Unfortunately, due to time constraints, not all questions could be answered by the speakers at the conference. So we have asked the speakers to answer those questions handed in at the close of every session.

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John Guillebaud (currently busy on a speaking tour) refers delegates to his book for answers to questions related to contraception. Any questions not covered in his current book he promises will be addressed in the next edition!

Book details as follows:

“Contraception: Your Questions Answered (Your Questions Answered)” by John Guillebaud

Paperback: 582 pages

Publisher: Churchill Livingstone; 4th edition (March 2004)

Language: English

ISBN: 0443073430

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Questions and Answers

• Professor Ian Frazer
• Professor Ian Hammond
• Clare Boothroyd
• David Johnson
• Ian Findlay

Answers prepared by Professor Ian Frazer:

At what age do we vaccinate our daughters?

Answer: Likely 12-15 will be recommended in Australia, though 9 -26 will be in the product data sheet.

In 10 years will we know about booster shots?

Answer: Yes from the studies in Finland as follow up to the Phase 3 trials.

Age of 1st sexual activity, has it any effect on prevalence/or risk of cancer?

Answer: It’s said that younger age at first intercourse increases the risk of subsequent cancer (this is epidemiological evidence rather than direct evidence)

How will developing world finance a vaccination programme?

Two answers: Firstly, the major companies have indicated that they will introduce differential pricing for the vaccines asap (though I expect that they would have to sell vaccine in the developed world first to cover costs).
Secondly, the WHO is considering recommending the vaccine as part of its global vaccine program which might provide funding via the World Bank or the Gates Foundation as well as promoting vaccine uptake in the developing world.

Will indigenous women benefit from the HPV vaccine?

Answer: Yes, presuming that they elect to be vaccinated, as they have from the cervical cancer screening program

Confused re Adenocarcinoma of Cervix – if HPV doesn’t affect glandular cells how come 100% cervical cancer has HPV?

Answer: HPV does affect glandular cells – HPV 18 is generally the type found. The figures of 100% for cervical cancer include both squamous and glandular (adenocarcinoma) of the cervix.

Can the HPV 6, 11, 16 &18 subtypes be non-sexually transmitted eg could a mother transmit them to a child during vaginal delivery? If this occurred is it likely that the infection would persist to age of first intercourse?

Answer: This is a controversial issue, with no definite answer. There is clear evidence of mother to child transmission (recurrent respiratory papillomatosis due to HPV 11 is a rare consequence of such transmission). Whether this occurs in the genital tract is unknown – however the genital HPVs seem to need sex steroids to replicate effectively so maybe if such transmission occurred it would likely not be persistent or productive.

What argument is there to stop GPs testing everyone for HPV antibodies?

Answer: There are no licensed or commercially available assays.

Can a couple with no other sexual partners catch genital HPV?

Answer: No, if the definition of sexual activity extends not only to penetrative intercourse but other sexual contact.

How common are any adverse effects from the vaccine?

Answer: Short lasting pain at the site of injection is almost universal and is no more common in vaccine recipients than placebo recipients. Other side effects are rare and also no more common in vaccine than in placebo recipients.

Answers prepared by Professor Ian Hammond

- using NHMRC 2005 guidelines document as the main reference. When the questions are outside the scope of the new guidelines document, the answers are the opinion of Ian Hammond and reflect current accepted practice.

In addition Professor Hammond has received permission from the Editor of The RANZCOG magazine to allow us to publish on the website an article authored by Penny Blomfield, Marg Dayy, Ian Hammond and Gerry Wain on the New pap smear guidelines featured in O&G, Vol 7, No 3, Spring 2005: 25-27.

When to stop screening if previous high grade abnormality? Age 70? Any guidelines?

Answer: Assuming that women who have been treated for HSIL have had negative Pap and HPV DNA tests on 2 consecutive occasions (one year apart), then these women return to the routine screening interval (currently every 2 years) and cease having Pap smears at age 70 years.

Do the new guidelines cover persistently negative endocervical cells on the pap smear of a woman?

