1.       Alpha-fetoprotein (AFP) and maternal serum AFP (MSAFP)

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MCQ Paper 1

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1. A raised MSAFP level at 16 weeks

 a.  may be due to incorrect  assessment of gestation. True
 b.  may be due to gastroschisis. True
 c.  is more likely with multiple pregnancy. True
 d.  is more likely after threatened miscarriage. True
 e.  is more likely in Afro-Caribbeans False
 f.  is more likely in women with diabetes. True
 g.  is more likely in women with antiphospholipid syndrome True
 h.  is more likely if the fetus has T18. False
 i.  is more likely if the fetus has T21. False
 j.  is more likely with fetal parvovirus infection True
 k.  should trigger a repeat test as soon as possible after 7 days False
 l.  should be investigated by amniocentesis. False

k. There is no point in repeating the test - why believe a different result?

 

2. A raised MSAFP level at 16/52 with a normal scan at 20/52  is linked to an increased risk of:

 m.  intra-uterine growth restriction True
 n.  premature labour. True
 o.  placental abruption. True
 p.  abnormal placental adherence: accreta and percreta. True
 q.  gestational diabetes. False
 r.  fetal cleft lip False

3. Serum Alphafetoprotein:

 s.  is not present in those who are not pregnant. False
 t.  Caucasians have higher levels than Afro-Caribbeans in pregnancy. True
 u.  is raised in women on the Pill.   False

 

List of contents.

  1. abbreviations

  2. introduction

  3. is AFP still of clinical significance?

  4. exam questions

  5. note the scope for tricky questions

  6. key facts for the DRCOG

  7. expanded information for the MRCOG

  8.         history of AFP

  9.        what is AFP's role

  10.        AFP and the non-pregnant 

  11.        MSAFP

                   background

                   parvovirus

                   consequences of raised MSAFP for the normal baby

                   MSFP and anti-phospholipid syndrome 

  12.        what factors influence the interpretation of the results

  13.        MSAFP and screening for Down's syndrome 

  14.        MSAFP and T18.

 

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Abbreviations.

 AFP  alpha-fetoprotein
 APS  anti-phospholipid syndrome
 BMI  body mass index
 DOH  Department of Health
 DRCOG  Diploma of the RCOG hDiploma of the RCOG
 DS  Down's syndrome
FTCS   first trimester combined screening
 G6PD  glucose-6-phosphate dehydrogenase deficiency
 hCG  human chorionic gonadotrophin
 IDDM  insulin-dependent diabetes mellitus
 IUGR  intra-uterine growth restriction / retardation
 MCQ  multiple-choice question
 MOET  Managing Obstetric Emergencies and Trauma
 MRCOG  Membership of the RCOG
 MSAFP  maternal serum AFP
 NICE  National Institute for Health and Clinical Excellence
 NSC  UK National Screening Committee
NT  nuchal translucency.
 NTD  neural tube defect
 OSCE  objectivem structured, clinical examination
 PAPP-A  pregnancy-associated plasma protein A
 RCOG  Royal College of Obstetricians and Gynaecologists
 T18  trisomy 18
 T21  trisomy 21 see MCQ paper 6, question 24
 UKNSC  UK National Screening Committee

 

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Introduction.

You are likely to get a question about MSAFP in the MCQs.

It will usually be about things associated with a raised or reduced MSAFP value.

It could even be about elevated levels & the non-pregnant.

The following tells you all you need to know and probably a bit more.

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Is AFP still of clinical significance?

AFP has been of fluctuating significance in O&G.

It was the basis of screening for neural tube defects (NTDs) and Down's syndrome (DS).

Ultrasound scanning has replaced it for screening for NTDs.

This left it with a role in biochemical screening for DS in the second trimester.

But screening for DS has now moved to the 1st. trimester: "combined 1st. trimester screening".

This involves a scan for nuchal translucency and blood tests for PAPP-A and hCG, but not AFP.

 I tell you this now to start the process of cementing it in your head, but it will be discussed again later: MCQ4, question 26, MCQ6, question 24 and MCQ11, question 10.

So, AFP is left with a much diminished role:

biochemical screening for those who book too late for the preferred 1st. trimester DS screening

and as a tumour marker in a number of cancers.

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Exam questions.

Exam questions will usually be about maternal serum AFP.

