5. Cytomegalovirus infection in pregnancy.
| a. | is
the commonest cause of congenital infection in the |
True |
| b. | maternal infection is usually associated with ‘flu’ like symptoms. | False |
| c. | >25% of mothers have evidence of past infection. | True |
| d. | ~ 1% of all babies have evidence of congenital infection. | False |
| e. | 95% of infected babies are asymptomatic at birth. | False |
| f. | fetal damage usually results from primary maternal infection. | True |
| g. | spiramycin is an effective treatment in pregnancy. | False |
| h. | is associated with "echogenic" bowel. | True |
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CMV is a favourite in both the DRCOG & MRCOG.
It is a herpes virus.
If you are infected, you develop some immunity, which stops the disease progressing and limits shedding of the virus.
But you don’t get rid of the virus.
It remains
dormant and can flare up if your immune system takes a dive – much like with
herpes zoster.
CMV is the commonest neonatal viral infection and potentially devastating.
It is the commonest infectious cause of mental retardation and childhood deafness.
It is not a Mickey Mouse problem!
But we are making little headway in:
identifying infected mothers or affected fetusus,
developing means of preventing infection,
or treating affected mothers and babies.
It is a particular problem in pregnancy and the immuno-compromised.
Vaccines are under development, but not yet in routine use.
Spiramycin (answer "g") is used for toxoplasmosis and even then is of doubtful value. (See MCQ3, question 4.)
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The word “symptomatic” and “asymptomatic” are used several times in this answer in relation to the neonate.
Symptoms are usually things of which we complain: having a headache, feeling “off-colour” or feverish etc.
Neonates do not complain!
The words are used loosely to denote babies with or without signs of infection at birth.
Most writings on the subject use them, so I have continued with them, though they grate on my ears.
Things are changing, though, and I note that the TOG article mentioned below uses the words “clinical manifestations”.
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| CDC | Centers for Disease Control and Prevention |
| CMV | cytomegalovirus |
| DEFRA | |
| DNA | |
| DOH | |
| DRCOG | Diploma of the Royal College of Obstetricians and Gynaecologists |
| EBV | Epstein-Barr virus |
| HSV-1 | Herpes simplex virus 1 |
| HSV-2 | Herpes simplex virus 2 |
| IgG | |
| IgM | |
| IUGR | intra-uterine growth restiriction |
| MRCOG | Membership of the Royal College of Obstetricians and Gynaecologists |
| PCR | polymerase chain reaction |
| RCOG | Royal College of Obstetricians and Gynaecologists |
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Commonest neonatal viral infection in the UK and the developed world.
Can cause mental retardation, developmental delay and visual impairment.
One of the main causes of childhood deafness.
The principal reservoir of infection is small children.
Hence the risk to staff working in nurseries etc.
Sexual transmission also occurs.
50 - 70% of antenatal women show evidence of old infection.
Maternal infection is asymptomatic in 90% and the features are non-specific.
Diagnosis has to be done by the laboratory.
Primary maternal infection is vastly more dangerous than re-infection.
And early infection is more likely to cause fetal damage than in late pregnancy.
Primary infection occurs in ~ 2% of women.
40% of their babies will be infected in the womb: “vertical transmission”.
It is a shame that this is how this term is used.
I keep chickens and DEFRA insists that they have an area with a hard roof within which they can be confined if there is a potential outbreak of bird flu.
The idea is to protect them from droppings from infected birds flying overhead.
I think I might start a campaign to have “vertical transmission” dedicated to this form of aerial bombardment.
10% of babies infected will be “symptomatic” at birth, putting them in the very high risk group.
10% of 40% of 2% works out at 0.8 per 1,000 births.
Or, roughly one baby in a thousand falling into the high risk, "symptomatic at birth", group.
Secondary infection (re-infection) is uncommon.
Fewer babies will suffer vertical transmission than in 1ry infection: <1 in 50.
Of these, < 1% will be symptomatic at birth.
1% of <1/50 of "uncommon" works out at < 1 in 5,000 of "uncommon".
So it is most likely to come your way, we are getting into “hens’ teeth” territory.
The biggest risk is to the baby which is “symptomatic” at birth after infection in the womb.
