gestation in transplantation

GESTATION in TRANSPLANTATION

POWH MEDICAL GRAND ROUNDS

Dr Kenneth Yong, Dr Karen Keung, Dr Katrina Tang, Dr Angela Chou

1st CASE: JC 31 years• Systemic Lupus Erythematosis

• Arthritis, alopecia and serositis in 2008• Cerebral lupus 2009• Lupus nephritis :

2013: active urine sediment, class IV (diffuse proliferative)2015: nephrotic range proteinuria- class IV/VI (advanced sclerosis)

• Hypertension

• Prior aplastic anaemia with azathioprine (low TPMT) 2010

• Progression to end stage kidney disease, peritoneal dialysis from January 2017

Medications• Mycophenolate mofetil• Prednisolone• Hydroxychloroquine• Irbesartan• Mircera• Labetalol • Sevelamer• Calcium carbonate

KIDNEY TRANSPLANT

• 7 months of dialysis• August 2017: Living unrelated kidney transplant from husband

• 5/6 major HLA mismatch with no anti-HLA donor specific antibodies• Uncomplicated post-transplant course• Prednisolone 5mg, tacrolimus and mycophenolate mofetil (MMF)

• May 2018: No regular menses, discussions re: alterations to immunosuppression prior to conception planning.

- BP ↑, commenced on low dose amlodipine- Serum Creatinine 94umol/L, no proteinuria/microhaematuria

UNPLANNED PREGNANCYJuly 2018: Pregnant on urine testing

• Prednisolone, MMF, tacrolimus, amlodipine, BactrimMMF azathioprine (hx of aplastic anaemia, low dose 50mg~ 1mg/kg)Amlodipine LabetalolBactrim ceased

• Blood tests for confirmation of pregnancy• Referral to high risk pregnancy clinic at RHW• Dating scan• Review in 2 weeks

• Miscarriage

PREGNANCY PLANNING 2020

• February 2020- revisited plans to conceive• MMF ceased• Prednisolone increased from 5 to 10mg, tacrolimus higher target trough levels (2 agents)

• April 2020: pregnant G1P0M1, serum Creatinine ~ 100umol/L, no proteinuria/haematuria

• High risk pregnancy clinic ~ 6 weeks gestation-Aspirin prophylaxis after 8 weeks gestation (pre-eclampsia)-Risk of lupus flare during pregnancy, particularly in the post-partum period-Prednisolone therapy – risk of worsening hypertension, gestational diabetes and pre-term labour

-Small risk of worsening renal function, increasing proteinuria and urinary infection.

PREGNANCY COURSE

• Relatively uneventful

• Mid-trimester physiologic fall in BP- Labetalol ceased but later reinstituted

• Slight increment in serum Creatinine 86 105umol/L

• Anaemia- reviewed by Haematology service ~ mid-term, multifactorial (renal/pregnancy/iron deficiency)

DELIVERYSeptember 2020

• Labour at 25 weeks + 5 days• Vaginal bleeding and likely small abruption• Emergency C-section, ~800mL blood loss• No issues with blood pressure or renal function

• Baby 1: Female, 794g, Apgar score 5-8• Baby 2: Female, 817g, Apgar score 6-8

May 2020• Cessation of breast feeding- Mycophenolate reintroduced,

- Prednisolone weaned back to maintenance dose 5mg- Tacrolimus continued

• Cr 99 umol/L

2nd CASE: CM 30 years

1989Medullary cystic diseaseJuvenile nephrolithiasis

2003

PeritonealDialysis

2004

1st Cadaveric Renal Transplant

2008

Allograft FailureNephrectomy

NoncomplianceChronic rejection

2014

2nd Cadaveric Renal Transplant

Peritoneal Dialysis Nov 2019

Pregnancy(G1P0)

Mar 2020

POWH admission: ?PET/IUGR

30yo femaleWollongongLives with partner/step-children (x2)

Pulmonary embolism x2 (2009)Peripheral vascular disease (L iliac-femoral bypass 2008)Eosinophilic asthma (multiple respiratory arrest)HypertensionBilateral hearing lossGORD

Wanted own child

Counselled against pregnancy!!

