Extended Carrier Screening - Beyond Down Syndrome

Opening Pandora’s Box: Beyond Down Syndrome to Extended Carrier Screening.

Sharon: Hello and welcome to Opening Pandora’s Box: Beyond Down Syndrome to Extended Carrier Screening. We would like to acknowledge that this meeting is being held on Noongar Country, the traditional lands of the Whadjuk people, and we acknowledge their Elders, past, present and emerging. I would just to welcome our facilitators today, Dr Michael Gannon who is a general obstetrician and gynaecologist and also our local GP, Helen Wilcox who works in our Shenton Park clinic and also is an academic at The University of Western Australia. Additional details on them are on the screen for you at the moment. Also you can see that for Dr Gannon we have some disclosures as well.

So what I would like to do now is introduce Dr Gannon and Dr Wilcox and they will be running the session for you today.

Michael: Thank you for joining us. This is an important area. Down syndrome screening is highly acceptable to the community. It has become regarded as very much a part of antenatal care and extended carrier screening is in some ways an extension of that process, but it is a lot more complicated. My disclosures there are relevant. One of them is being a board member of doctor-owned Medical Defence Organisation. There is enormous growth in claims against general practitioners for failure to warn. This, tonight’s webinar I suppose is an opportunity to discuss what might be regarded as the standard of care in terms of very substantial abnormalities in unborn babies. The next disclosure is not cute but one conclusion you might derive from this is that the future is in IVF and assisted reproduction. I do not work in assisted reproduction IVF nor do I have any shareholding in any of the listed companies in Australia who make money out of IVF, nor the diagnostic companies which are seeking to you know, appropriately recoup their billions of dollars of research and investment in these tests when they offer them direct to your patients. One final disclosure if you think that the moderator is being too gentle on me, Helen Wilcox was my resident when I was a Registrar at King Edwards and we have known each other for some time.

Helen: Yes. Thanks very much, Mike. Good evening to all. And I think my job here as the resident GP listening, is to listen to the theory and the evidence that Mike is going to put forward, and then for me to say, okay, how am I actually going to apply this to a patient that I see for shared care in my clinic tomorrow morning. So, there is a level of familiarity that GPs have in regard to antenatal care and managing the first trimester pregnancy and I know that differs. And for some people on line tonight, you may have come on to this webinar because it is a strong area of interest and you have already got a lot of familiarity and you are very comfortable with counselling patients on this space. For other people tonight, you may have come on line because you recognise that it is an area of knowledge that you would like to improve. So as much as possible, we will try to cater to the spectrum of knowledge of antenatal testing here and we will make the information that Mike gives us into tangible strategies that we can easily implement in the consulting room. So over to you, Mike.

Michael: So, what I propose to do tonight is to give you a quick history lesson on Down syndrome Trisomy 21 screening. We will talk about what in many ways is the established test. We have been using first trimester screening for nearly 20 years and we will talk about the emerging test which is very popular amongst patients. So non-invasive prenatal testing, NIPT, whatever you want to call it. And then we will go on and talk about reproductive carrier screening, what is already available and Mackenzie’s Mission which we will see rolled out in coming months.

You are invited to respond to a few questions prior to the webinar, so I think it is worth just having a quick look. At the moment for the majority of you, you see antenatal patients are often or frequently as part of shared care, possibly as GP obstetricians so this is clearly an important area. Possibly you will feel more confident about seeing antenatal patients. Possibly by the end of tonight’s webinar you might feel less confident about seeing antenatal patients. In regard to your ability to provide accurate Down syndrome screening, nearly 25% of you do not feel confident in the accuracy of the information you give to patients. Now that is a problem. Hopefully tonight helps. In terms of out of pocket costs, so nearly 50% have accurately opined that it typically costs your patients $250 to $300. There is limited Medicare input into first trimester screening. There is a whole list of preconditions in terms of subsidised ultrasound around 12 to 13 weeks and women over the age of 37 can access a Medicare rebate. But those of you who have said yes to typically costs to $600 or $700, that is correct if patients are having non-invasive prenatal testing, and appropriately they are also having an ultrasound scan. We will talk more about that later.