The perinatal mortality rate is 20% and the survivors have a 90% risk of damage.
The baby infected in the womb but not symptomatic at birth has a low perinatal mortality.
But still has a 10% risk of damage.
Clinical features at birth include:
chorioretinitis,
deafness,
hepato-splenomegaly,
evidence of IUGR,
microcephaly,
jaundice,
and skin rashes.
Inguinal hernia is always mentioned, though I have not seen a case.
However, it is rare and odd, so examiners are attracted.
Breast milk from mothers with 1ry infection in pregnancy usually contains the virus.
But the benefits of breast feeding outweigh the risks to the baby.
Interpretation of IgG and IgM levels in maternal serum can be difficult.
Expert advice is advisable in making the diagnosis or telling the mother she is immune.
Maternal infection is not serious for her unless she is immuno-compromised.
There is no vaccine and no effective antiviral drug.
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There are two articles in TOG.
One by McCarthy et al: . McCarthy et al: TOG 2009 11: 96-100
The other by To et al: TOG 2009 11: 108-116.
OGRM has two articles of interest.
A practical one with clinical examples by Agrawal and Gillham: OGRM. 2010. Vol 20, Issue 1, P. 22 - 26.
And a more general one on infectious disease in
pregnancy by
Price: OGRM. 2008. Vol 18, Issue 7, P.
173 - 9
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Expanded information for the MRCOG and to help facts stick.
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It would be useful to stick these on cards as they might get a mark or two in an essay or MCQ.
And it might be helpful to have it all in one place.
CMV is a herpes virus and the commonest congenital viral infection in the UK.
It is the commonest infectious cause of congenital brain damage, neuro-developmental delay and deafness.
It ranks second to Down's syndrome in the causes of mental retardation.
And is one to the top causes of childhood deafness.
The main risk to the fetus is from 1ry. maternal infection, especially early in pregnancy.
Early infection is the more serious as it is more likely to damage the brain.
Late infection damages other organs, e.g. the liver and marrow producing hepatosplenomegaly, neonatal jaundice, thrombocytopenia and petechiae.
50 - 70% of women in western countries have IgG, showing evidence of old infection.
Re-infection, perhaps by a different strain, can occur but is uncommon.
And now two facts relating to the number 40:
about 1 woman in 40 will sero-convert in pregnancy, i.e. have a 1ry. infection,
about 40% of women with 1ry. infection will transmit the virus to the fetus.
The neonate most at risk of damage is the one showing evidence of infection at birth.
And now two facts relating to the number 90:
fortunately, about 90% of neonates show no sign of infection and fall into the low risk group,
but of the unfortunate 10%, with evidence of infection, 90% will have long-term damage.
Evidence of infection:
this includes ante natal stuff:
echogenic bowel, IUGR, intracranial calcification, etc.,
and clinical features in the neonate:
IUGR, hepato-splenomegaly etc.,
and the ones you are likely to forget:
laboratory and other test anomalies:
hearing loss, anaemia, prolonged elevation of bilirubin etc.
IgG and IgM interpretation is difficult.
Routine maternal antenatal screening is not done.
Fetal diagnosis is by amniocentesis, but could be by CVS or cordocentesis.
There is no proven antenatal treatment: hyper-immune immunoglobulin may have a place.
There is no vaccine, thought trial vaccines exist.
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Cells with inclusions have been known about for more than 100 years.
Goodpasture and Talbert suggested that they were due to a virus in 1921.
A number of groups isolated the virus in the 1950s.
Weller et al suggested the name "cytomegalovirus" in 1960.
CMV ranks number 5 in the classification of the eight human herpes viruses.
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Reservoirs and mode of spread.
The main reservoir of infection is small children.
They can excrete the virus for months from the urinary and respiratory tracts.
Not surprisingly, nurseries are a common source of infection.
The infected neonate can excrete the virus for 5 years or more, which I find gob-smacking.
But it is a reminder that a characteristic of herpes viruses is their ability to hang about in the body:
HSV-1 & cold sores,
HSV-2 & genital herpes,
herpes zoster & shingles
EBV & infective mononucleosis etc.
Sexual transmission also occurs, with infected men excreting the virus in semen for ages.