Changed azathioprine (2016)

5/6 HLA MMClass I/II DSA (1500-2500)Standard immunosuppression

Failed ovulation stimulation/surrogacy

2nd POST-TRANSPLANT COURSE

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Day 0 Day 1 Day 5 Day 10 3 months 1 year 3 year 5 year

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Normal tx biopsyNo scarring

Tacrolimus 8-11ug/L Tacrolimus 3-5ug/L

Protein:Creatinine <10 Protein:Creatinine 80-100

20192014 2015

1st TRIMESTER: NOV 2019

Well

No leg oedema

Pregnancy 11/40 weeks

BP 120/60mmHg

Aspirin/clexane

GRAFT FUNCTIONSerum Cr 111umol/L

Albumin:Cr ratio 77mg/mmolProtein:Cr ratio 86mg/mmol

IMMUNOSUPPRESSIONPrednisolone 5mg odAzathioprine 75mg od

Tacrolimus 1.5mg bd (level 1-3ug/L)

PREGNANCY COUNSELLINGIUGR 40%

Preeclampsia 40%Preterm delivery 60%Perinatal mortality 5%

>25% kidney function loss during pregnancy 40%>25% kidney function loss post-partum 20%

1-year post-partum ESKD 2%

2nd TRIMESTER: FEB 2020

Tired/fatigue

No leg oedema

Pregnancy 22/40 weeks

BP 120/60mmHg

GRAFT FUNCTIONSerum Cr 125umol/L

Protein:Cr ratio 67mg/mmol

IMMUNOSUPPRESSIONPrednisolone 5mg odAzathioprine 75mg od

Tacrolimus 4mg bd (level 2-3ug/L)

MARCH 2020

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24th Feb 10th March 24th March 2nd April

Creatinine Protein:Creatinine RatioPOWH Admission

IUGR/Preeclampsia

Hypertension (SBP >140mmHg)Graft dysfunction (?cause)Diagnostic dilemma (sFlt-1/PIGF negative)

Headaches/oedemaAnaemiaEmergency C-section (19/03/20)

Renal transplant biopsy

(25+4)/40 weeks gestation

27/40 weeks gestation

POST-PARTUM COURSE (2020)

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6th April 15th April 22nd April 5th May

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1st biopsy

Borderline TCMRArteriolar fibrin thrombiGlomerulopathy: ?TMA

Pulse IV steroidsIncreased CNI doseHaemolysis screen

2nd biopsy

Chronic active TCMRArteriolar fibrin thrombiGlomerulopathy: ?TMA40-50% IFTA

?uncertain reversibility

1st & 2nd BIOPSIES April 2020: TMA

1st & 2nd BIOPSIES April 2020: EM

1st & 2nd BIOPSIES April 2020: TCMR


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1st biopsy



2nd biopsy


3rd biopsy

Borderline TCMRGlomerulopathy: ?TMA40-50% IFTA

Pulse IV steroidsAnti-proliferative changed (myfortic)BP management

Worsening BPThrombocytopaenia


aHUS/TMA screenChange CNI (cyclosporine)?non-CNI immunosuppression?role for eciluzimab

3rd BIOPSY May 2020: TMA

3rd BIOPSY May 2020: Glomerulopathy

3rd BIOPSY MAY 2020: TCMR


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1st biopsy



2nd biopsy


3rd biopsy

Borderline TCMRGlomerulopathy: ?TMA40-50% IFTA

Pulse IV steroidsAnti-proliferative changed (myfortic)BP management

Worsening BPThrombocytopaenia


aHUS/TMA screenChange CNI (cyclosporine)?non-CNI immunosuppression?role for eciluzimab

No role for eciluzimabContinue current treatment

Commenced dialysis Feb 2021

Overview

• Reproductive health in CKD

• Maternal outcomes • Foetal outcomes • Drugs

Who is this? A. Twins

B. Children of the first woman who

successfully gave birth after kidney

transplantation

C. The first woman to successfully

give birth after kidney transplant

and her donor

D. A and B

E. A and C

Who is this? Edith Helm 23-year-old

• First successful pregnancy in kidney

transplant recipient in 1958

• Lived to age 76

• Passed away in 2011

Background

• Sexual dysfunction common in CKD• Fertility is improved within months after successful transplantation.1-2

• Level of evidence to guide clinical practice – registry data, case studies

Davison et al. 1991 Am J Kidney Dis Anantharaman et al. 2007 Adv Chronic Kidney Dis

Effect of Pregnancy on Allograft function

Renal allograft is able to adapt physiologically with increase CrCl by 30% in 1st trimester small decrease in 2nd trimester Returns to pre-pregnancy levels by 3rd trimester

↑24 hour protein excretion: 3-fold higher by 3rd trimester

Maternal Outcomes

• Pregnancy rates lower than general population • Live birth rates comparable (71-79%)

The Pregnancy Rate and Live Birth Rate in Kidney Transplant Recipients

American Journal of Transplantation, Volume: 9, Issue: 7, Pages: 1541-1549, First published: 29 June 2009, DOI: (10.1111/j.1600-6143.2009.02662.x)

Gill et al. 2009 Am J Transplantation

Risks

• Maternal complications • Pre-eclampsia (21-38%) • Hypertension (52-73%)• Urinary tract infections (40%)• Graft function decline

