Slide 1

Good afternoon. I’m Liz Lightstone and I’m a nephrologist. I run the renal antenatal clinic at Hammersmith in Queen Charlotte’s Hospital and increasingly see women for preconception counselling.

Slide 2

There’s a number of issues that I need to discuss with a woman when she comes to see me but before she even gets to me my colleagues need to decide who should have preconception counselling. So all of you who look after women of child bearing age should be aware of this. What information do I require that makes my life easier when I see her, but what the woman wants to know is how will my disease affect my pregnancy. The issues that I want to discuss with her clearly are her hypertension, how impaired renal function might affect the outcome for the baby. Most importantly and I think with new data most importantly for those of you who are looking after women, what medications is she on that she ought to stay on and what medications is she on that she ought to stop and disease specific issues such as those illustrated here.
Of course, the question that actually most women don’t ask, except those with transplants, is will my pregnancy make my renal disease worse? That will be embedded in my answers to these other questions.

Slide 3

In a perfect world all women with chronic kidney disease that particularly causes hypertension or proteinuria should be referred but as a minimum women with CKD 4 or 5, if they’ve got adverse risk factors, I think all women with kidney transplants and many women with kidney transplants think that’s their goal ticket. Now they can go and get pregnant and what John Davidson says is when he started in practice many years ago all women were referred to him who were thinking about pregnancy and now most are not and don’t consider it an issue.

One would discourage women on dialysis to contemplate pregnancy but they absolutely do need counselling beforehand if they’re going down that road and other people with multisystem diseases. It is much, much easier to discuss heritable renal disease before a woman is pregnant than during early pregnancy.

Slide 4

I don’t need to tell this audience what a minimal data set would be for establishing degree of renal impairment but the most important factor I want to know is rate of change of eGFR. There is an enormous difference in counselling a woman who’s had a creatinine of 150 for 10 years after some acute insult and who’s been completely stable and good blood pressure than somebody whose eGFR was 60 last year, is 40 this year and is heading on a downward slide.
Clearly these other issues, don’t forget fertility. If you’re looking after patients with lupus who’ve had cyclophosphamide, they may well be heading for a premature menopause and telling them to go off and try for a year and not to worry is not good advice as they’ll be menopausal before they get pregnant.

Slide 5

I always like to focus things around a patient and this was a woman I saw initially about 3 years ago for preconception advice. 29 year old teacher, she’d had type 1 diabetes since the age of 7. She had absolutely diabolical control and along with that she had nephropathy, retinopathy and hypertension. I’m not going to discuss the fact that she also had hypothyroidism and a family history of cystic fibrosis.

This was not a ten minute consultation. She was on insulin, she was on a statin,  she was on an ACE inhibitor, a thiazide and thyroxine.

Slide 6

The key issues I wanted to discuss with her are generalizable to most of the patients I see. For her poorly controlled diabetes was actually number 1, 2 and 3 but her hypertension, her renal impairment and proteinuria and the medication she was on.

Slide 7

It’s worth reminding you that of course, bad diabetes means bad outcome. She was much more likely to have foetal loss, congenital malformations, macrosomia and pre-eclampsia. There was an interesting tension between the diabetologists who were advising her about pregnancy and me because the diabetologist wanted her to control her diabetes not unreasonably. My view was she hadn’t managed it in 22 years, she was unlikely to get there now. My view was her renal function was declining and just as Michele has told you, I spend a lot of time telling my patients to go out and get pregnant now and not wait. If you’ve got progressive renal dysfunction, now is the best time to get pregnant not in a few years time.

Slide 8

The most important determinant of outcome in women with renal disease is their hypertension. Most women with renal impairment fail to have a mid-trimester fall in their hypertension. If you have uncontrolled blood pressure at baseline, you do much worse and I’ll show you a graph on the next slide. If you’re normotensive pre-pregnancy almost regardless of your renal function, you can expect a much better outcome. There is again a tension with our obstetric colleagues and I quote from a publication that says ‘blood pressure as low as 170/110 can cause serious maternal mortality’ and clearly we’re working in orders of magnitude different beliefs about blood pressure.