So in terms of the evolution of Trisomy 21 screening, of course back into pre-history there was nothing and that was well into the modern era. With the emergence of ultrasound, we saw women being offered invasive diagnostic testing in the form of amniocentesis based purely on maternal age. The cut off was roughly 37 years of age, where the age-related risk is around one in 200 and the risk of losing the pregnancy was around one in 200. So if we go back to the 60s, 70s and 80s, that was where the community sat. They equated the loss of a normal pregnancy and roughly similar as an acceptable risk in if you like, avoiding having a baby with Down syndrome. With the gradual, steady improvement in the technology behind ultrasound scan, the 18 to 20 week ultrasound anatomy scan might be typically expected to detect about 50% of cases. We then saw the emergence of the triple test, a measurement of 15 to 17 weeks of alpha-fetoprotein, beta hCG and oestriol. There are different versions now. Typically detected around 75% of cases and also enabled for the early detection of major neural tube defects. And many of you on the webinar will recall a time where ultrasound machines were the size of a small room and they were also very much limited to tertiary centres. So, identifying a small group of patients that might be transferred to a tertiary centre or a regional centre for a scan was more than appropriate. I will remind you that that test remains available. So if you do book a patient that has missed the traditional window, this test should be offered to patients and 75% detection is pretty good. The assays that also add in inhibin the quadruple test are even better.

The next evolution in Down syndrome screening was a measurement of the nuchal translucency, the fluid filled fold behind the neck at around 12 weeks. And that evolved into integrated first trimester screening which can be done anywhere between 11 weeks and 13 weeks and six days and has constituted the main stay of Down syndrome screening. Very much normalising the 12 week scan for a generation of Australians, and obviously people around the world. And in the last five years we have seen the emergence of NIPT for cell-free DNA where peripheral blood is collected after 10 weeks.

So if we look at first trimester screening developed by Professor Kypros Nicolaides in London, typically detects between 83% and 90% of cases of Trisomy 21 with a false positive rate set at 5%. Demographics including most importantly maternal age go into the calculation and then weight. Two biochemical measures, ideally bloods collected at 10 to 11 weeks. The blood is sent to the ultrasound provider so that the ultrasound measurements of crown-rump length and the nuchal fold measurement can be put into the algorithm and certainly for the women’s ultrasound providers around Australia, typically patients are then counselled and given their results on the day. The radiology provider tend not to do that, they tend to send the report to the referring doctor for post-test counselling. It is a fabulous test. It has served us well for a long period of time. It is relatively inexpensive and we are also able to get a great deal more information from the scan. We have reached the point where, or we had reached a point where 40% to 50% of major foetal anomalies were diagnosed as early as 12 weeks. It enables for accurate determination of the chorionicity of twins. Another disclosure I missed a twin pregnancy earlier this year. I have done that twice in my career. If you do a 12 week scan, you will pick it up and you will get the chorionicity right to determine the safest place to look after those twins. It gives the opportunity to potentially change dates. You might look at ovaries, you might look at fibroids. And it is also important, there is an important group of women that should have the cervical length measured at the 12 week scan.

NIPT, the dominant brand around Australia is the Harmony test. Here in Western Australia, Harmony is the platform that is used by Clinipath which is Sonic’s pathology arm in Western Australia and PathWest, the Government owned group. It has also been used by some of the other pathology providers from time to time. It is my preferred modality only because the blood goes to Sullivan Nicolaides in Brisbane and the five day turnaround is much desired and useful to patients. Very simply, 10 ml of peripheral venous maternal blood is collected and cell-free DNA is subject to commercial in confidence. This is a truly brilliant test for Trisomy 21. This is close to the Holy Grail. Highly sensitive, more than 99%. Highly specific and in fact for the majority of patients that have other markers of Trisomy 21, including those who have had first trimester screening, this is so accurate with such a low false negative rate that it has, it should replace invasive and therefore dangerous testing for women who have a calculated risk between one in 50 and one in 300. It is often said that it is not as good for Trisomy 13 or Trisomy 18. Well that is true, but it is still better than first trimester screening.

The testing for foetal gender is very accurate. Most women should not have Y chromosomes floating around in their blood stream and therefore I am quite happy for women to tick that box. Where I get a bit wary is when it comes to sex chromosome aneuploidy. So testing for Turner syndrome and for Klinefelter syndrome. Two non-lethal abnormalities with phenotypes that are not overly limiting for an individual’s potential in life. Both associated in the year 2019 with infertility. But neither are lethal and neither are associated with any substantial social dysfunction or intellectual disability. You can also chose for an added cost to be tested for DiGeorge syndrome which is a deletion on chromosome 22 which is responsible for a variable phenotype of congenital heart disease.

Helen: I am actually going to jump in there with a couple of questions, Mike. So, GPs we are as you may well know, are moderately heavily marketed to by the different pathology providers and most of us will have four or five different sets of request forms. What in your opinion is the difference between the different providers of I am going to say, firstly antenatal testing when it comes to, should we be looking for a specialist gynaecological or obstetric sonographer as our first port of call? And secondly, the different providers of NIPT, is there much difference apart from costing, between the quality of the product?

