Pregnancy and renal transplantation

post renal transplantation mohamed abdelmoniem

1. Pregnancy and renal transplantation Mohamed AbdelMonem MD ( cAIRO ),FRCP (London) Senior specialist-transplant nephrology Organ Transplant center -Kuwait 1

2. Is pregnancy safe after kidney transplant What is the ideal time to become pregnant after kidney transplant What increases the risk of poor pregnancy after renal transplant What are the possible maternal complications What are the possible fetal complications Does pregnancy increase the risk of graft failure What changes to immune suppression are required before and during pregnancy Does pregnancy increase the risk of infection Is breast-feeding safe in renal transplant recipients 2

3. Fertility In CKD and ESRD: - Delayed onset of puberty -Elevated LH levels with decease pulsatile secretion ,absent midcycle LH surge, increase LH/FSH ratio, increase prolactin. - Anouulation due to HPO- axis dysfunction. -Decreased libido Following a kidney transplant : - Most resume menstrual cycles within one year -average time 5 months -Luteal phase defects are more common - Premature ovarian failure is 4-20% -contraceptive counseling at every visit more than 50% of pregnancies are unplanned Duglas , NC 2007 3

4. Successful pregnancies after human renal transplantation Murray JE,1963 4

5. Physiology of pregnancy 24 hours creatinine cl earance at 10 weeks 124 + 15.9 in healthy women (38% increase ) 125+ 28.1 in transplant recipients (34% increase ) In late pregnancy Cr Cl decreased by 19% in healthy and 34% in transplant recipients Davison JM,1985 5

6. Physiology :Proteinuria Proteinuria increased through out pregnancy -More than 500 mgs in the 3 rd trimester in transplant recipient - Returned to pre pregnancy by b 8-12 weeks post partum Davison JM,1985 6

7. Introductions Epidemiology Complications Criteria for considering pregnancy Antenatal management Labor management Breast feeding Contraception Pregnancy counselling 7

8. Epidemiology Pregnancy is estimated to occur in 12% of transplanted women of childbearing age . The number of kidney transplant recipients who conceive seems to be increasing The incidence of preterm delivery premature rupture of membranes and fetal growth retardation is as high as 60 % Acute rejection in pregnancy occurs in ˜ 4-9 % 8

9. Epidemiology Most women treated with azathioprine and prednisolone The ectopic pregnancy rate is higher and this is related to adhesions from previous surgery and peritoneal dialysis If pregnancy continued beyond 1 St trimester ,90% has successful outcome Superimposed pre-eclampsia and urinary tract infection occur in up to 40% 9

10. complications Fetal complications Maternal complications 1.Miscarriage 2.Ectopic pregnancy 3.Preterm delivery 4.IUGR 1.Hypertension 2.Preeclampsia 3.Allograft rejection 4.Infections 5.Diabetes 10

11. Criteria for renal transplant recipients contemplating pregnancy:(David et.al 2015) At least 6 months after transplantation Stable allograft function and creatinine < 1.4 mg/dL No recent episodes of acute rejection Blood pressure ≤ 140/90 mmHg or minimal antihypertensive medication No or minimal proteinuria ≤ 500 mg /24 hours Prednisone ≤ 15 mg /day Azathioprine ≤ 2 mg /kg/day Stopping mycophenolate mofetil and sirolimus 6 weeks prior to conception 11

12. Antenatal management All pregnant renal transplant recipients should have access to high level multidisciplinary prenatal care (maternal fetal medicine specialist, obstetricians, renal physicians and renal transplant surgeons) Close observation Treatment of bacteriuria Follow up of immunosuppressive medications Monitoring renal function and blood pressure 12

13. Antenatal management Women should tested for CMV,HIV,HSV,HBV and HCV Those found to have CMV negative should have their titers rechecked in each trimester Oral glucose tolerance tests should be arranged to diagnose gestational diabetes 13

14. Transplant physician monitoring scheme. Josephson MA etal ., 2007 14

15. Proposed frequency of controls during pregnancy in women with a kidney transplantation 15

16. Labor management Delivery is timed for 38-40 weeks of gestation in absence of any obstetric complications Vaginal birth is the preferred route - Prostaglandins and syntocinon both safe to use for cervical ripening or induction -The allograft located in the false pelvis ,does not obstruct delivery of the fetus 16

17. Labor management Cesarean section may be necessary for obstetric indications or if there are concerns related to severe pelvic osteodystrophy Multiple studies have demonstrated higher cesarean section rates in transplant recipients when compared to the general obstetric population due to higher risk of severe early onset pre eclampsia and fetal growth restriction necessitating early delivery prior to 34 weeks Available help from the urology surgical team or renal transplant surgeons when elective section is planned Stress dosage of steroids should be administered 17

18. Breast feeding Transplant recipient taking prednisolone, azathioprine, cyclosporine and tacrolimus should not be discouraged from breast feeding Clinical information on breast feeding is inadequate for mycophenolate ,sirolimus and everolimus ,breast feeding should be avoided 18

