Pregnancy and Kidney Transplantation
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POSTGRADUATE SCHOOL OF MEDICINE Pregnancy and Kidney Transplantation Dr WS McKane Transplantation Science A MEMBER OF THE RUSSELL GROUP CONTINUING PROFESSIONAL DEVELOPMENT Pregnancy and Kidney Transplantation • Renal physiology in pregnancy • Pregnancy in CKD • Transplantation and pregnancy – – – – Fertility after transplantation Epidemiology of pregnancy after transplantation Influence of pregnancy on recipient/transplant Influence of transplantation on the pregnancy • Management – – – – Preconception counselling Prescribing in pregnancy Practice guidelines Breast feeding Pregnancy and Kidney Transplantation • Renal physiology in pregnancy • Pregnancy in CKD • Transplantation and pregnancy – – – – Fertility after transplantation Epidemiology of pregnancy after transplantation Influence of pregnancy on recipient/transplant Influence of transplantation on the pregnancy • Management – – – – Preconception counselling Prescribing in pregnancy Practice guidelines Breast feeding Renal physiology in pregnancy • • • • • Accommodation begins early after conception Drop in systemic vascular resistance - BP Increase in renal haemodynamic function Glomerular hyperfiltration Dilation of urinary collecting system Renal physiology in pregnancy • Increase in Erythropoetin and Vitamin D production • Fall in plasma albumin • Protein excretion >300mg/24 hrs abnormal • +/-Glycosuria • Alterations in uric acid levels • Electrolyte alterations Physiological changes to the kidney during healthy pregnancy. Williams D , and Davison J BMJ 2008;336:211-215 ©2008 by British Medical Journal Publishing Group Summary of physiological adaptation in pregnancy Pregnancy and Kidney Transplantation • Renal physiology in pregnancy • Pregnancy in CKD • Transplantation and pregnancy – – – – Fertility after transplantation Epidemiology of pregnancy after transplantation Influence of pregnancy on recipient/transplant Influence of transplantation on the pregnancy • Management – – – – Preconception counselling Prescribing in pregnancy Practice guidelines Breast feeding Outcome of pregnancy in CKD • Prognosis determined by – Degree of dysfunction – Proteinuria – Hypertension Why does CKD affect pregnancy? • Inadequate renal physiological adaptation – Loss of rise in GFR – Loss of fall in BP – Proteinuria – Loss of Erythropoetin response • Dilated urinary tract – infections Why does CKD affect pregnancy? • Failure of plasma volume expansion • Vitamin D deficiency • Maternal kidney vulnerable to loss of renal blood flow Maternal outcomes Renal and foetal outcomes Pregnancy and Kidney Transplantation • Renal physiology in pregnancy • Pregnancy in CKD • Transplantation and pregnancy – – – – Fertility after transplantation Epidemiology of pregnancy after transplantation Influence of pregnancy on recipient/transplant Influence of transplantation on the pregnancy • Management – – – – Preconception counselling Prescribing in pregnancy Practice guidelines Breast feeding Pregnancy and transplantation • All the principles outlined for CKD apply – Baseline eGFR, proteinuria and BP determine risk • Additional issues to consider – Immunosuppression – Infection – Anatomical Fertility after transplantation • Rapid restoration of fertility in females – Menses and ovulation in about 60% of premenopausal women transplanted • Improved fertility in males – Less dramatic effect • Increased risk of impotence in males Epidemiology of pregnancy after transplantation – USRDS/Medicare Epidemiology of pregnancy after transplantation – USRDS/Medicare • 44.6% foetal loss rate – – – – 30% in general population Falling therapeutic termination Rising unexpected loss rate Lower if transplanted for longer Epidemiology of pregnancy after transplantation - registries • Registries in US and UK – Similar live birth rate • 33/1000 female patient years – Much lower foetal loss rate 21-26% • Likely that early foetal loss underestimated • US meta-analysis Effect of pregnancy on the recipient • Graft function – Acute • Acute rejection • Infection • Pre-eclampsia – Long term • Anaemia • BP control • Gestational DM Acute Graft Dysfunction • No increase in rate of acute rejection – 4.2% in meta-analysis • Graft function risk determined by baseline – eGFR, proteinuria, BP • UTI rate up to 40% – Often asymptomatic – Significant risk of pyelonephritis • Increased risk pre-eclampsia – Often hard to make confident diagnosis • Obstruction – Rare, may require nephrostomy Timing and aetiology of AKI in pregnancy Other effects on the recipient Anaemia 74% 13.5% in controls Long term graft dysfunction • No high quality studies – No clear evidence for adverse effect on graft survival – Meta-analysis • 7% graft loss at 5 years • 10% at 10 years Effect of transplantation on pregnancy • Obstetric outcomes • Foetal outcomes Obstetric outcomes • Increased rates of – Premature delivery – Caesarian section Foetal outcomes • Data on live birth rate contradictory – Registry versus Medicare data described above • Increased rates of – IUGR – Premature delivery – Caesarian section • All above determined by usual risks – GFR, BP, Proteinuria at baseline – Maternal age Obstetric and Foetal Outcomes US meta-analysis Pregnancy and Kidney Transplantation • Renal physiology in pregnancy • Pregnancy in CKD • Transplantation and pregnancy – – – – Fertility after transplantation Epidemiology of pregnancy after transplantation Influence of pregnancy on recipient/transplant Influence of transplantation on the pregnancy • Management – – – – Preconception counselling Prescribing in pregnancy Practice guidelines Breast feeding Preconception counselling • Consider in all women of childbearing potential – Before transplantation – Early after transplantation – Transplant physician and obstetrician • Discuss risks – Maternal – Foetus – Allograft • Advise to wait 1 year – Some centres advise 2 years • Plan therapeutic strategy and timing • Contraception Preconception counselling • Prescribing changes to be made in advance of conception – Stop MMF or MPA Sodium • Replace with Azathioprine if needed – Switch mTORi to CNI – Stop ACE/ARB or switch to safe alternative • Or advise to stop as soon as pregnant – Stop statins – Start Folic Acid 400ug od • Prescribing changes to start once pregnancy confirmed – Aspirin 75mg od Ante-natal care • Treat all as “high-risk” pregnancies • Joint clinic – Transplant physician – Obstetrician with expertise in high-risk – Other physicians as appropriate (eg DM) • Baseline transplant US at 12 weeks • Foetal US at 20-24 weeks – Blood flow to assess IUGR risk – Anomaly scan Ante-natal care • Monthly review – MSU • Treat asymptomatic – BP • Treatment threshold 140/90mmHg – Monitor graft function, anaemia and CNI levels – Serial US if at risk or evidence of IUGR – Therapy for • Anaemia, iv iron +/- ESAs – CNI dose titration – Thromboprophylaxis Prescribing for pregnant transplant patients • • • • • Immunosuppression Anti-hypertensives Thromboprophylaxis Anaemia UTI Immunosuppression 1 • Prednisolone – Safe below 15mg/day – Foetal blood level 10% of mother • CNIs – – – – Considered safe 40% dose increase required to maintain levels Foetal blood level 35-70% of mother Foetal anomaly rate same as control – 3% • Azathioprine – Considered safe although not recommended – Minimal foetal blood levels Immunosuppression 2 • MMF and MPS Sodium – Avoid - increased risk of foetal anomalies – Cleft palate/lip, short digits etc • The NTPR’s 2011 report notes outcomes in 61 pregnancies with exposure to mycophenolate products. There were 30 spontaneous abortions (49%) and 7 of 27 live-born