Slide 9

This is data from the collaboration of obstetric and renal disease that I do with my colleagues in Birmingham, Leicester and Hammersmith and we’ve looked retrospectively initially and now prospectively this is retrospective data on about 270 women. There was a small group who did not have hypertension pre-pregnancy and you’ll see that none of those with a creatinine of greater than 125 at baseline had no hypertension but compared with 130.000 controls they actually did very well whether their creatinine was less than 80 or 80-125 and nearly all of them got to 32 weeks gestation. In stark comparison if these women had a diastolic blood pressure pre-pregnancy of greater than 90 or were on treatment for hypertension and that includes all of those with a creatinine greater than 125, 50% had delivered by 32 weeks. That has enormous knock-on implications for the baby as well as for the pregnancy.

Slide 10

There is a controversy about the ideal blood pressure in pregnancy and from the obstetric point of view lowering the blood pressure is associated with lower birth weight. There is an ongoing prospective randomised controlled trial about tight control versus looser control in hypertensive women without renal disease. My view is that we’re probably not aiming for what we would like to have in the non-pregnant patient but certainly these women shouldn’t be running at greater than 140/90.

Slide 11

How do you treat the hypertension in pregnancy?  And this has become more problematic. When I advised this woman back in 2005, I said she should stay on her ACE inhibitor until she got pregnant about 5-7 weeks, if she had regular periods just to stop it. They are absolutely contraindicated in the second and third trimesters due to foetopathy but there was no good data about first trimester exposure. That changed in 2006 with a study of women in the States and showed there was 4.7-fold increased risk of congenital malformations in first trimester only exposure of ACE inhibitors. The absolute increased risk of malformations from background about 3-8%. The counsel of perfection must be to advise these women to stop their ACEs and ARBs. If you think about your CKD practice that will be a lot of women. Just makes my consultations longer and in fact, I would still advise this woman exactly as I did then because the risk of stopping it I think outweighs the benefit of stopping it because she would have lost 2 years of renoprotection had I switched her over at that point to a pregnancy safe anti-hypertensive.

Slide 12

To most of my women who are proteinuric, particularly with progressive renal disease, I say continue but I counsel them of the risks. We’re very old fashioned in pregnancy, it’s still methyl dopa, it is safe but I’ve got a woman only in the last week who’s got a rampant hepatitis probably due to methyl dopa and I swapped her preconception. She was one of Michelle’s IVF at 40 with a creatinine of about 300.
Labetalol, 100 mg again a huge dose range very safe, if they’re not asthmatic. Nifedipine is fine my obstetric physician colleagues use doxazosin, hydralazine.

Do not use unopposed beta blockade, don’t use atenolol causes intrauterine growth retardation.

Slide 13

Michelle has already touched on this, it’s very hard to diagnose pre-eclampsia in the hypertensive proteinuric woman. In reality it doesn’t really matter. If the baby’s growth restricted, if there’s bad hypertension and severe proteinuria and the baby’s of a reasonable gestation, it will tend to bale out.

Slide 14

There is very little good data out there on how renal impairment influences outcome it’s almost all retrospective studies. This is an interesting paper from Jones and Hayslett in 1996. They looked at a group of women with a creatinine greater than 180 at conception and 50% were completely stable and remember these were women who were often told do not get pregnant. But 50% of them were completely stable during pregnancy, 30% rocked on off through pregnancy and afterwards, 8% got worse and these are actually the nightmares because you sit there and they get worse and worse and then they got better. You can’t tell who these women are going to be and 10% decline post partum. That’s illustrated here. This was a woman I looked after who’d had an acute kidney injury, got a little bit better but had a creatinine of 300 had an unplanned pregnancy, declined termination, she carried on through, did well, got to 36 weeks, a normal vaginal delivery and then within 3 weeks she was on dialysis, rocked off post partum and you need to see these women.