19. Contraception Low dose of estrogen/progesterone or progestin only oral contraceptive in renal transplant recipients if hypertension is well controlled IUD may may increase the chance of infection and in addition lead to contraceptive failure due to reduced anti-inflammatory properties Barrier method is safe but not an optimal from contraception due to potential for contraception failure Tubal ligation should be advised in women who have completed their families 19

20. Contraceptive Methods 20

21. PREGNANCY COUNSELING This must include a discussion on the impact of pregnancy on acute rejection and graft loss The risk of acute rejection correlates with pre-pregnancy serum creatinine levels as well as the interval between transplant and pregnancy 21

22. Immunosuppressive and other drug regimens during pregnancy 22

23. Immunosuppressive regimens during pregnancy 23

24. Medication in women in relation to conception, pregnancy and lactation.( Adapted from Wiles et al.) 24

25. Medication in women in relation to conception, pregnancy and lactation. (Adapted from Wiles et al.) 25

26. Medication in women in relation to conception, pregnancy and lactation. (Adapted from Wiles et al.) 26

27. Medication in women in relation to conception, pregnancy and lactation. (Adapted from Wiles et al.) 27

28. Medication in women in relation to conception, pregnancy and lactation. (Adapted from Wiles et al.) 28

29. Medication in women in relation to conception, pregnancy and lactation . 29

30. Management of hypertension Alpha methyldopa : Safe Beta blokes (atenolol and metoprolol): Safe especially in late pregnancy Hydralazine: Safe Calcium channel blockers (Nifedipine, nicardipine and verapamil ) can be used safely in first trimester ( avoid use with magnesium ---- can potentiate hypotension especially in pre eclampsia Labetalol: Safe ACEi :contraindicated Diuretics: contraindicated 30

31. Management of infection Bacterial: UTI ------- The most common 40% Asymptomatic bacteriuria: should be treated for 2 week The selection of antibiotics should consider potential fetal toxicity 31

32. Management of infection Viral: CMV : The most common viral infection post transplant HSV : Infection before 20 weeks of gestation is associated with an increased risk of abortion -Positive HSV cervical culture at term is indication for CS to minimize the risk of neonatal herpes -Acyclovir can be used safely in pregnancy HBV: An infant of HBsAg Positive mother Hepatitis B immunoglobulin within 12 hours of birth HBV vaccine within 48 hours then booster injection at 1 and 6 months HCV : Vertical transmission is low ( less than 7% ) unless the patient is also infected with HIV 32

33. Pre existing disease in RTR pregnant Thrombotic microangiopathies ESRD due to TTP/HUS-risk of recurrence during pregnancy in RTR. Management similar to patients without renal transplant. SLE Pregnancy and renal outcomes in RTR women caused by lupus nephritis are comparable with outcome in RTR with other cases of ESRD Reflux nephropathy Common in women of childbearing age Antenatal and post natal surveillance for presence of hereditary disease in offspring is recommended 33

34. Pregnancy outcomes 34

35. Pregnancy outcomes reported by major registries: 35

36. Maternal outcomes 36

37. Fetal outcome 37

38. Preterm delivery and low birth weight Increased risk of preterm- 45% ( 13% general population). Low birthweight infants are common- RTR 2420 gms compared to 3298 gms in general population. Predictors are: Pre pregnancy graft function Proteinuria Conception on MMF Pre existing hypertension Diabetes, and Black ethnicity Few studies show two or more transplants and acute graft rejection episode are also Risk predictors. 38

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40. Pre eclampsia and renal transplantation 40

41. Pre eclampsia and renal transplantation Rate of recovery decreases the more severe the stage of AKI Risk of preeclampsia in subsequent pregnancies increases 4 fold, despite complete resolution Therefore flag these patients for high risk obstetric care in future pregnancies. 41

42. Maternal organ dysfunction on pre-eclampsia : New proteinuria (u PCR >30 mg/mmol or ACR >8 mg/mmol) AKI (S. creatinine ≥ 90 µmol/l in a woman with previously normal creatinine concentrations) Liver involvement (ALT or AST > 40 IU/L) with or without right upper quadrant or epigastric pain. Neurological complications (eclampsia, altered mental status, blindness, stroke, clonus, severe headache, persistent visual scotomata) Hematological complications (platelet count < 150,000/ µL, disseminated intravascular coagulation, hemolysis) Uteroplacental dysfunction (fetal growth restriction, abnormal umbilical artery Doppler wave form analysis, still birth. 42

43. Pre eclampsia and renal transplantation Is a major cause of renal dysfunction in pregnancy Results in glomerular endotheliosis They usually have a mild reduction in GFR but When complicated by HELLP syndrome ,may progress to AKI and cortical necrosis They require meticulous fluid management to avoid pulmonary oedema Ultimate treatment to prevent further deterioration is delivery 43

44. Differential diagnosis for pregnancy-related AKI in kidney transplant recipients based on pregnancy trimester 44

45. Pregnancy-related acute kidney injury classified by prerenal, renal, and postrenal etiologies in the kidney transplant population 45