You are likely to get a question about it the MCQs in both DRCOG and MRCOG.

It will usually be about a high or low MSAFP.

But you could be asked about elevated levels in the non-pregnant.

The following tells you all you need to know and probably a bit more.  

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Note the scope for tricky questions.

Background levels of MSAFP are higher in Afro-Caribbean women than in Caucasians.

But, perversely, Afro-Caribbean women have a lower incidence of NTDs than Caucasians.

Laboratory reports must take this into account.

Once the levels are corrected for ethnicity, Afro-Caribbean women have a reduced risk of a high result as they have a reduce risk of NTD.

The converse is true of women with IDDM and obesity who have higher risk but lower levels of MSAFP..

More of this below, but it means reading the question carefully.

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Key facts for the DRCOG.

First of all, is the test result reliable?

MSAFP levels and their interpretation are affected by:

gestation,

diabetes,

high or low BMI

and ethnicity.

Raised MSAFP:

The biggest link is with neural tube defect.

   but other abnormalities cause increased values:

abdominal wall defects

and upper gut atresias.

   there are various benign causes of high values:

dates errors,

bleeding,

multiple pregnancy etc. - see below.

Raised MSAFP but no obvious explanation such as fetal anomaly:

There is a ­ risk of fetal and placental problems in late pregnancy:

IUGR,

placental abruption,

premature labour,

placenta accreta and percreta.

          and an association with anti-phospholipid syndrome.

Low MSAFP

Is associated with chromosomal abnormalities, particularly T21 and T18. 

Raised AFP levels in the non-pregnant:

These are found in cirrhosis, liver cancer, some germ-cell tumours etc.

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Expanded information for the MRCOG and to help facts stick for the DRCOG.

You probably don’t need to know more than what is above, but the following might just help it stick.

Don’t worry about the references; they are included for those who might want to look at original paper.

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History of AFP.

The fetus produces large amounts of AFP in the liver and yolk sac.

Fetal levels are maximal at about 12 – 14 weeks, but MSAFP levels continue to rise, peaking in the third trimester

AFP was found in the 1950s by Bergstrand and Czar. Scand J Clin Lab Invest. 1956;8(2):174.

By the 1970s, raised MSAFP was linked with anencephaly and NTDs.

Leighton et al. 1975. Lancet, 1975. Vol 306, Issue 7943, P 1012 - 1015.

Screening programmes based on raised MSAFP were rapidly introduced.

But things move on and by the 1980s, ultrasound scanning had become very accurate in screening and diagnosing anencephaly and NTDs.

AFP-based screening for NTDs was phased out and it looked as though it would become of historical interest only.

Then, in 1984, Cuckle et al published the link between low MSAFP and DS. Lancet, 1984 Vol 323, Issue 8383, P 926 - 929.

Merkatz et al, also in 1984, described a case of "undetectable" MSAFP in a pregnancy that resulted in a baby with trisomy 18.

They did a retrospective survey of >3,000 pregnancies and identified 32 pregnancies resulting in trisomy.

All of these pregnancies had low MSAFP. Am J Obstet Gynecol. 1984 Apr 1;148(7):886-94.

This created a new life for AFP in screening for trisomy, particularly T21.

The history is interesting, but you are not going to be asked in the DRCOG.

You might quote it in a MRCOG OSCE viva if you are going for the gold medal.

 

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What is AFP's role?

.We have no clear idea of what AFP’s role is.

Some say it is the fetal equivalent of adult albumin.

Others that it has a role in the immunological interplay between mother and baby.

But there is a rare genetic abnormality leading to failure of production of AFP and the babies develop normally.

 Sharony, Zadik & Parvari R. Eur J Hum Genet. 2004 Oct;12(10):871-4.

No one is going to ask for your opinion or this level of detail in the DRCOG and you would be a shining star to quote this in the MRCOG!

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AFP and the non-pregnant.

Levels in the neonate fall rapidly and only minimal amounts are present after 6 months.

It is detectable in the non-pregnant but in miniscule amounts.

Levels rise in a variety of conditions:

cirrhosis,

liver cancer,

acute and chronic hepatitis,

ovarian and testicular germ cell tumours

and some bowel cancers.

In some of these it is used as a tumour marker.