Michael: Thanks for the question, Helen. So, my preference is just to use this platform, but all of them are broadly equivalent. So for the first three years of NIPT blood had to be collected at a very specific time under very strict conditions for it to get in the equivalent of a diplomatic bag, and either be flown to Beijing or to California. Obviously things have got a bit simpler. I think the biggest problem with NIPT and I will get to this with a future slide, is if you will excuse the language, the coke and fries which goes with the test. I think that I do have a slide coming up which refers to the weaknesses of NIPT, so I might get to it at that point. As to whether or not you should be referring to an obstetrician or gynaecologist, who make a living out of ultrasound or should you be referring to radiology providers, I think again that is personal preference. Not all of us have the luxury of organising those scans. I practice private obstetrics in the middle of a large capital city, so I have got ready access to those scans and because I refer so many patients they look after my patients very well. Many radiologists now do fellowships in ultrasound, or in women’s health and develop a substantial skill set and probably would regard themselves every bit as talented as those people with a FRANZCOG who have chosen a potentially very relaxing form of O and G practice.

Helen: Yes. And I have got a couple of other questions coming through which are a step before NIPT. So they are talking more about more traditional methods of first trimester screening. And one is just a couple of the logistics. Are patients, especially in second and subsequent pregnancies, practicalities are important and a lot of women chose to have the bloods at the same time as they have their ultrasound at 12 to 14 weeks or so. Is that going to reduce the accuracy of the test?

Michael: So in terms of NIPT, it does not. I spoke before about, that you have not missed out if the pregnancy has been concealed until late you can do biochemical testing at 15 weeks. Or you can do NIPT much later as well. So there will be cell-free DNA. It basically falls off the placenta. It does diminish with advancing gestation, but my understanding is that you can detect it all the way through the pregnancy. In terms of having the bloods, many patients have their first trimester screening bloods on the day of the scan because they have forgotten. It just means they cannot be given a result on the day because they need to be plugged into the algorithm to give the calculated risk. There is no great rush. The appropriate diagnostic test for the majority of women is amniocentesis which should be ideally delayed until closer to 16 weeks anyway. One really important point that I have not put in my slides is that it is absolutely essential that no matter how good NIPT is, results should be confirmed with a formal diagnostic test before anything like, even any consideration of interrupting the pregnancy, especially if there is an absence of foetal abnormalities on ultrasound.

Helen: And that was, I think you have taken the words out of my mouth, because I think many of us, we are not that close to tertiary level management of these patients and fortunately most of the pregnancies that we look after in general practice are, they start and they continue as low risk. So if we have a woman who will have a chromosomal abnormality detected on NIPT there is still a routine invasive test to confirm the abnormality in the tertiary centre before further pregnancy planning is undertaken.

Michael: Yes, that is largely true. It is not universally true. There might be major abnormalities at 12 to 13 weeks that are consistent with a lethal abnormality like Trisomy 13 and most people would say it is a reasonable standard of care to offer termination of pregnancy at that stage, bearing in mind, the law of the land in many parts of Australia is that there needs to be in fact, no clinical indication for termination of pregnancy prior to 20 completed weeks. So people can make their own decisions on whether or not to continue the pregnancy based on any of these test results.

Helen: Right, right. Thanks very much. I will let you go on.

Michael: So this slide is important. So this is available to your patients. They can put NIPT or Harmony or whatever else they like into their preferred search engine and this will come up. The current rate is $425, a bit extra for screening for DiGeorge syndrome. So, I have referred to weaknesses of NIPT as I see them. Many of these can be overcome. The first of these is the higher cost. Now, because you are missing out on the information that you would otherwise get from first trimester screening, best practise is to refer these patients to have an early anatomy survey at 13 weeks. So you start getting up towards $425 for your NIPT potentially, and then maybe between $100 and $250 for your scan. It is not appropriate to request both tests. Because NIPT is so vastly superior to first trimester screening, there is just the risk, when it comes to Trisomy 21, that they, if the ultrasound provider works out that they have NIPT they should not run the numbers, because all you can do is increase the rate of false positive testing without much increase in the true positive test. But an early anatomy survey, maybe including a measurement of the nuchal fold is appropriate.