Answer: This is not specifically covered in the new guidelines. In asymptomatic women, with an otherwise normal Pap smear result, there is no evidence to support being over concerned about the persisting absence of endocervical cells. The rate of endocervical cell detection is used by laboratories to gauge the ‘adequacy’ of the sampling of the cervical transformation zone. It is especially helpful in assessing the ‘performance’ of new smear takers, such as nurse practitioners etc. In terms of poor outcome for women with no endocervical cells in their smear, there is no evidence to show that these women are at greater risk of developing a cancer prior to the next screening opportunity. There is a reference to this subject in the guidelines, Chapter 9.5

What is the percentage risk of low grade abnormalities progressing to high grade?

Answer: As discussed in the NHMRC document, Chapter 3: Current concepts of HPV infection and the natural history of cervical neoplasia, the paper by Schlect et al (2003) reports a progression from LSIL to HSIL over 12 months in 3.6%. This is in keeping with the known regression rates and supports the new guidelines for the management of LSIL smears….most will go away, and those that don’t or progress to a HSIL smear will be colposcoped and appropriately managed without an increased risk for the development of an interval cancer.

If pap normal but clinically Cervix looks unhealthy what do we do?

Answer: In an asymptomatic woman with a normal Pap smear and an “unhealthy” cervix, it is very unlikely that any malignant lesion will be found on the cervix. The important word here is ‘unhealthy’. What does this mean? Usually it is an appearance of numerous Nabothian cysts, a wide area of red glandular epithelium or copious contact bleeding when taking the Pap smear. If the GP is concerned about the appearance (which she has not seen before) then it is entirely appropriate to refer for gynaecologic review with colposcopy. It is essential that the GP receives honest feedback from the specialist, which provides an excellent learning experience.

In women with cervical stenosis following previous treatment or menopause should they be sent off to Gynae for dilation in order to get sample of cervical cells?

Answer: In an asymptomatic woman there is no evidence to support any intervention to gain a sample of endocervical cells.

At what age should screening start according to the new guidelines?

The new guidelines relate to the management of screen detected abnormalities. There has been no change to the start date of screening with cervical Pap smears.

Any role for Truscreen as adjuvant to pap smear?

No. The evidence in support of Truscreen is somewhat variable. In the context of the National Cervical Screening Program there is no evidence to support its use nor is there any obvious benefit to women who are having a regular Pap smear.

How common are complications of treatment of high grade abnormalities?

In 1997 the RACOG reported the results of the National Quality Assurance in Colposcopy Project (RACOG 1997). In this study, 5710 women were treated for cervical disease (high and low grade at that time, but complications will be the same). Three hundred and forty two women (6%) experienced acute complications such as primary and secondary haemorrhage, infection and other problems. Seventy seven (1.3%) required readmission to hospital.
In a recent systematic review and meta-analysis published in the Lancet ( Kyrgiou et al, Lancet 2006; 367:489-98) it was concluded that all excisional procedures of the cervix to treat cervical intraepithelial neoplasia present a similar pregnancy-related morbidity. In particular there is a small but real risk of preterm delivery and premature rupture of the membranes but there was no apparent neonatal morbidity associated with this risk. The Lancet paper urged caution in the treatment of young women with mild (low grade) cervical abnormalities, which is entirely consistent for the new Australian guidelines (NHMRC 2005) recommendation that women with biopsy proven low grade lesions (HPV or CIN1) should not be treated.

Which patients deserve special consideration & are at higher risk of rapid progression under the new guidelines? Indigenous, immunosuppressed, transplant patients, smokers????

Immunosuppressed and transplant patients (who are usually immunosuppressed) are at higher risk of persistent HPV infection and therefore of developing high grade cervical disease. There is no evidence to support a more rapid progression. However, any immunosuppressed woman should be referred for colposcopy even if the lesion is ‘low grade’ as cytological surveillance alone may not be adequate in this special group of women. If these women are shown to have a high grade lesion they should be treated by excisional methods (NHMRC 2005, Chapter 9.2). Indigenous women do have a higher incidence and mortality from cervical cancer (NHMRC 2005, Chapter 2) but there is no evidence to support a different management approach, unless the GP feels that the woman is likely to default follow up cytology, in which case early referral for colposcopy may be appropriate. Most of the problems for indigenous women result from inadequate screening.

How do we screen women exposed to DES? Is it yearly pap & vault smears or yearly colposcopy?