For further data go to: http://www.medicinenet.com/alpha-fetoprotein_blood_test/article.htm.

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MSAFP.

Small amounts of AFP get into the amniotic fluid and even smaller amounts into the maternal circulation.

MSAFP levels rise steeply during the second trimester.

When checking values, careful dating is essential.

I refer to gestation assessment, not social encounters, though I might have some fatherly advice about those too.

Anything that breaches the fetal skin allows more AFP to leach into the liquor.

Hence neural tube and abdominal wall defects cause higher than normal levels.

Levels are increased with twins, bleeding in early pregnancy and invasive procedures such as amniocentesis.

The fetus gets rid of some AFP by swallowing liquor, so upper gut obstructions are associated with raised levels.

There are also rare conditions such as congenital nephrosis and placental or cord tumours.

Parvovirus infection.

In the group of rare causes is parvovirus infection. (See MCQ paper 5, question 36.)

More small print stuff!

The main problem with this virus is bone marrow suppression and anaemia that can be bad enough to kill.

Some affected pregnancies will have raised MSAFP.

This only occurs in a minority of the pregnancies and not early enough to allow intervention.

So, it is no use as a screening test for the severe fetal anaemia which is the main worry.

It might interfere with second trimester biochemical screening for Down’s syndrome (see MCQ paper 4, question 26 and MCQ paper 6, question 24).

Particularly as some of these babies will also have a raised maternal hCG.

You won’t be asked about this in the DRCOG exam.

Even in the MRCOG it would only be one mark in a MCQ.

Raised MSAFP: consequences for the normal baby.

There is an increased risk of

IUGR,

placental abruption,

premature labour

and placenta accreta and percreta

in pregnancies with a normal baby but a raised MSAFP,

presumably reflecting impaired placentation.

This is ill-understood, but it is important as it is common.

The assumption is that some form of failure of placentation allows increased AFP transfer to the mother.

And that the abnormal placentation subsequently manifests itself in the risk of IUGR etc.

(See also MCQ 2, question 3 and MCQ 10, question 1.) 

The risk of IUGR increases up to tenfold, in proportion to the degree of elevation of MSAFP.

But even with slight increases these are high-risk pregnancies.

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MSAFP and APS.

A raised MSAFP is also found in association with APS.

This is thought to reflect placental damage caused by thrombosis.

There is a good case for antenatal clinics to have a protocol for the management of raised MSAFP with no identified fetal anomaly.

The association with placenta accreta and percreta is not well known, but was first described in the early 1990s. Ginsberg et al. described the first case in 1992.

J Assist Reprod Genet. 1992 Oct;9(5):497-500.

McDuffie et al reported a dramatic case with acute abdomen at 17 weeks due to haemoperitoneum.

The patient had had a MSAFP of 5 MOM the previous week.

Am J Obstet Gynecol. 1994 Aug;171(2):565-6.

Knowledge of the association is likely to improve as it is highlighted in the MOET Course Manual.

The importance for the MRCOG candidate is that the association is likely to be in the MCQ database.

Even more important, you would be deemed negligent if a patient with a high MSAFP came to harm from placenta accreta or percreta because the diagnosis had not been considered and appropriate steps taken to diagnose and treat it.

There is a good review article on the internet: http://www.obgmanagement.com/article_pages.asp?AID=2963&UID=.

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What factors influence the interpretation of the results?

Diabetes.

Patients with IDDM are at increased risk of fetal abnormality, including neural tube defects, which are several times more common.

Perversely, they also tend to have lower than average MSAFP levels (by 10-20%).

Test results must be interpreted with this in mind.

Being Afro-Caribbean.

Afro-Caribbeans have about half the risk of neural tube defect of Caucasians.

But higher normal MSAFP levels (10-15%).

To digress: questions about the prevalence of different hereditary conditions in various ethnic groups can be crop up.

As a rule of thumb, Ashkenazy Jews have the highest incidence and Afro-Caribbeans the lowest, if one takes out sickle cell anaemia and G6PD.)

Maternal weight.

Maternal weight also influences MSAFP interpretation.

Overweight women having lower than normal levels and thin women raised levels.

The simple explanation is that the bigger the woman, the greater the blood volume and degree of dilution of AFP.

Extremes of weight lead to appropriate interpretation by the laboratory.

You don’t need to remember all the percentages, that’s for the MRCOG.

