-A) and measurement of nasal bone, tricuspid flow and ductus venosus flow. This "full combined" test can be carried out in the first trimester and has a detection rate of 93-96% with false positive rate of 2.5%.

Table 1: Performance of different screening methods for trisomy 21 (Nicolaides, 2011)

New techniques of massive parallel processing (Chiu et al, 2011) allow detection of trisomy 21 by maternal plasma DNA sequencing with very high detection rates but it is currently very costly and unviable on a large-scale.

As shown by Nicolaides (2011), ultrasound imaging has become a critical element of prenatal screening. 2D scan is used to check normal fetal development, to find out about major structural anomalies, screening for aneuploidy and major cardiac defect, and can be used in interventional fetal therapy and finally can reduce perinatal mortality by identifying high risk pregnancies and help monitoring during pregnancies. It is important to realise that different images of one particular structure should be obtained for more precise and accurate screening like 4-chamber view would detect 63% of major congenital heart diseases (CHD) and outflow tract view would detect 91% of CHD (Sklansky et al, 2009).

3D scan can provide an advantage when 2D is not sufficient, for example to detect a cleft lip. MRI is better for brain anomaly images like agenesis of corpus callosum, to see extent of cystic lesions (Hagberg et al, 2008) also in ventriculomegaly. MRI of placenta in case of placental insufficiency could predict the severity of the ongoing disease (Damodaram et al, 2010) and specialised diffusion weighted MRI may be used as an early marker in case of intra-uterine growth restriction (IUGR) (Bonel et al, 2010). MRI can also be used for diagnosis of placenta accreta along with ultrasound to access extent of placental invasion (Lax et al, 2007) but it is not cost effective.

Non-invasive screening using cell free fetal DNA technique first used by Lo et al (1997) has no risk of miscarriage, no parental anxiety and has earlier availability especially for dominant inherited disorders in which the father is carrying the mutation can be detected by sex determination as early as 7 weeks with sensitivity between 95-100% (Bischoff et al, 2005), but this reduces to 70-95% in case of euploid sample. The technique can also be used to detect the fetal Rhesus D blood group who are at risk of developing Rhesus hemolytic disease(RHD) in Rhesus negative mothers if the fetus is positive then it will need anti-D injection but if it negative then there is no need to give injection. This technique can save money to a healthcare system and avoid mothers having unnecessary blood product and risk of infection and anaphylaxis (Finning et al, 2004).

Many major diseases can be predicted at early screening at 11-13 weeks gestation like pre-eclampsia (Akolekar et al, 2011) by measuring the uterine artery Doppler. Factors like maternal biophysical profile, increased NT, reverse ductus and low PAPP-A can predict risk of miscarriage (Akolekar et al, 2011). Increased NT can help about the risk for aneuploidy but can help detect anomalies, such as major cardiac anomalies (Hyett et al, 2004).

Increasing need for accuracy in prenatal screening is pushing experts to achieve high standard in available screening methods.

Disadvantages of prenatal screening

Recently a Cochrane database review has shown that serum markers could lead to abnormal results like unusually high β hCG alone, which may not be significant but if accompanied by increased level of other markers like maternal serum AFP correlated with adverse pregnancy outcome (Gagnon et al, 2008). Similarly low unconjugated estradiol level associated with rare genetic conditions like Smith-Lemli-Opitz syndrome and more often X-linked skin conditions (Schoen et al, 2003) makes the situation very complex and a medical geneticist need to be involved in this case and this facility may not be available in all hospitals and patients may need to go to a specialised tertiary centre for further assessment which will add extra stress and anxiety.

Quality of ultrasound markers is difficult to achieve as compared to serum biochemistry which means that to achieve quality standard results of ultrasound makers, patients may have to be referred to specialised centre or ensure to have properly trained staff as results may vary due to poor quality control (Cuckle et al, 2010). But on the other hand, using first trimester ultrasound is cost effective, easily available, and can be used not only for detection of major anomalies but also for identifying high risk pregnancies and as a result, women can be given an "all-clear" at the beginning of pregnancy or have the option of termination in case of adverse outcome (Nicolaides, 2011).

MRI can used as adjunct but not as main tool in situation where the ultrasound is not helpful (Levine et al, 2006), so it can only be used in complicated pregnancies, but it is poor at diagnosing heart conditions, cord insertion and external genitalia (Zaretsky et al, 2003). It is expensive, not widely available and no randomised controlled trial has been done.

In some cases like thoracic scoliosis, 3D scan may be more appropriate than 2D scan which fails to assess rib anomalies (Chapman et al, 2010) while brain, lung and complex genetic syndromes can be better assessed by fetal MRI (Pugash et al, 2008).