Women seeking to avoid infection are advised to wash carefully after dealing with children.
Particularly cleaning up after their various messes.
Some advise the use of gloves.
They should also avoid infected partners or ensure that they use condoms.
Most women who have 1ry. infection during pregnancy excrete the virus in breast milk.
And breast milk has been shown to be the main source of new infection in the neonate.
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Prevalence of immunity in the pregnant population.
Surveys have shown about 50% of ante-natal patients have evidence of past infection.
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About 2% of women will experience 1ry. CMV infection in pregnancy.
And it is 1ry. infection that carries the greatest risk of fetal damage.
2ry. infection is uncommon.
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Timing of maternal 1ry. infection and fetal and neonatal risk.
Feldman et al published data on this in the Am. J. of O&G in 2011.
They analysed 508 pregnancies with full investigation of mother and baby.
None of the 97 pregnancies in which the mother became infected preconceptually showed evidence of congenital infection.
4.6% of cases in which the mother became infected after conception showed evidence of congenital infection.
Vertical transmission rates were:
1st. trimester: 34.8%,
2nd. trimester: 42%,
3rd. trimester: 58.6%
They found that 3rd. trimester infection had no clinical effects on the fetus.
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This is not recommended by the RCOG or the DOH.
It would mean taking blood at booking and then repeating the test later in pregnancy for evidence of seroconversion.
I don’t think this will happen until there is a beneficial therapeutic intervention.
At the moment, with no effective intervention and primary infection only occuring in 2% of women in pregnancy, it is viewed as not cost-effective.
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Reducing the risk of infection in pregnancy.
Prevention relies on basic, common-sense measures as there is no vaccine and no prophylactic drug.
This means basic hygiene, particularly in dealing with small children.
They excrete the virus in body fluids, especially urine and saliva.
So wear gloves when changing nappies or wiping snotty noses.
Don't share cutlery or food.
Don't kiss their snotty faces. Ugh!
And wash your hands carefully after contact with the little darlings.
The CDC gives detailed advice.
Infected partners should be shunned or, more practically, made to use condoms.
Possible vaccines are under development.
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Maternal infection is asymptomatic in 90%.
It can produce a self-limiting illness with flu-like symptoms.
But without the specific features that might enable you to make the diagnosis clinically.
You have to rely on laboratory tests, though these require specialist interpretation – see below.
The woman may produce abnormal leucocytes, similar to infectious mononucleosis.
The infected individual will continue to excrete the virus for months.
In obstetric practice, we rarely diagnose the condition.
And I can’t see an improvement without routine screening for seroconversion.
This would mean taking blood at booking and then repeating the test later in pregnancy for signs of infection.
I can’t see this happening until there is a beneficial therapeutic intervention.
Intriguingly, Xie et al found a link between maternal CMV infection and an increased risk of PET.
Whether other studies will cofirm this waits to be clarified.
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Diagnosis of maternal infection.
Almost always the clinical scenario is a woman who has been in contact with a suspected or proven case.
But you might check for maternal infection in a case of IUGR.
Diagnosis of CMV in early pregnancy poses problems.
This will not feature in the DRCOG, but might in the MRCOG MCQs.
If you have a possible case, get advice from your local virologist or Public Health Laboratory
The difficulty lies in interpreting IgM and IgG levels.
Normally IgM is an early, transient response to infection, with IgG replacing it in a matter of weeks.
The usual interpretation, with which your are sure to be familiar, is as follows.
|
Antibody present. |
Interpretation. |
|
IgM only. |
Recent infection. |
|
IgG only. |
Old infection. Immune. |
|
IgM + IgG. |
Recent infection with long-term immunity developing. |
|
Neither IgM or IgG. |
No immunity. |
Our problem is that IgM persists for months in CMV infections.
Let us say you test a woman who has been in contact with a case and had some symptoms.
You find IgM.
In most infections you would take this as evidence of recent infection.
But with CMV IgM could represent infection before the pregnancy and not an infection during the pregnancy.
She could be immune!
I understand that there is also a potential problem with reinfection: you may get raised IgG but no IgM.
So you may think that the woman is immune, when in fact she has had reinfection.
There are special “avidity” tests to see how aggressively the IgG links to the virus in vitro.