The problem with NIPT is that it does not detect non-chromosomal anomalies, whereas a 12 or 13 week scan will pick up some of these. It will not diagnose miscarriages. So if your embryo has Trisomy 16 or Trisomy 4, the pregnancy will fail, usually prior to eight weeks but sometimes not until nine or 10. The patient might have had a dating scan going through their pregnancy thinking everything is going beautifully, telling the world and they turn up for a 19 week scan to be diagnosed with a nine week miscarriage. That is catastrophic for many patients. The other problem is false positive Turner syndrome results. There is a significant minority of phenotypically normal women who are mosaics for Turner syndrome who have a normal heart. Who have normal fertility. They may or may not be at risk of early menopause but it gets turned up in these results. They are sometimes hard to counsel. I would with the current technology, counsel against offering patients DiGeorge syndrome testing. If they turn up positive, you will send them, you are duty bound to send the patient for genetic counselling. That is easy if they live in the middle of a capital city with good services like we enjoy here in Perth. Women across Western Australia have fabulous services that use Telehealth et cetera. I do not know a great deal about the services elsewhere in Australia. But they will dutifully be informed that they are unable to predict the phenotype which will vary between completely normal and lethal congenital heart disease, and they should wait till 19 weeks to have a high quality scan. So that is largely entirely unhelpful. About 5 to 2% of the time, they do not get enough DNA so they will invite the patient in for a redraw free of charge. Inconclusive testing. Some of the time they get nonsense testing and that it is not worth repeating with them. There is low specificity in twin pregnancy but first trimester screening is also weaker in twin pregnancy. I must admit too, my great concerns about the potential for unethical use including sex selection after early diagnosis of the vulgar concept of preferred gender.

Helen: I am just going to go back to what you said about nonsense testing, how do you mean?

Michael: We do not understand how these algorithms work and these companies have spent billions of dollars. So I for example, do not know where their test chromosome is. I suspect they have got numerous test chromosomes, but let us pretend that the test chromosome is chromosome 1. That is how it works. They count the number of chromosome 1’s they pick up and then they count the number of 21’s, 13’s and 18’s. But how these tests work, is commercially in confidence and they are not telling you or me soon.

Helen: So it is possible to get a result where they say this will be inconclusive and in that setting it will remain inconclusive on this particular patient, despite repeating the test, is that right?

Michael: That is exactly right. So that is different to a redraw. So I always counsel my patients to wait until at least 10⅟₂ weeks to have their blood taken. Obese women are one group of women who are more likely to need a redraw. And the companies will not report unless they get a foetal fraction of 4%. So in other words, unless they can measure at least, they obviously look at maternal DNA. Unless they can get at least that aliquot if you like of DNA, they will request a redraw.

Helen: Okay. So if I am going to sum that up before we move on, I think GPs will potentially get four kinds of results coming through. We will get normal. We will get abnormal. We will get a request for a redraw, and we will get inconclusive testing, is that right?

Michael: Yes. So inconclusive testing is extremely rare. Not much more than one in one thousand. Redraw requests will happen from time to time. Of course most patients get very reassuring news. So you will see there, all of these weaknesses can be overcome if you do not order the coke and fries, or, and you organise a 12 to 13 week ultrasound scan.

Helen: And you appropriately counsel your patients about the out of pocket costs for these tests at the outset.

Michael: So a reasonable approach – now this is not a perfect approach, sadly – but a very reasonable approach bearing in mind that the financial resources available to our patients varies significantly depending on where we practice. But if you use first trimester screening, and you ask of that test, bearing in mind I told you it has got 83% to 90% detection, and of course it varies with maternal age with the false negative rate lowest for women well into their forties and highest for teenage girls and women who should be offered Down syndrome screening. If your risk is one in fourteen hundred at age 17, you should still be offered the test. But if you ask of your calculated risk that it is at least more than your age related risk, and you at least get a threefold reduction in age related risk, so I will use the example of a 30-year-old woman with a one in 700 risk, if she can drag her risk to less than one in two thousand one hundred, I would also ask of the test that the calculated risk is less than one in one thousand. If you do that, you detect well over 99% of cases for a test that gives a pile of information. And I think as long as you counsel patients clearly about the false negative rate then you, I would say you have reached the standard of care. And you have offered them a test that might be within their means.

Helen: Alright. I have had a couple of questions coming through about, is there still a role for biochemical testing and PAPP-A levels in particular in terms of predicant preeclampsia risk? So where does that test sit?

Michael: Yes, I think that PAPP-A as a stand-alone test should not be offered. So there is absolutely no circumstance, it is just not that good a test that you should be saying I am going to do NIPT but I am going to do PAPP-A to look for risks of growth restriction or preeclampsia. It is, I am sorry that many of you have read teaching hospital guidelines that told you different, but teaching hospitals are not the, all wisdom does not lie within them and those guidelines have changed over the years. We told armies of women over the years with a PAPP-A of between 0.3 and 0.5 MoMs that they had some sort of intermediate risk and that has been disproven over time. I must admit I still do keep a very close eye on patients who have a PAPP-A of less than 0.3, but I do not believe it has a role as a stand-alone test. Maybe it goes in the benefits of first trimester screening column.