Placental glycoprotein A Disintegrin and Metalloprotease 12 (ADAM 12) has been discovered as potential Down's syndrome biomarker done at 8-9 weeks of gestation along with PAPP-A with detection rate of 91% and false positive rate of 5% (Laigaard, 2006) but would require an additional test and cost and stepwise screening regime. Another sonographic marker, increased hepatic artery peak systolic velocity (PSV) has been shown or demonstrated in Down syndrome (Zvanca et al, 2011). All these markers add to parent anxiety where there is lack of evidence.

Some parents are exploited by buying CD and DVD of 3D ultrasonography of their baby at the cost of £200. If something goes wrong with the pregnancy later, these clinics can be sued for negligence or providing inappropriate service and trigger a bigger trauma for the patient.

Extensive screening of minor or cosmetic aspects can mislead parents into deciding to terminate a child, such as for a baby having a cleft lip which can be corrected by surgery but the parents feel that they can not go through the whole ordeal of going through the pregnancy and the postnatal surgery they might opt to have termination which could lead to society at risk of selection of sex, personality and physical characteristics and eventually eugenics.

Use of prenatal screening to identify the sex of the baby may lead to female feticide in some countries due to social pressure, such as in India where there is an abnormal excess of male newborns due to terminations of female fetuses as demonstrated by the study carried out by Jha et al (2006).

Increased NT with normal karyotype is linked with adverse outcome like cardiac defect, genetic syndromes mainly sporadic and possible neurodevelopmental delay and death, while very high NT is linked with worst outcome (inversely proportional) and need geneticist counselling (Bilardo et al, 2010).

Ultrasound soft markers in 2nd trimester scan have not proven to replace amniocentesis in high risk pregnancies (Smith-Bindman et al, 2007).

Pregnancies with low PAPP-A (less than 0.3MOM) have 5 fold increased risk of low birth weight and preterm labour which may require increased surveillance during pregnancy (Barrett et al, 2008).

There are ethical and logistic issues about prenatal screening. Firstly, management after a negative result may not be available in all hospitals and in case of implementation, the cost would be a big issue. Secondly, as with any screening, there is risk of finding rare conditions.

Screening for conditions like spinal muscular atrophy will cost $4.9 million, so to prevent one case is not cost effective and targeted screening of patents with family history would be an alternative option (Little et al, 2010).

Thirdly, counselling needs to be patient-oriented and ensure the delivery of information was accurate but there is always risk of jeopardising this. Finally, there is need to set a distinction between treatable and untreatable diseases.

Prenatal screening and diagnosis over the next 10 years

Prenatal diagnosis is a method firstly to detect fetal structural malformation and genetic anomalies, secondly identify and monitor complicated pregnancies like preeclampsia, IUGR by assessing the growth and development of fetus in utero. These methods include Ultrasound, Amniocentesis, Chorionic villus sampling (CVS) and maternal serum screening. Invasive techniques pose a risk of miscarriage. CVS does not effect normal placental development (Khalil et al, 2010) but is less sensitive than amniocentesis due to placental mosaicism but available in first trimester so the patients know information earlier in case of abnormal results. Invasive procedures can be more traumatic for the patient due to sheer anticipation during the procedure as there can be pain, bleeding, post procedure risk of miscarriage, risk of limb deformity, preterm labour and infection (Philip et al, 2004). More recently, not only fetal defects are identified but also treated in utero by using different treatment modalities named collectively as fetal therapy. The fetus is taken as a patient and this has revolutionised the field of prenatal diagnosis but it has yet to establish itself as a new standard (Schoenwolf et al, 2010). Fetal therapy includes fetal transfusion, fetal medical treatment, fetal surgery like placing shunt, repairing spina bifida and congenital diaphragmatic hernia and removing cystic lesion in lung and finally, stem cell transplantation and gene therapy as the fetus does not grow immuno-competence before 18 weeks and it may be a good opportunity to transplant tissues or cells (Schoenwolf et al, 2010).

Molecular cytogenetics is another major part of prenatal diagnosis. Fluorescent insitu hybridisation technique (FISH) can be used more accurately in case of common aneuploidies like trisomy 13, 18 or 21 (Tepperberg et al, 2001). This method is fast, low cost but of limited diagnostic value. More recently, array comparative genomic hybridisation which is a way to scan the whole genome by checking for a gain or loss of chromosomal material seems a more detailed test but the reliability is hampered by inherited genetic variants. Techniques like polymerase chain reaction (PCR) in which DNA sequencing of whole genome of a single cell are ideal as it test for genetic variants as well (Lee et al, 2010). Multiplex PCR has become the new upcoming method of choice (Chiu et al, 2011).