This helps to distinguish between old and new IgG.
But they are not readily available and there is some doubt about their accuracy.
The biggest help in most cases will be blood left over from booking, which can be tested for IgG and IgM.
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Transmission of the virus to the fetus and neonate.
The virus can be transmitted “vertically” from the mother:
across the placenta,
directly from the genital tract during delivery
and in breast milk,
this being the commonest source of infection of a neonate that was uninfected at birth.
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Mostly you will be seeking to make the diagnosis in the fetus of a woman who has been shown to have been infected in pregnancy.
But you could be investigating a baby with evidence of IUGR.
Viral DNA can be identified in amniotic fluid using PCR.
But in rare cases it may be maternal in origin.
PCR can also be used to determine viral load in amniotic fluid.
The virus can also be sought in fetal blood by cordocentesis.
But that is even more invasive and with a higher risk of fetal loss.
It might well be done if TOP was being considered.
Ultrasound is used to look for evidence of fetal damage.
Damage is not diagnostic of intra-uterine infection; any detected abnormality could be due to something else.
Classic features include:
enlargement of the ventricles,
and periventricular leukomalacia and calcification.
MRI has been used, but has not proved superior to ultrasound and is not recommended for routine use.
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The main risk is with primary maternal infection, which is reckoned to occur in about 1-2% of pregnant women.
The earlier in pregnancy the infection occurs the greater the damage to the baby.
With the first and early second trimesters being especially bad.
40% of babies will be infected in primary infections.
In recurrent infection, fewer than 2% of the babies will be infected.
In addition, few babies will have signs of infection at birth after recurrent infection.
And it is the symptomatic neonates who are at the highest risk of neonatal death and long term handicap.
A key message is that if you are infected in-utero, you are at high risk of damage if you are born with signs of infection.
If you are infected in-utero, but born in a healthy condition, with no signs of infection, you are at much less risk.
This is a vital fact to get into your head, hence its reiteration throughout this answer.
The other important fact is the vastly lower risk of vertical transmission from mother to baby with secondary infection.
It is interesting that recurrent infection occurs at all. It is rare with rubella and many other viral infections.
There is evidence that it happens due to infection with a different strain of the virus.
Perhaps there is some protection from the original IgG, which will still be about, to explain why secondary infection is less severe for the baby.
But I know of no evidence to justify this.
A side issue to store in the memory bank is that IgG is a relatively small molecule and crosses the placenta, providing some protection to the baby.
IgM., on the other hand, is a big molecule, does not cross the placenta and can be of no help to the developing baby.
IgM is the initial response to infection and is gradually replaced over a period of months by IgG.
Thus, in the early days of an infection, the baby gets no help from the maternal response as it is IgM.
Remember the fact that CMV IgM can persist, confusing our diagnostic efforts.
The risk to the infected baby is highest if it is symptomatic when born.
Regardless of whether the maternal infection was primary or secondary.
Have you heard this before?
Will you hear it again, raising homicidal thoughts about your author?
Symptomatic neonates have a perinatal mortality of about 20%.
The survivors don't escape.
90% will be damaged, with mental retardation, delay in hitting developmental milestones and hearing and visual impairment.
After primary infection, 40% of fetuses are infected.
10% of them will be symptomatic at birth, of whom few will survive and be normal.
Take 100 symptomatic babies.
20 will die.
Of the 80 who remain, only 8 will emerge completely unscathed.
Secondary infection is not so disastrous.
It is much less common.
Fewer than 2% of fetusus will be infected.
And fewer than 1% of those infected will be symptomatic at birth.
Even those babies who were infected, but not symptomatic at birth, do not escape.
After primary infection, 15% will suffer long-term damage.
After secondary infection, <10%.
However, the damage can be significant.
The virus is not only transmitted across the placenta, it can also be shed from the cervix.
So the baby can be infected in utero or on its way into the world.
And from breast milk.
This table is an attempt to portray the risks.