Helen: Okay. And I have just two more comments based on some of the questions. There has been a few questions about the implications of the positive test and is the rationale for doing the test solely to counsel the woman about termination of the pregnancy? I think that is an issue we will discuss a little later when we look at the reproductive carrier screening and the implications and management of abnormal testing. There has also been a couple of queries about Medicare and the Medicare rebates here. Look I am actually going to get you to do your own homework here, but one place that I have found very helpful for looking up Medicare information is on imaging, is the website, MedicalImagingforGPs.com.au. I should say also on the basic prenatal testing, if people were to go to the RACGP website and under clinical guidelines, there is a probably little red but extremely useful genomics in primary care handbook, and the section on prenatal testing is a really good confirmation of the principals that Mike is putting forward. But again, back to you.

Michael: Okay, so we will move onto the potentially even more vexed issue of extended carrier screening. I asked you to let me know whether testing was available for the following conditions. You should have spotted, we should have guessed that there was one trick question in there. We have talked about DiGeorge syndrome, that is part of NIPT. You pay extra. We are going to, when we talk about extended carrier screening in a moment, we are going to talk about testing for cystic fibrosis, for fragile X syndrome and spinal muscular atrophy. One of the risks of NIPT is that we will miss the triploid foetus. So because the triploid foetus has an exact multiple of 23, it may well be reported as normal on NIPT, whereas a 12 week scan will either show a partial hydatidiform mole or it will show a grossly abnormal foetus with central nervous system other abnormalities, particularly involving facial clefts and the heart. So again, if you are doing NIPT without doing a scan, you are not serving this small group of patients. Most triploid foetuses miscarry early, but a proportion will reach diagnosis and it is another weakness of NIPT.

Mackenzie’s Mission. Mackenzie Casella was a little girl born to a couple in Sydney who died at the age of seven months from spinal muscular atrophy. They got organised, they directly lobbied Health Minister Greg Hunt and said no one else should go through what we have gone through and that is the basis of Mackenzie’s Mission. The Australian Reproductive Carrier Screening Project is a project where women, more correctly couples, are going to be recruited in three states, Western Australia, Victoria and New South Wales and ten thousand of them will have carrier screening. They will have blood collected that will test for 500 recessive and x-linked genetic conditions including spinal muscular atrophy and then it will counsel those women - actually they can also have a cheek swab, that is correct, as to whether or not they are at any risk. Interestingly they are only informed if both them and their partner / husband are recessive carriers when it comes to autosomal recessive carriage, so that in some ways troublingly, in some ways mercifully they are not going to be told about these other genes some of which are, well I can tell you I cannot name all 500 of them that is for sure.

So what are the options? Well we are going to get to this but one of the things that is going to happen through Mackenzie’s Mission is that if you are diagnosed prenatally with an autosomal recessive disorder, you will be counselled that you have a one in four chance and you will be offered a single cycle of IVF and pre-implantation genetic diagnosis. The other patients will receive accurate information. This test will be evaluated to see whether it should be expanded population wide.

This is different. This is what is already available. This is what is out there. So your patients can ask you to write them a referral for the three gene panel or they can ask you for the expanded carrier screen looking at 300 autosomal recessive genes and another 28 X-linked genes. These tests are available for around $400. Some of the pathology providers will test, will encourage you to send maternal blood and then they will test the partner / husband for free if they are positive. This is out there. This is available now. So Mackenzie’s Mission will roll out in the coming months, this is there now.

The three gene panel. Three conditions. $400. For spinal muscular atrophy, around one in eight thousand births like baby Mackenzie, a neuromuscular disorder usually leading to death in the infant period.

Cystic fibrosis you are all familiar with. The most common recessive gene mutation in Caucasian Australians. Typical survival from the chronic lung disease, malabsorption, infertility et cetera picture, now well past age 40. Roughly one in 25 Caucasian Australians will carry this recessive gene.

And then the X-linked condition, fragile X syndrome. Around one in seven thousand boys. There is a syndrome in girls due to please do not ask me to explain penetrance in women with their XX carrier type, but there is usually a lesser syndrome expressed in women. But this is a mild to moderate form of intellectual disability which does not manifest fully until the boys are in their teens.

So you can go and have blood taken for these conditions. So what do you do with that information? Well this where I think it is easier to be an obstetrician than it is to be a general practitioner. Maybe not. It is interesting to view the standard of care, but certainly I think it is the standard of car for myself when I am seeing the small number of women I see preconception. So it is not that small, I see women with infertility, I see women with endometriosis, polycystic ovary syndrome, all matter of gynaecological conditions. But women can go and have tests and they can then inform their decision making. They can be referred for genetic counselling. They can go have IVF and pre-implantation genetic testing. Now the problem with that, is that this typically costs between $10,000 and $15,000 per cycle. This is a bonanza for those listed companies. This is a potential bonanza for those elements of the Australian IVF industry that are now owned by Chinese state-owned enterprises. So not only is the future in offering your 25 to 34-year-old patients social egg freezing just in case they do not meet Mr Right, there are other opportunities for growth in this area.