Low level evidence and significant consumer anxiety among DES exposed women have led to a recommendation (NHMRC 2005, Chapter 9.4) that all DES – exposed women should be offered annual cytological screening and colposcopic examination of both the cervix and the vagina. It is also recommended that DES – exposed women who have a screen detected abnormality should be managed in a specialist centre by an experienced colposcopist.

What about older women who show low grade changes repeatedly after negative colposcopy? Do we keep doing yearly Pap smears?

Yes. This is in keeping with the new guidelines. In addition there is a new recommendation about women who have ‘fluctuating repeat Pap test results’.
It is recommended that referral for colposcopy is considered for woman if she has two LSIL/possible LSIL reports (at least 12 months apart) within a 3 year timeframe, regardless of intervening normal cytology reports.

Does Aldara have a place in treating abnormal smear tests?

None that I am aware of.

If HPV serotyping performed at request of patient and positive for high risk HPV but smear normal, what then – colposcopy or routine pap follow-up at what interval?

Firstly, one should try to avoid this situation whenever possible. There is no evidence that HPV DNA testing has any place in a country with an organised approach to cervical screening using cervical cytology. In the event that the woman has this test and it is positive, there is no evidence to support any particular course of action. In the presence of a normal smear, I would do nothing more than to explain the significance of the HPV DNA test to the woman ( new consumer booklets accompanying the new guidelines do this very well) and recommend routine screening every 2 years.

If genital warts present should colposcopy be performed?

In general the answer is NO. Colposcopy should be performed only if the Pap smear is abnormal and referral should then be based on the new guidelines. Most women with active genital warts will have a low grade squamous abnormality (LSIL) if at all, and should only be referred for colposcopy if the LSIL smear persists or she develops a high grade lesion.

Should we do pap smears in virgin women, lesbians?

Virgins do not require a Pap smear. Lesbian women who have ever had sex with men carry the same risk of cervical abnormality as non-lesbian women, and should have routine Pap smears. Partners of women who have ever had sex with men, even if they have not themselves, may be at risk of transfer of HPV infection to their genital tract during sexual activity, and it is suggested that they should have routine Pap smears.

Did the NHMRC group consider liquid based technologies?

No. This was outside the terms of reference for this group.

What screening do you advise partners of women with persistent HPV 16 & high grade Pap abnormality?

In the absence of clinical genital warts in the male there is no evidence to support screening of the male partners of women with persistent HPV DNA type 16 or 18 or a proven high grade abnormality.

Answers prepared by Clare Boothroyd.

For a woman on aromatase inhibitors with symptomatic UG atrophy, who chooses short-term estrogen therapy is there any less absorption of Ovestin (oestriol) compared to Vagifem (17 β oestradiol)?

Answer: This is an uncertain area. The data are not in and therefore caution should be used.

The ATAC and BIG trials which were large pharmaceutically funded trials evaluating the mortality benefit of aromatase inhibitors vs tamoxifen “discouraged the use of vaginal oestrogens” and therefore any effect of vaginal oestrogen – either positive or negative – is not seen in the reported trials. I am not aware that the company has reported the subgroup of women who did use vaginal oestrogen, although I suspect the data is available as the researchers would have recorded who did vaginal oestrogen. The fact that it has not been reported is of interest.

The paper Sue Davis referred to during the conference was published in Jan 2006 in Annals of Oncology – a study suggesting that vaginal oestradiol is associated with systemic levels of oestrogen in women using aromatase inhibitors. This is a report on 7 women (yes seven!) – in whom 2 had recordable levels of oestrogen ~240 pmol per litre after 2 weeks of vagifem and in whom one had a level of 219 at week 7-10. The assay of oestradiol is poorly validated and I am amazed this paper was published.

It is, in my opinion, way too early to make a conclusive recommendation though that the use of vaginal oestrogen in women on aromatase inhibitors remains uncharted territory, in need of future research.

My line would be – explain the uncertainty to the woman, liaise with the surgeon/oncologist, try alternatives and if necessary use either preparation as neither has known benefit over the other. Monitoring is problematic as the oestradiol assay is capricious and potentially misleading (although the labs would have you believe otherwise).

Answers prepared by David Johnson

How to determine eGFR in people with single kidneys?