infants had characteristic congenital anomalies. • MTORi – Contra-indicated Immunosuppression and male fertility • Overall equivalent outcomes to pregnancies fathered by healthy controls • MMF and MPS Sodium – Generally considered safe – No evidence of effect on male fertility in pre-clinical animal studies • mTORi – Contra-indicated – Inhibition of spermatogenesis • Partially reversible • Consider sperm banking if mandatory BP therapy • ACE/ARB contraindicated – Renal abnormalities mid-trimester – Cardiac first trimester • Best stopped in advance but some centres stop once pregnant, running the risk of cardiac abnormalities • Labetolol – Favoured over conventional beta blocker • • • • Methyldopa CCB Hydralazine Diuretics usually avoided – But may be needed in nephrotic state Thromboprophylaxis • Aspirin 75mg – Most obstetricians support use of aspirin in anyone considered at high risk for PET • LMWH prophylaxis – Usually reserved for those with history of or at high risk of VTE • Eg nephrotic, serum albumin <30g/l, UP > 3g/day Anaemia therapy • Aim to keep Hb > 10g/dl • Oral Fe • IV Fe in 2nd/3rd trimester – Risk benefit judgement • ESA Infections • • • • UTI/Pyelonephritis CMV Toxoplasmosis HSV Delivery • Timing – Balance of risks to mother and foetus – Early in context of severe PET, IUGR or renal decompensation • Steroid conditioning • Method – Practice guidelines support vaginal, but operative common – Risk of graft injury – Advisable to have transplant surgeon present if atypical transplant/ureter lie Breast feeding • Convention is to advise against • More recent data suggests Tac levels on breast milk are negligible http://www.ncbi.nlm.nih.gov/pubmed/23349333 Practice Guidelines • EBPG – www.european-renal-best-practice.org • KDIGO (AST endorsed) – www.myast.org/content/guidelines-andopinions Reading List • • • • • • • • • • • • • • • • • • • • • • • • • • 1. Pregnancy outcomes in women with chronic kidney disease: a systematic review. http://www.ncbi.nlm.nih.gov/pubmed/21940842 2. The pregnancy rate and live birth rate in kidney transplant recipients. http://www.ncbi.nlm.nih.gov/pubmed/19459800 3. Pregnancy outcomes in kidney transplant recipients: a systematic review and meta-analysis. http://www.ncbi.nlm.nih.gov/pubmed/21794084 4. Pre-pregnancy counseling for women with chronic kidney disease. http://www.ncbi.nlm.nih.gov/pubmed/22641575 5. Pregnancy in renal transplant recipients. http://www.ncbi.nlm.nih.gov/pubmed/23928390 6. Interpreting tacrolimus concentrations during pregnancy and postpartum. http://www.ncbi.nlm.nih.gov/pubmed/23274970 7. Breastfeeding and tacrolimus: serial monitoring in breast-fed and bottle-fed infants. http://www.ncbi.nlm.nih.gov/pubmed/23349333 8. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.10. Pregnancy in renal transplant recipients. http://www.ncbi.nlm.nih.gov/pubmed/12091650 9. Chronic kidney disease in pregnancy. http://www.ncbi.nlm.nih.gov/pubmed/18219043 Key learning points • Multidisciplinary working • Planning before pregnancy • Risk determined by eGFR, BP, proteinuria, maternal age – Safe in most well functioning transplant recipients – Modest increase in most adverse outcomes, proportional to above risk factors • Careful prescribing • Careful monitoring Pregnancy and Kidney Transplantation • Renal physiology in pregnancy • Pregnancy in CKD • Transplantation and pregnancy – – – – Fertility after transplantation Epidemiology of pregnancy after transplantation Influence of pregnancy on recipient/transplant Influence of transplantation on the pregnancy • Management – – – – Preconception counselling Prescribing in pregnancy Practice guidelines Breast feeding POSTGRADUATE SCHOOL OF MEDICINE Pregnancy and Kidney Transplantation Dr WS McKane Transplantation Science A MEMBER OF THE RUSSELL GROUP CONTINUING PROFESSIONAL DEVELOPMENT