There are alternatives to PGT. You can use donor sperm. Hard to get hold of. You can use donor eggs. Hard to get hold of. You can use donor embryos. Very hard to get hold of. You can chose surrogacy, very difficult. You can chose adoption, very difficult. Or you can make the decision not to have children on the basis of your risk of these conditions. Now not all of those sound like fabulous options but I would contend that they are vastly superior to making the diagnosis once the patient is pregnant. If you make the diagnosis once the patient is pregnant, the patient might be able to make informed decisions, they can be referred for genetic counselling, but then potentially they risk the loss of an unaffected baby or they chose to have termination of pregnancy. This is obviously a great deal more vexed and a great deal more complicated. I was national AMA President when Greg Hunt thought to consult me about Mackenzie’s Mission. I said many positive things, but I reminded him that with the current technology available, we do not have gene slicing. It might not be that far away, but as it stands the only interventions are disposal of embryos or termination of pregnancy. If you do not count the ability to be informed about what is ahead of you. That is important but it is important also to understand that they are the interventions we are talking about and we should not white wash it that these are difficult issues for you to potentially discuss with patients who just came in for a pill script.

So, I am taking you all the way back to 1968. Dr Wilcox was not even born then. Actually neither was I. So the Wilson and Jungner criteria, the World Health Organisation asked Wilson who ran the NHS, or one element of the NHS and Jungner, a Swede to come up with these principles and practices for screening for disease. Now these criteria largely stand the test of time, but no they are a bit out of date so we will move forward to the synthesis of emerging screening criteria which recognised the evolution of genomics and the evolution of technology and these are the guidelines for a screening test. So this is across the board. This includes screening tests for pre-invasive cancer of the uterine cervix, breast cancer, bowel cancer and all manner of conditions.

My concern about reproductive carrier screening is that it might fall short in some of these areas. Does the screening program respond to a recognised need? Well, there is no question that the parents of Mackenzie Casella thought that there is a need and there is no question that the parents of a child born with fragile X syndrome will often ask, you know, could this have been identified previously? Could I have done something about it? But this is a question I think for society to ask itself and maybe that will wash out in Mackenzie’s Mission. Where I think we have got a real problem is that this program does not promote equity and access to screening for the entire target population. The most attractive intervention for one or more of these recessive or X-linked conditions is to refer a patient for one or more cycles of in vitro fertilisation to then create a family of embryos somewhere between eight and 15, eight and 25, so that you can screen them at the 16 cell morula stage and only put back in an unaffected embryo. So this ethically is acceptable to the majority of the population. Not all. But it is beyond the reach of many, many Australians. And the final point, the overall benefits of screening should outweigh the harm. I think that is where we have opinions.

So, a cautionary note there, but what is the standard of care? Well, my college has the standard of care that carrier screening is available and it should be offered to all women planning a pregnancy. I routinely measure, for many years now I have spoken to patients about the option of cystic fibrosis screening. I lament the downturn in the private obstetric market where you used to refer me patients for a Pap smear just so they were on my books. Those days have long passed, but I used to value add and talk about cystic fibrosis screening. This is the standard of care for gynaecologists seeing patients pre-conception and I think an IVF clinic that does not talk about this is failing in their duty. It is probably regarded as the standard of care for you to discuss this with reproductive aged women. I talk about it in a more roundabout way with patients who are already pregnant because I do not like the interventions that I can offer them. I will observe that every year that goes by, my patients become more and more anxious about less and less and I am concerned that we are potentially losing our way with such an emphasis on you know, dare I say, search and destroy testing. I have my concerns and yet we all know the catastrophe for that small number of people that are handed one of these children without the opportunity for diagnosis. I think the standard of care is that you need to at least find a way to have this conversation with your patients. A lot to think about. Thank you for your time. Helen, you are now in charge.

Helen: Alright, so Mike I am going to jump straight in off your last point there. So, you mentioned the discussion by an informed clinician and I guess I would say, if you are in that good situation yourself of being able to see a woman pre-conception who is at low risk, she and her husband are at low risk based on their environmental and their own knowledge of their family history, can you give us a succinct explanation of how you would state the role of these tests to a patient. You would say these tests are available. What do you say then?

Michael: I think you say that there are tests available for serious non-lethal or lethal and non-lethal conditions that cost money. You then can offer them information from a credible site.

Helen: Such as? Such as?

Michael: Well the, our patients are very used to using the internet. There are credible sources of information. Now where do I refer my patients? I actually when it comes to genetic conditions, I frequently patients to Wikipedia would you believe because it is actually very good. We all know the internet fails patients who google itch and weight loss because invariably they end up diagnosing themselves with leukaemia, but when it comes to very specific questions, there are decent resources available from the learned colleges. I use Jean Hailes a lot for women’s health. The NIH has good resources. The American College, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists have information which is appropriate for lay-people.