But you should know the various links.

The standard form for MSAFP tests includes a reminder to mention diabetes, ethnic background and weight.

This allows the laboratory to use the correct reference values.

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MSAFP and screening for Down's syndrome.

Screening for Down's syndrome screening has now shifted to the first trimester.

Both the DOH’s NSC and NICE have recommended this with implementation by 2010.

All screening does is give an estimate of the woman’s risk of having a baby with DS. It starts with the risk derived from maternal age.

Different authorities give slightly different numbers. Here are four easy-to-remember ones.

Maternal age

Risk of Down’s syndrome

20

1 in 1,500

35

1 in 350

40

1 in 100

45

1 in 40

Screening by maternal age.

In ancient times, this was all we had to quantify risk.

Most units had a policy of offering amniocentesis to women ≥ 35 years.

This was not very good.

Most babies with DS are born to women < 35 years, as most babies are born to younger women.

So, this policy missed most babies with DS, i.e. its sensitivity was low.

In addition, women of 35, whose risk was only 1 in 350 were being offered amniocentesis which has a 1 in 100 risk of causing miscarriage.

2nd. trimester biochemical screening.

This has been the mainstay of screening for decades.

The age-derived risk is refined by adding other measurements.

MSAFP was added – the lower the level, the greater the risk of DS.

Further refinement was brought with the addition of assay of hCG, oestriol and inhibin.

The test is usually done at 16 weeks and after a scan has been done for gestation.

This is a significant disadvantage, meaning that termination of any affected pregnancy has to be done by inducing labour.

And the woman has to go through the horrors of that and delivery.

1st. trimester combined screening.

The UKNSC recommended that from April 2010 screening for DS should be done in the first trimester.

Increased NT is associated with higher DS risk and is the key component of FTCS. (MCQ paper 10, question 35).

Screening gets even better when you add 1st. trimester maternal biochemistry:

serum PAPP-A (MCQ paper 3, question 36)

and beta-hCG levels (MCQ paper1, question 33).

FTCS obviates the horrors of late termination of affected pregnancies.

Second trimester serum screening will remain for those who book too late for first trimester screening.

AFP will not be relegated to the history books quite yet. 

In real-life counselling you give the facts in as emotionally-neutral a fashion as possible,

But I like to point out that even at the age of 45 there are 39 chances in 40 that the baby does not have Down’s syndrome.

Older women getting pregnant are having a bad time now because of publicity about the risks.

Don’t add to their potential worry and guilt by exaggerating them.

Remember that no screening test is perfect and that all of them lead to normal pregnancies being lost after amniocentesis.

This is a terrible price to pay for having a test! (see MCQ4, question 2 and MCQ8 question 16).

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MSAFP and T18.

MSAFP is also lower in T18 (See MCQ2, question 35). T18 and T21 are the only conditions associated with low MSAFP levels (apart from the rare congenital absence of AFP) and this will feature somewhere in the exam, especially the link with Down’s syndrome.   R412.                                                                                                  

creening for Down's syndrome has now moved to the first trimester.

Both the DOH’s NSC and NICE have recommended this with implementation by 2010.

Programmes will be based on 1st. trimester nuchal translucency (MCQ paper 10, q. 35).

To this will be added 1st. trimester maternal biochemistry: serum PAPP-A and beta-hCG levels.

This is called 1st. trimester combined screening.

This will obviate the horrors of late termination of affected pregnancies.

Second trimester serum screening will remain for those who book late.

So AFP will not be relegated to the history books quite yet.

Some argue that it should be retained as a predictor of IUGR even if first trimester combined screening has been done for aneuploidy.

 

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MCQ Paper 1

Return to MCQ Paper 2, answer 13. "Neural tube defect"

Return to MCQ Paper 2, answer 26. "Screening for DS"

Return to MCQ Paper 3, answer 12. "Premature delivery"

Return to MCQ Paper 3, answer 36. "PAPP-A"

Return to MCQ Paper 4, answer 2. "Amniocentesis"

Return to MCQ Paper 4, answer 26. "Biochemical screening"

Return to MCQ Paper 4, answer 35. "FDIU"

Return to MCQ Paper 5, answer 22. "Hyperemesis"

Return to MCQ Paper 5, answer 36. "Parvovirus"

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