Primary infection is on the left, secondary on the right.
|
|
1ry. Infection |
|
|
|
2ry. Infection |
|
|
|
|
|
|
|
|
|
|
|
~ 2% of mothers å æ |
|
|
|
Uncommon
å æ |
|
|
60% of fetuses not infected |
|
40% of fetuses infected |
|
< 2% of fetuses infected |
|
>98% of fetuses not infected |
|
¯ |
|
¯ |
|
¯ |
|
¯ |
|
No problem |
|
¯ å ¯ |
|
¯ ¯ æ |
|
No problem |
|
|
90% not symptomatic at birth |
10% symptomatic at birth |
|
<1% symptomatic at birth |
>99 % not symptomatic at birth |
|
|
|
¯ |
¯ |
|
¯ |
¯ |
|
|
|
low perinatal mortality |
~ 20% perinatal mortality |
|
~ 20% perinatal mortality |
low perinatal mortality |
|
|
|
¯ |
+ |
|
+ |
¯ |
|
|
|
15% have long term damage |
~ 90% long term damage |
|
~ 90% long term damage |
<10% have long term damage |
|
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Clinical aspects of neonatal infection.
Congenital infection comprises numerous features:
auditory impairment,
chorio-retinitis,
hepato-splenomegaly,
inguinal hernia jaundice,
microcephaly,
petechiae,
purpura
and reduced size for gestational age.
All babies at risk of congenital infection should:
be seen by a paediatrician within 3 weeks of birth for testing using blood, saliva or urine.
Laboratory tests may show evidence of:
haemolytic anaemia,
abnormal liver function,
thrombocytopenia
and hyperbilirubinaemia.
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Development problems in the child.
The cortex of the fetal and infant brain may not mature properly with failure to develop the normal convolutions.
Development problems include:
mental and developmental retardation,
deafness,
and visual impairment.
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Diagnosis of CMV in early pregnancy can be a problem.
This will not feature in the examination.
But if you have a possible case, get advice from your local bacteriologist or Public Health Laboratory.
The difficulty lies in interpreting IgM and IgG levels.
Normally IgM is an early response to infection, with IgG coming on later.
The usual interpretation goes as below.
|
Antibody present. |
Interpretation. |
|
IgM only. |
Recent infection. |
|
IgG only. |
Old infection. Immune. |
|
IgM + IgG. |
Recent infection with long term immunity developing. |
|
Neither IgM or IgG. |
No immunity. |
The problem apparently lies with reinfection.
My understanding is that you may get raised IgG but no IgM.
So you may think that the woman is immune when in fact she has had reinfection.
There are special “avidity” tests to see how aggressively the IgG links to the virus in vitro.
This helps to distinguish between old and new IgG.
This will not appear in the DRCOG!
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There is no treatment.
Attempts to treat infected babies in utero with anti-viral drugs:
e.g. acyclovir and variants on it:
ganciclovir & valaciclovir.
But there are no conclusive results.
Ganciclovir has been used in the neonate:
with some evidence of reduction in the hearing loss,
but it is toxic and has to be given i.v.,
so needs more evaluation.
Hyperimmune globulin therapy has been suggested as a potential treatment and looks promising.
But needs further evaluation as the main study relating to its use was not prospective, randomised etc. etc. (Nigro et al)
It is produced from pooled blood, so has the usual concerns about such products.
TOP remains an option and likely in cases with evidence of severe damage such as microcephaly.
There is no vaccine.
Possible vaccines are under development.
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Is Caesarean section indicated in active infection?
No!
I think the argument is that the mature fetus and neonate are not at great risk of damage from the virus.
Remember that damage is most likely in the 1st. and early 2nd. trimesters.
In addition, the mother is likely to transfer some protective IgG, especially if she breast feeds.
And, to help you remember, breast feeding is OK, even though the majority of mums will excrete the virus after infection in pregnancy.
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This is OK.
It is accepted that the benefits of breast feeding outweigh any risk.
This is true for the healthy, mature baby.
The pros & cons need to be assessed for the premature baby.
For them the breast milk might need to be treated to kill the virus.
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Vaccines are under development.
The first report of a successful vaccine came in 2009.
It was only 50% effective.
But this is significant in such a potentially disastrous infection and gives hope for the future.
Pass et al. NEJM. Volume 360: 1191-1199. March 19, 2009.
We look forward to the development of safe, effective drugs too.
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Spiramycin is used for toxoplasmosis and even then is of doubtful value. See MCQ3, question 4.
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