Helen: Okay, excellent. And also, New South Wales Health has their Centre for Genetics Education and that covers a lot of screening tests during pregnancy. Again, it does not have the fine granular detail that you alluded to on some of the more recent reproductive carrier screening, but there is a little bit of information there as well.

Okay, so as you say, it may be as simple as a Wikipedia. It may be as simple as a RANZCOG or ACOG guideline and as many of us do in practice, we often look for the guideline right there and GPs are quite good at seeing a web page and being able to make an assessment of whether it is appropriate or not likely to be an accurate source of information.

Okay, so you mentioned before when we were talking about options for management during pregnancy and I saw you said informed decision making. So, by that do you mean the decision on whether or not to continue with the pregnancy? Tell me more what you mean by that term.

Michael: So there are genetic counselling services available across Australia. I am not familiar with how ready the access is in different parts of Australia but the service afforded to women in Western Australia is an outstanding specialist-led service, led by clinical people with medical degrees and also highly trained genetic counsellors. Typically they get access to appointments within a fortnight. There is no preference for insured or uninsured patients. So the genetic services in Western Australia is at Agnes Walsh House on the King Edward Campus in Perth. Similar resources existing in different parts of Australia.

Helen: Alright. And so when you talk about options for termination of pregnancy, it was often said in the past that if the test is not going to change your management then do not do the test. Is this in your view, is this still true of a condition like Trisomy 21 where a woman will continue to continue with the pregnancy regardless? Is there still a benefit from an obstetrician and paediatrician’s point of view of going into that woman’s labour and delivery with a diagnosis suspected if not certain?

Michael: Look, I think the days of medical paternalism are long dead and I think that patients are entitled to accurate information at every step of the way and I think the situation changes. So, one of the emerging trends in Australia is the substantial number of East African women, many of whom have not been educated past year 7 level, many of whom are of even from animist faiths et cetera, will not terminate pregnancies for lethal abnormalities and so we have to support that decision making. Now things might develop and if they get what is called mirror syndrome, if they get big horrible hydropic foetuses and big hydropic waterlogged placenta, they can preeclampsia, they can get very sick. Same with Down syndrome, I think there is a very big difference between Down syndrome, sorry a very big difference between Trisomy 21 and Down syndrome with severe congenital heart disease obvious at a 13 week or 19 week scan. Same with Turner syndrome. This is again one of the strengths of the old first trimester screening. 89% of women diagnosed with Turner syndrome on NIPT with a normal nuchal translucency, it will be false positive testing. So if you have got a nuchal translucency of 6 mm at 12 weeks, there is a high probability that child will have congenital heart disease and a patient therefore might have a different value system. The majority of women diagnosed with a foetus with Trisomy 21 in Australia in the year 2019 would elect to terminate the pregnancy and of course the legality of that and how easy that is varies according to the gestation at which the diagnosis is made, where they live, what their means are. In terms of the other conditions, I think it is our job to give them as accurate as possible information and I do not expect every GP to be an expert in every question on spinal muscular atrophy. That is where I think genetic counselling is a minimum standard if there is going to be any conversation on whether or not you might continue the pregnancy.

Helen: Okay. And so, I have had a couple of other questions come through about, it is a brave new world and in countries apart from Australia such as the US, there are even more comprehensive genetic screens that are offered. So, Eugene being one of the companies that offers them, and is there an extension to extended reproductive carrier screening that is practiced in other countries as far as you know?

Michael: Well, I wish, I hope I am talking accurately but my understanding is that because of the high prevalence of recessive genes in Ashkenazi Jews, it is a requirement in the state of Israel to have this kind of testing before you marry. Of course in Australia, many babies are born, as in Israel, many babies are born out of wedlock.

Helen: Fatherhood is not always known with certainty.

Michael: Yes, absolutely, yes. Some measures have non-paternity as high as and higher than 20%. Only 50% of pregnancies are planned. Now, that makes the importance of these conversations early in relationships more important. There is no limit to the number of tests you can do and that is the risk and that is where ultimately society needs to have a say. I have always felt that the pace at which these tests have rolled out has reflected the need for the venture capitalists that have developed these technologies to recoup their multibillion dollar investments. Often the need to, the ability to offer the test is a long way ahead of the ethics of it and the ability to manage it in an appropriate way. But there is no end to the number of microdeletions that could potentially be detected in cell-free DNA.