• Risk factors associated with poor outcomes:

• History of drug-treated hypertension

• Serum Creatinine >120µmol/L• Proteinuria (>0.5g/24 hours)• Recent rejection • Foetal complications

• Premature birth (40-60%, vs. 5-15%) • Low birth weight (70%)• SGA • Miscarriage (11-26% vs. 8-9%)

Maternal complications –PET and HTN

Pre-eclampsia - 6-fold higher risk compared to general population

- Diagnosis can be challenging- Low dose aspirin recommended for all patients - Safe antihypertensives:

- Methyldopa, hydralazine, beta blockers and calcium channel blockers, thiazides

Maternal complications – Allograft function

• In the absence of risk factors, pregnancy does not increase rate of graft loss

• In a single centre study (n=48) in 2008, younger age of transplantation was associated with greater likelihood of live birth

• Graft failure not different at 10 years (19 vs. 21%)

Kim et al. Transplantation, 2008

Maternal complications – Allograft function

• Acute rejection rates during pregnancy and first 3 months post partum, comparable to general population

• Current guidelines no recommendations about HLA typing and risk-stratification of prospective fathers

McKay et al. NEJM, 2006

Kim et al. Transplantation, 2008

Bachmann et al, BMC 2019

Pregnancy After Kidney Transplantation and Its Impact on Graft Function

• Retrospective cohort study: 295 pregnancies in 197 renal Tx recipients since 1971 (Netherlands)

• 55% had 1 pregnancy and 85% conceived after >2 years of Tx

• Non-significant decline in eGFR after 1st pregnancy but nil effect of subsequent pregnancies

Claes et al. Transplantation 2021

Prognostic determinants of eGFR:

Renal functionTx vintageAcute rejection before pregnancyTx to conception time

Maternal complications

• Increases up to 40% • U/A should be performed every clinic visit and urine MCS 4

weekly• Asymptomatic bacteriuria should be treated for 2 weeks, and

prophylactic antibiotics continued throughout pregnancy.8

Urinary tract infections

Caesarean section – higher rates (43-64%)

Gibbs et al. Maternal Fetal Medicine Principles and Practice, 2004.

Which immunosuppressant is generally considered safe to use in pregnancy?A. Sirolimus B. Mycophenolate C. Tacrolimus D. Leflunomide

Chandra et al. Transplantation 2019

Foetal complications

Immunosuppressants• Mycophenolate crosses placenta teratogenic • Calcineurin inhibitors: Tacrolimus (less data

compared to CysA) • Safe in pregnancy

• mTOR inhibitors• Decreased foetal weight and delayed

ossification of skeletal structures, increased foetal mortality when combined with CNI

• KDIGO advises against use of mTOR inhibors


• Preterm delivery – 40-60% vs. 5-15% in general population

• High serum creatinine and maternal hypertension are risk factors

• Low birth rate (42-46%) • IUGR (30-50%)

• Mean gestational age for newborn 35.6 weeks, mean birth weight 2.4kg

• Miscarriage rates 11-26% (vs. 8-9% in general population)

• No higher risk of perinatal mortality in absence of risk factors of HTN, proteinuria and graft dysfunction.


• Rate of congenital infections overall is not

higher than general population

• CMV infection

• Primary CMV infection results in 40-50%

transmission to foetus with 5-18% chance of

being symptomatic at birth.

• Diagnosed with amniotic fluid culture

• Foetal hearing loss, microcephaly, mental

retardation, perinatal death

Gibbs et al. Maternal Fetal Medicine Principles and Practice, 2004.Kociszewska-Najman et al. Transplant Proc 2016

Timing of pregnancy

• Controversial

• KDIGO Guidelines recommend waiting after the 1st

year, and attempting when renal function stable, proteinuria <1g/day

• Retrospective study of 729 pregnancies in KTR from 1990-2010 showed association between first-year pregnancy and increased risk of allograft failure (HR 1.18).10

Definitions of the Australian Categories for Prescribing Medicines in PregnancyCATEGORY

A Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.

B1Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.

B2Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.

B3Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

C Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the humanfetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

D Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetalmalformations or irreversible damage. These drugs may also have adverse pharmacological effects.

Drugs generally considered safeDRUGS generally considered SAFE

Comments

Prednisolone FDA pregnancy class B.

Tacrolimus FDA class C.

Tac and cyclosporin linked to foetal growth retardation and preterm

delivery, but generally felt to be safe.

Cyclosporine FDA class C.

Azathioprine FDA class D, however azathioprine has not been found to be a human

teratogen.

Doses below 2 mg/kg have not been associated with an increased risk

of congenital malformations, stillbirth and miscarriages.All compatible with breast feeding

DRUGS generally considered UNSAFE

Mycophenolate mofetil FDA class D. Teratogenic, particularly orofacial.