Slide 15

There is a prospective study of women with CKD stages 3-5. This was published last year. 49 non-diabetic women with  GFRs less than 60. The only thing that predicted poor renal outcome and low birth weight both good hard endpoints was the presence of a GFR less than 40 and more than 1 g proteinuria. So you had to have significant proteinuria and significantly impaired renal function to have a significant hazard ratio of losing renal function.

Slide 16

This is the data I cite to my patients. It’s from years of John Davison collecting on 908 pregnancies and essentially he always divided up creatinine less than 125 which as you know covers a multitude of symptoms. 125-250 or greater than 250. There’s a doubling of problems during pregnancy and I’ll show on the next slide what those are likely to be. Most women up to this range of function will take home a live baby and that is actually what most women are interested in. This is less true once you have more severe renal impairment. The likelihood of an acceleration of your renal problem is very great once you have severe renal impairment but significant with modest renal impairment. These women should get away with it.

Slide 17

What are the problems they have?  Hypertension becomes almost universal in the worst renal function. Pre-eclampsia, you heard from Michele the baseline risk is about 5-10%, so even those women who we predict will do well have at least a doubling of the risk of pre-eclampsia. These are not women who should be having water births with their midwives and never seeing a doctor. There is still a risk of premature birth and small – babies and this increases dramatically with worse function but it is difficult to assess how much of that is due to the hypertension as opposed to the renal impairment.

Slide 18

Medications are incredibly important and it’s important to tell people what they should take as well as what they should stop. If they’re planning a pregnancy, they should start taking folic acid and I advise women if there are no contraindications take aspirin to reduce the risk of pre-eclampsia. They can have EPO in pregnancy and they can IV iron in pregnancy and women with modest CKD can become profoundly anaemic in pregnancy and need support and remind them about contraception, if you don’t want them to get pregnant.

Slide 19

They should not stop, there’s this automatic thing get pregnant, stop tablets. Actually it has to be said my group of patients have many other things that precipitate that manoeuvre. But you must tell them do not stop your steroids, your azathioprine, your cyclosporine, your tacrolimus or your hydroxychloroquine, they are fine in pregnancy.
The difficulty and the big difficulty is mycophenolate mofetil and the ACEs and the ARBs. Sirolimus is used less widely but it is a problem.

Slide 20

Mycophenolate is a big problem. We use it hugely in our practice in the Hammersmith it’s in our transplant patients, in our lupus patients. It is teratogenic and the animal studies particularly show problems with ear development. It’s recently been reclassified to worse classification by the FDA. The babies see it, they have therapeutic levels in their cord blood and there are case reports of major abnormalities.

Slide 21

There is a series reported from the American Transplantation Pregnancy Registry showing high rates of spontaneous abortion, very high rates of malformation, the background rate is 3%, 28% and it is not clear whether early exposure in changing to Aza is fine or not. The counsel of perfection must be to come off it.

Slide 22

Roche to the end of December 2006 had reported 137 pregnancies with again very high rates of abnormalities. I think you should be seriously thinking about individualising immunosuppression. In my stable lupus patients I switch them from MMF to Aza. There are some patients I keep on it but you have to counsel them. We’ve had 8 pregnancies I think now at the Hammersmith all fine and the babies have all been fine but it’s early days.

Slide 23

Sirolimus would be predicted to have horrible effects. There are actually only case reports out there and those babies have been fine but it’s tiny numbers and you probably need to see many more pregnancies. Again, it can’t be recommended.

Slide 24

So what happened to my lady?

Slide 25

Well, she got pregnant 2 years later, so thankfully she hadn’t stopped her ACE and she stopped it in early pregnancy. She booked early all the things I told her to do, her diabetic control was absolutely appalling in her early pregnancy. By 34 weeks she was hypertensive, nephrotic and had declining function illustrated on this 1/creatinine plot. She had an elective caesarean section for foetal distress and hypertension. The baby was fine and I think was the perfect weight between the pull of macrosomia and intrauterine growth retardation he ended up somewhere in the middle.