Helen: And I think one of our people on line has actually mentioned about thoughts on the power of microdeletion testing which as you say, contains a number of different deletions that we could possibly look for, so I think this question will probably get even greater and be even more of an issue for GPs as the years or maybe months roll by. I think, I guess my comment here is that I am, and I guess I am saying this perhaps to some of the more junior or some of the more early career GPs online, is that I do not think there is any reason to apologise for only working within scope and I think the vast majority of our sensible patients would understand, look I am a GP I am not a genic counsellor, I am not a maternal foetal medicine specialist. This is the extent of my knowledge. This is truly important for you to clarify in your own mind the value of these tests, if this is going to, if we generally feel that this is important to allay anxiety going forward with pregnancy then you may send them elsewhere. I think a lot of our difficulty is that many of our patients do not have the option of going to tertiary level care or specialist obstetric and gynaecological care in which case, they are reliant on some of the good web based resources that you have mentioned so far.

Look, that actually leads into a question that has been when I am talking about you know, working within scope and knowing your limits, is there may be a few people on line who have thought about patients who are currently under their care for shared care and may be in their second or third trimester of pregnancy now, and perhaps the initial discussions in the first trimester care did not involve these discussions with the patient. What is a GP to do in that situation? Is it worth going back in the books to look at these things now? The retroscope being such an overused piece of medical equipment.

Michael: Yes, that is a really good question and it is very difficult when protocols change and when policies and procedures change and guidelines change. Now look I do not think that is the duty of care that you should be discussing with patients in the third trimester at the moment. A lot of these guidelines are new. This is an evolving space but I think it is food for thought and I think that, yes I think that the, you know, certainly my college statement is clear that you have a duty of care to tell patients that these tests are available. Whether that means going as far as recommending them, I think that we all set our values in different ways but your patients will become increasingly aware of these tests and they are not, they will often tell you that they have decided what they want. Sadly, the majority of patients who say they want NIPT do so because they are under the illusion that finding out the gender at 10, 11, 12 weeks is the most important thing in their antenatal care. I derive great joy from looking after those patients who do not find until their baby is born. It is rarely, very rarely important in their antenatal care, almost never important, and yet for many people that is how it is being sold.

Helen: So, and I guess I will say this is probably a main closing statement then, we have talked at length tonight about one small area of that booking visit or the first trimester or the antenatal care, so if you were able to shift the focus back to what other priorities in terms of delivering really good quality shared antenatal care, where would your priorities be for us as GPs?

Michael: Yes I think we are very, very good at telling women what not to eat in pregnancy but not what to eat. We are very good at telling them the whole variety of tests that they need to have rather than trying to accurately give them information on where these words they have heard of, where they sit in the pregnancy space. There is not enough emphasis given to their care in the postnatal period. There is increasing competition in this space from public hospitals who promise the world and then perhaps come short in terms of delivering the appropriate care to our patients, which concerns me greatly. I gave an appropriate disclosure as someone who makes a living out of private obstetrics previously. I think that an observation that I frequently make is that every year that goes by, I find pregnant women to be a more and more anxious group of women. They are already worried about all sorts of things. They are more worried about body image. They are more worried about things that might happen to them and there is the potential for every one of these tests to further medicalise pregnancy and for a minority of patients to drive them away from the evidence based stuff that we do so well. That has always been my fear, that by the time you finished talking about pertussis and influenza vaccination, group B streptococcal colonisation, diabetes screening, Down syndrome screening, epidurals and induction of labour, they, a small majority will reject the medical model and chose much less safe models of care.

Helen: Alright so, I was listening in the car on the way here on the MJA podcasts on the 2019 pregnancy care guidelines and I really liked the message they got across. The two main messages they got across there, which is just remembering that pregnancy by and large the model that we should be putting across to all our patients is that this is a healthy space to be in. That the vast majority of women manage to nurture their growing baby over the course of nine months, have a straightforward delivery and then continuing to mother that baby to the best of their ability so that it grows up healthily. And I hope that what people have taken away tonight is information that will just help them give, information to patients that reduces anxiety and makes them realise that the vast majority of pregnancies are healthy babies with good outcomes and I think that is what we like to see and that is why we all focus on shared care in antenatal care.

Michael: I think positive health messaging is so important for pregnant women and you need to stay alert for abnormalities or problems as they develop, but the risk in the expansion of testing is that it normalises a pathological model of care when although things do go wrong in pregnancy, you are exactly right, most mother and baby pairs come out of it in one piece and we should be focussing on much more important deliverables like the really strong evidence based stuff like boring old screening for preeclampsia, screening for postnatal depression risk. Looking after their mental health in the postnatal period and then you know, my job as an obstetrician is to deliver you back a human being for the lifelong care that you guys provide.

Helen: Alright. Thanks very much. I think that takes us to the very end of our time for this webinar tonight and I would like to thank all of those on line who have continued to be attentive and thank you for those who have written in provoking questions. And I would also like to thank Mike very much for his time and expertise this evening.

Michael: Thank you.