46. Does twin or triple pregnancy occurs in renal transplant recipient 46

47. Description of studies reporting the number of pregnancies, number of twin pregnancies, and complications in twin pregnancy after kidney transplantation 47

48. Rejection episodes in renal transplant recipients 48

49. Causes of elevated creatinine in pregnant kidney transplant recipients Cause Clinical features Pre renal /Renal Normal physiologic return to pre pregnancy levels in 3 rd trimester No concerning features identified Hypoperfusion Hyperemesis, antepartum hge, sepsis, excessive antihypertensive medications Pre eclampsia Worsening or new onset HTN, worsening or new onset proteinuria, abnormal LFTs, low platelets, fetal restriction CNI toxicity High trough drug levels UTI Positive midstream urine Viral infection Polyoma virus (decoy cells in urine), CMV PCR Acute rejection Diagnosis confirmed by kidney biopsy Post renal(obstruction) Hydronephrosis on U/S with no other cause identified ; exclude urinary retention 49

50. Renal graft biopsy in renal transplant pregnant Data for native kidneys Can be done safely in women with well-controlled blood pressure Biopsy after 32 weeks is not recommended (if applies to transplant patients ) 50

51. Allograft rejection during pregnancy and postpartum Uncommon .metanalysis (102/2412) incidence is 4.2%. Timing and nature of rejection is not known due to small and limited studies. Renal allograft biopsy at early gestation is necessary for management Acute rejection optimal management –unknown. High dose corticosteroid treatment is safe Baziliximab , aletuzumab and ATG – not recommended in pregnancy 51

52. Conclusions A successful outcome of pregnancy was shown with close monitoring and daily dialysis in a kidney transplant patient with thymoglobulin-resistant T-cell-mediated rejection. The risks and uncertainties of treating rejection episodes should always be discussed with and understood by the patient before an informed decision is made 52

53. Long term graft survival outcomes According to US National transplant Pregnancy Registry (NTPR) -Lower pre pregnancy graft function (pre pregnancy creatinine >105 mg/dl -Rising creatinine during pregnancy -Black women (13 %) within 2 years post pregnancy Are predictive of graft loss post partum, independent of hypertension ,preeclampsia ,and immunosuppression 53

54. Long term graft survival outcomes Post partum –there is restoration of immunity and reactivation of T –cell mediated activity and hypothetic increase in risk of allograft rejection Studies comparing RTR with pregnancy /without pregnancy – No difference in graft outcomes (1/2/5 years -5.8%/8.1%/6.9% respectively) Hence, due to absence of evidence –postpartum empirical increase in immunosuppression is not recommended 54

55. KDIGO guidelines : We suggest waiting for at least 1 year after transplantation before becoming pregnant, and only attempting pregnancy when kidney function is stable with < 1 g/day proteinuria. (2C) We recommend that MMF and MPS be discontinued or replaced with azathioprine before pregnancy is attempted. (1A) We suggest that mTORi be discontinued or replaced before pregnancy is attempted. (2D) 55

56. KDIGO guidelines : - Counsel female KTRs with child-bearing potential and their partners about fertility and pregnancy as soon as possible after transplantation . (Not Graded) -Counsel pregnant KTRs and their partners about the risks and benefits of breastfeeding. (Not Graded) -Refer pregnant patients to an obstetrician with expertise in managing high-risk pregnancies. (Not Graded) 56

57. Summary of Obstetric Management for Pregnancy After Transplantation After Transplantation 1. Delay conception for at least 1 year with adequate contraception 2. Assess and monitor graft function 3. Maintain immunosuppressive regimen 4. Manage comorbid conditions Preconception counseling 1. Discuss the effect of pregnancy on transplant function 2. Discuss the risks of maternal complications: hypertension, pre eclampsia ,diabetes, rejection and graft loss 3. Obtain good control of hypertension and diabetes 4. Discuss risks of neonatal complications prematurity and low birth weights 5. Modification of immunosuppressive regimen if necessary 6. Test for CMV and other potential infections 57

58. Summary of Obstetric Management for Pregnancy After Transplantation Early pregnancy 1. Accurate and early diagnosis and dating of pregnancy 2. Close monitoring of graft function and immunosuppressive drug levels 3. Surveillance for bacterial infection urine (C/S )and viral infection (CMV and HSV) 4. Fetal surveillance for malformations, fetal growth, and well being 5. Maternal surveillance for hypertension, gestational diabetes, and pre eclampsia 58

59. Summary of Obstetric Management for Pregnancy After Transplantation Labor and delivery 1. Aim to delivery at term 2. Perform cesarian delivery for appropriate obstetric reasons Postpartum 1. Monitor immunosuppressive drug levels and alter doses and regimen as necessary 2. Begin contraception when appropriate 3. The documented benefits of breastfeeding may outweigh the potential risks of infant immunosuppressive exposure 4. Mental health counselling if needed for postpartum depression 59

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