During counselling parents should be informed of post natal investigation for confirmation of diagnosis and recurrence risk assessment (Khalil et al, 2011).

Future of prenatal diagnosis is not only diagnosing the condition with hundred percent precision but also treating it or rectify its adverse effect.

Firstly to make prenatal diagnosis more accurate as discussed earlier, massive parallel sequencing of DNA can provide high accuracy, detection of chromosomal aneuploidies, diagnosis of monogenic diseases at a high cost but brought a new horizon in the field of prenatal genetics, making invasive screening a thing of the past and accessibility of non-invasive prenatal screening to everyone in the future with the hope that the sequence of whole fetal genome from the mother's blood would be available in the near future (Lo et al, 2010).

Secondly as described in Ndumbe et al (2008), recently diagnosis of genetic defects and chromosomal aneuploidies is geared towards first trimester so parents can decide earlier and it is achievable due to advanced ultrasound machines and techniques which combined with blood test can detect 97.5% Down syndrome and 80% CNS anomalies in first trimester.

More and more risk identification of complications such as diabetes, preeclampsia and preterm labour is assessed in first trimester and pregnancies with possible adverse outcome can be monitored accordingly (Nicolaides et al, 2010). As some argue that it adds anxiety during pregnancy (Fisher et al, 2011), better counseling skills will be required to combat this problem.

Thirdly, more speciality oriented approach for accurate diagnosis becoming a practice where a fetal echocardiography is done by a fetal echo specialist for a detailed analysis of the heart.

Fourthly, the fetus is treated as a patient and after being diagnosed, it is given treatment such as in case of cardiac arrhythmias in fetus. It is also offered surgical treatment in case of congenital diaphragmatic hernia and spina bifida.

Finally, gene therapy appears to be ideal in the fetus as it has low risk of rejection due to the fetal immune system not fully developed. It can cure some of genetic blood disorders for this purpose, fetal own cord blood can be used as it has highly retrieval of stem cells especially after freezing without rejection.

On the other hand, it can be argued that all theses new techniques will increase the likelihood of finding abnormalities which consequently require expert counselling regarding these tests results, possible outcome of these abnormalities which would provoke high demand of invasive testing in first trimester by experienced experts in a regional specialised genetic centres so parents can decide early about the ongoing pregnancy (Wapner, et al 2010).

Well established prenatal therapies like fetal transfusion for anaemia (Inge L et al, 2005) and laser surgery for twin to twin transfusion syndrome (Senat at el, 2004) are step towards robotic fetal surgery for repair of fetal anomalies such as spina bifida which is an incomplete closure of the spinal cord (Zhang et al 2009). With exponential progress in prenatal diagnosis, nanotechnology in neurodevelopment disorder like Down's syndrome by gene therapy or rectify the underlying defect (Woolfe et al 2010) and intrauterine stem cell therapy, gene therapy or epigenetic alterations using non-coding mRNA or "nanobots" are potential areas for significant breakthroughs over the next decade (Choolani et al, 2010) not only common genetic diseases would be treatable but the adverse effect of rare debilitating diseases will be dealt with. The prospect of gene therapy during pregnancy to correct genetic conditions like cystic fibrosis, thalassemia and many neurological disorders, appears exciting and certainly has open new horizons for prenatal diagnosis. Why fetal gene therapy is needed? And the answer is well described by David and Peebles (2008), Davey and Flake (2011). It can be used for a disease which can not be rectified or improved after birth. Secondly, it can overcome major problems faced in adult gene therapy such as rejection, whereas the fetal immune system is growing and can be tailored to accommodate foreign genes. Thirdly, as a baby is very small during the first trimester, it would only need a small dose and as it has large amounts of its own stem cells which are not available after birth, this will eventually increase the effectiveness of gene therapy and potentially reduce effect of early onset diseases. It also offers parents an option other than termination. With improved methods of delivery of gene (Rahim et al, 2009), it is becoming an attractive treatment modality for congenital neurological disorders.

On the other hand, there has been incidence of liver tumour following in utero gene transfer in animal model (Coutelle et al, 2005) and it is argued that it has no place at present while pre-implantation genetic diagnosis is available for genetic diseases (Coutelle et al, 2008) as it is vital to check the safety of the technique before its clinical application in humans and this needs continuous research on the topic.


Prenatal screening and diagnosis are rapidly evolving and offering more and more accurate, non-invasive methods such as new DNA sequencing techniques (Chiu et al, 2011), with the prospect of early genetic intervention to correct or minimise the effect of the detected condition.

On the other hand, progress is also need for genetic counseling due to the increasing complexity and finding of new syndromes and conditions.