The same way as one does with 2 kidneys (the kidney number does not influence the eGFR calculation).

Use of diuretics in patient with CCF and chronic kidney disease?

Desirable. Larger doses of diuretics are usually required in CKD. Moreover, thiazide diuretics become progressively less effective at eGFRs below 50 mL/min, such that loop diuretics are preferable under these circumstances.

Will salt restriction help in controlling eGFR?

Yes, indirectly via improving BP control.

What to do with elderly patients on ACE/AT II with declining renal function?

In most cases, the appropriate response is to keep the patients on the ACEi/ARB. If there is an acute fall in eGFR (>=30%), then it is appropriate to cease the ACEi/ARB and consider further investigations, such as RADU, USS and other appropriate investigations for acute-on-chronic renal failure.

Spot, timed or 24 hour urinary Albumin/Creatinine the best?

The available evidence suggests that they produce equivalent results as far as routine clinical requirements are concerned. My personal practice is to perform a spot urine albulmin: creatinine ratio.

What effect of high protein diets on eGFR result (eg CSIRO compared to vegetarian)?

There is no clinical evidence for dietary protein intakes above 1.1 g/kg/day (the upper achieved value in the MDRD study), but animal studies suggest that high protein diet intakes are deleterious to renal function. The current CARI guidelines advise a dietary protein intake of 0.75-1 g/kg/day in CKD patients.

Elevated potassium on ACE, creatinine stable – What to do?

Generally nothing if the serum potassium is below 6 mmol/L. For borderline high values or values above 6, I ensure that the patient is adhering to a low potassium diet and place them on a diuretic if necessary. If the potassium consistently remains above 6 mmol/L, I cease the ACEi.

Is the figure >60 considered normal?

Or should we aim for higher result? No, the lower limit of normal for GFR is 90 mL/min. The 60 cut-off was used for automated reporting because the current level of laboratory creatinine calibration is not sufficiently accurate or precise to give the abbreviated MDRD eGFR acceptable validity above 60 mL/min. This may change as labs improve their calibration against traceable methods, such as IDMS. In the interim however, MDRD eGFR values above 60 should be interpreted with caution (they may either represent normal or reduced renal function).

How should we manage an obese woman, say BMI>30, eGFR = 50 (but unreliable in obese), creatinine 90, what further investigations?

The recommended approach is that where they may be a reasonable suspicion that the patient has reduced renal function (as in this case), but the clinical circumstances are such that the MDRD eGFR may be potentially unreliable, direct measurement of GFR (eg by creatinine clearance) is important to try to verify the patient’s level of kidney function.

Answers prepared by Ian Findlay

What medium do you take the pap sample from, normal smear or liquid based? Must it be an endocervical sample?

We supply kits for the samples. Currently we are taking the surplus from
normal smears but hope to use thin prep soon. We use normal PAP samples
mainly because they are minimally invasive and most importantly safe. Other systems can detect fetal cells from cervical mucus much higher in the cervix but of course this has very significant risks of miscarriage.

How do you determine maternal cells in sample, do you have a separate sample from mother for comparison?

We use a number of physical characteristics as well as a number of specific antibodies to both enrich the fetal cells from the maternal (positive enrichment) and remove maternal cells (negative enrichment). We don’t need a seperate maternal sample as the majority of the PAP sample is maternal.

What happens if multiple pregnancy and PGD on pap smear?

Multiple pregnancy – we cannot determine which embryo contributed the fetal cells though we may obtain multiple fetal DNA profiles identifying if the embryos are monozygotic. Re PGD – same as normal pregnancy.

Is there a role for DNA fingerprinting at time of miscarriage to determine if genetic cause?

No role for the DNA fingerprint identification aspect, however the genetic diagnosis performed can determine if the embryo contains one or more major chromosomal abnormalities (21, 13, 16, 18, and 22).

How does blood interfere with the genetic test?

The haemoglobin in blood interferes with the PCR process making results unsatisfactory. This difficulty results in DNA routinely being extracted from blood to perform most types of DNA testing.

What is the likely cost of this pap smear screening PGD?

We are hoping that PAP testing will be as cost effective as possible to allow maximum availability to all women. However costs have yet to be determined but hopefully in region of few hundred dollars.