(No impact on sperm – men can stay on MMF) Leflunomide

FDA class X. Long half life. Consider colestyramine

No information of use of these drugs during breastfeeding, therefore alternative agents are recommended.

Drugs with limited safety evidence – generally not recommended

Sirolimus FDA class C. Unknown at this time whether teratogenic as insufficient human data. Separately, data suggests it affects male fertility (reduction in sperm count)

Belatacept FDA class C.

Other drugs generally considered unsafe and must be discontinued include: • Sulfamethoxazole/Trimethoprim- avoid in first trimester (neural tube

defects)

• Valganciclovir- can cause birth defects and should be avoided in both male and female transplant recipients 90 days before planned conception

• Angiotensin converting enzyme inhibitors (ACEI)/Angiotensin receptor blockers (ARBs). Should be ceased prior to the second trimester since Angiotensin II is crucial for foetal kidney development, especially towards the end of pregnancy.

Summary of Common immunosuppressive drugs use in transplantationF

FDA pregnancy category

InductionBasiliximab BAlemtuzumab CAntithymocyte globulin CMethylprednisolone C

MaintenanceAzathioprine DCyclosporine CTacrolimus CMycophenolate mofetil DSirolimus, rapamycin CPrednisone BBelatacept CLeflunomide X

Treatment of rejectionAntithymocyte globulin CBasiliximab B

Which statement is true?

A. Assisted fertilisation decreases the risk of pre-eclampsia B. Serum trough CNI levels may be misleading in pregnancyC. High dose methylprednisone for treatment of rejection should be

avoided in pregnancyD. Male transplant recipients should switch MMF to AZA to reduce the

risk of teratogenicity

Chandra et al. Transplantation 2019

Risk factors:• History of drug-treated hypertension

• Serum Creatinine >120µmol/L• Proteinuria (>0.5g/24 hours)• Recent rejection

Summary of Recommendations

• Pre-conception counselling and contraception (shared decision making)

• Pregnancy not advised in first 12 months post-transplant • Recommended maintenance immunosuppression:

• Calcineurin inhibitors (tacrolimus, cyclosporine) • Azathioprine • Low dose prednisone

• Low dose aspirin

• mTOR inhibors and mycophenolate should be stopped at least 6 weeks prior to conception

• Breast feeding not contraindicated and should not be discouraged • Proteinuria in pregnancy should not be attributed as normal and

common pathologies such as UTI or Pre-eclampsia should be excluded.

Summary of Recommendations

References1. Davison JM: Dialysis, transplantation, and pregnancy. Am J Kidney Dis 17 :127– 132, 19912. Anantharaman P, Schmidt RJ: Sexual function in chronic kidney disease. Adv Chronic Kidney

Dis14 :119– 125,20073. Hou, S. (2013). Pregnancy in Renal Transplant Recipients. Advances in Chronic Kidney Disease,

20(3), 253–259. https://doi.org/10.1053/j.ackd.2013.01.0114. Kim, H. , Seok, H. , Kim, T. , Han, D. , Yang, W. , Park, S. & (2008). The Experience of Pregnancy After

Renal Transplantation: Pregnancies Even Within Postoperative 1 Year May Be Tolerable. Transplantation, 85 (10), 1412-1419. doi: 10.1097/TP.0b013e318170f8ed.

5. McKay DB, Josephson MA. Pregnancy in recipients of solid organs—effects on mother and child. N Engl J Med. 2006;354:1281–1293.

6. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.10. Pregnancy in renal transplant recipients.

7. Kainz A, Harabacz I, Cowlrick IS, et al. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation. 2000;70:1718–1721.

8. R. S. Gibbs, R. L. Sweet, and P. Duff, Maternal Fetal Medicine Principles and Practice, Saunders, 2004.

https://doi.org/10.1053/j.ackd.2013.01.011

References

9. Kociszewska-Najman B, Pietrzak B, Czaplinska N, et al. Congenital infections in neonates of women with liver or kidney transplants. Transplant Proc. 2016;48:1556–1560.

10. Rose, C., Gill, J., Zalunardo, N., Johnston, O., Mehrotra, A., & Gill, J. S. (2016). Timing of Pregnancy After Kidney Transplantation and Risk of Allograft Failure. American Journal of Transplantation, 16(8), 2360–2367. https://doi.org/10.1111/ajt.13773

11. Shah S, Verma P. Overview of pregnancy in renal transplant patients. Int J Nephrol. 2016:4539342.

12. Chandra A, et al. Immunosuppression and Reproductive Health after Kidney Transplantation. 2019 Nov;103(11): e325-e333

https://doi.org/10.1111/ajt.13773

Thank you!

gestation in transplantation

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