Slide 26

She was seen promptly and that’s very important for your women who you see preconception and even more so for those you diagnose during pregnancy with renal disease. See them post partum. Make a plan. Don’t let them get lost to follow up. She has lost about 16 ml/min of GFR, her diabetic control remains poor and she’s as happy as Larry.

Slide 27

Just briefly to go through some specifics of different conditions. Transplantation you need to think about the comorbidity they may have acquired over the years, what their function is, what their immunosuppression is. Something I hadn’t thought of until recently of course, you can’t immunize against rubella once you’ve been transplanted, you’re immunosuppressed, so again something to think about in your CKD population.
Fertility comes back very quickly after transplantation and people need to be advised on contraception early and there are some very good best practice guidelines out there to refer to.

Slide 28

The outcomes are better the better your renal function, the better your hypertension and the lower your proteinuria as you might expect. If the function goes off, think of the obvious things infection and obstruction but rejection can occur and you may need to biopsy and treat.

Slide 29

This is data from the New England Journal in 2006. There are lower rates of live births in the transplant population because this is the one group our – who choose therapeutic abortion, if they think they’re going to risk their kidney. That’s not true in non-transplanted women. Getting to reasonable gestations and reasonable weights. You’re more likely to do badly if the creatinine is higher or the hypertension.

Slide 30

Lupus is a talk on its own. I’m quite pleased I got this into one slide. But patients should be in stable remission. They should be off their MMF ideally. There is an increased risk of spontaneous abortion. Look for antiRo and antiLa antibodies because the foetus is at risk of congenital heart block and you need to monitor from early on from about24 weeks. If they flare during pregnancy you’ve got some things up your sleeve you can use steroids, you can use azathioprine, you can add in HDQ, you can use tacrolimus and you can consider IV Ig. So you’re not without treatment options in pregnancy. I don’t give extra steroids, well I don’t change anything when they get pregnant and I don’t change anything immediately after pregnancy but I certainly don’t give a big dose of steroids post partum.

Slide 31

Reflux is the commonest disease I see in my renal antenatal clinic and it’s usually diagnosed in pregnancy. The women get multiple UTIs, they get scans, they’ve got scarred kidneys. They need some treatment if they’re to prevent pyelonephritis and if they’re getting recurrent urinary tract infections I would advise prophylactic antibiotics from early on, usually cephalosporin. There is strong heritable component to proper reflux nephropathy and they need to be advised to get their children screened.

Slide 32

Diabetes I don’t need to dwell on because we’ve discussed it but just to say the literature says that pregnancy does not alter the rate of renal decline but if you look at that literature, it’s entirely skewed to women with good renal function not like our girl.

Slide 33

As Michelle said, we’re seeing people older and later in the course of their disease and I’m sure that’s not true when they’ve got bad function and bad hypertension.

Slide 34

So the talk in one slide. The major determinant of outcome for your women that you see for preconception counselling is hypertension. Normotensive patients do better.
Bad renal function is associated with poor outcomes almost certainly as a multiplier of hypertensive effects.
If you are looking after women with CKD who have a transplant or are on dialysis of child bearing age, you need to consider whether they’re considering getting pregnant because they may not think it’s something they need to share with you.
All patients in that category should be offered pre-pregnancy counselling and they need renal review post partum and a plan for follow up that may be completely different from their pre-pregnancy state.

Slide 35

Then my collaborators on CORD group. Thank you very much indeed.

Slide 36

Chairman: Thank you very much for this excellent presentation. We finished exactly on time. We may have one or two comments. If not….  Yes one please here ?

Question: Only one question for you. If a patient with systemic lupus ---- on steroids and MMF gets pregnant would you convert her to azathioprine?

Dr Lightstone: It depends what their background had been. If they were on MMF just because they were on MMF and they had always been on it yes I would switch them to azathioprine warning them it could cause a flare or rejection if they are a transplant patient. If they were on MMF because they had bad problems with their kidney or with their lupus I might counsel them to stay on it. They’ve been exposed by then and I might say well you’ve got this far we’ll continue but monitor them and scan the babies carefully.

Chairman: Thank you.