2. A 29-year-old lady transplanted 7 months ago. Excellent kidney function (S Cr is 78 µmol/L), currently on sirolimus 3 mg OD, Mycophenolate Mofetil 500 mg BD and 5 mg of prednisolone. Her blood pressure is well controlled by perindopril 8 mg OD. No proteinuria and no history of rejection. She has IUD fitted before her renal transplantation.
- Council this lady regarding contraception, pregnancy, and lactation.
Council this lady regarding contraception, pregnancy, and lactation.
Contraception :
Should on proper contraception at least 1 year with stable renal profile and no evidence of rejection , well control blood pressure.
Pregnancy
Only allow after 1 year with stable renal profile, no evidence of graft rejection, well control blood pressure without ACE inhibitor. Urinalysis no proteinuria. stable immunosuppressants without MMF.
MMF and ACE should stop 6/12 before pregnancy.
Lactation
Allow breast feeding except mother on MMF.
As regard to contraception
must be sequduled before transplant process and choose suitable method per each women where no interaction with immunosuppressive medication
As regard to pregnancy in transplant women must be sequduled before transplant
studies suggested to be from 1-2 years after transplant with review of immunosuppressive medication 6-8 month prior to pregnancy plan
Council regarding contraception
Kidney transplant recipients are advised to delay pregnancy for a minimum of 1 year after transplant to reduce potential neonatal and maternal complications.
There is no ideal contraceptive method; the best is to individualize the method of contraception according to a patient’s individual risk.
Different methods of contraception can be used after kidney transplant. Combined hormonal contraceptives are commonly used for their effectiveness but they increase risk of thromboembolism. The benefits of estrogen-based contraceptives in an uncomplicated stable transplant recipient who have no contraindication to use combined hormonal contraceptives likely outweigh the potential for harm.They
Intrauterine devices are an effective method of contraception and should be considered as a safe and an effective method after transplant with no evidence to suggest increased infection rate in kidney transplant recipients.
Permanent methods of contraception are valid options for couples who decide not to have children.
Council regarding pregnancy
The timing of conception is not definite, but there are some criteria should be met to insure the safety of pregnancy. These criteria involve:
MMF and mTOR are contraindicated during pregnancy, MMF should be discontinued at least six weeks, preconception, sirolimus should be stopped 12 weeks preconception.
The best safe maintenance regimen during pregnancy includes CNI, azathioprine and prednisone.
The patient is on perindopril which is an ACE inhibitor and it is contraindicated in pregnancy (in transplant or non-transplant woman) as it is related to fetal pulmonary hypoplasia and oligohydramnios.
Perindopril should be stopped and the patient is advised to postpone pregnancy for at least six weeks after its stoppage
To control the blood pressure in that patient, we can use Alpha-methyldopa, beta blockers (particularly labetalol), hydralazine, or dihydropyridine calcium channel blockers.
Council regarding breast feeding
Breast feeding should be encouraged
The available data that breast feeding in a female receiving CNI, azathioprine and steroids is fairly safe. Exposure to these drugs via breast milk is lower than in utero and has not been related to any side effects
There are insufficient data address the safety of MMF, mTOR inhibitors and belatacept. So, breastfeeding should be avoided in whom receiving these medications.
Counselling regarding contraception
· Contraception method has to be used before the transplant operation to avoid peri-transplant conception.
· No ideal method regarding contraception in the post-transplant period as data is limited.
· Barriers are associated with potential contraception failure.
· Combined pills(category4) are risky because of VTE. Progestin only pills is advisable by the AST as it’s deployed of the risk of VTE and BP exacerbation. Depot medroxyprogesterone IV contains only progestin with similar adverse effect of weight gain and drug-drug interaction with immunosuppressants. Transdermal patch is composed of combined estrogen and progestin.
· IUDs(category 2) are safe post-transplant although it’s associated with risk of infection and theoretically may decrease the effect of immunosuppression.
· Advise: to continue the contraception policy u sing IUD until having one year passed post-transplant.
Counselling regarding pregnancy
· Shouldn’t attempt to be pregnant before completion of one year post transplant. Graft function and immunosuppression level have to be maintained before planning for pregnancy, beside no proteinuria of more than 500 mg/day.
· Sirolimus have to be stopped with discontinuation of Mycophenolate 6 weeks before planning for conception. Her maintenance immunosuppression can be TAC beside AZA and Prednisolone.
· Perindopril has to be stopped as it’s teratogenic and to be replaced with CCB(Nifedipine) or Methyldopa.
Counselling regarding breastfeeding
· Breastfeeding is advisable and can be encouraged in the post-transplant period.
· TAC, CsA, AZA and Prednisolone are safe with breastfeeding.
· Breastfeeding is not advisable with the followings: MMF, MPA, Sirolimus, Everolimus and Belatacept
As regards fertility and Contraception:
As Fertility is reverted within the first 6 months after transplantation contraception is mandatory in the first year post kidney transplantation to avoid unplanned and not advisable pregnancy to minimize the risk of acute rejection and risk of graft loss and to maintain adequate renal allograft functions (no proteinuria and well-controlled blood pressure) in the first year post-transplantation.
Methods of contraception may be temporary or permanent
Permanent methods include vasectomy of males and tubal ligation of females.
Temporary methods include:
A-Combined oral contraceptives:
they contain both estrogen and progesterone with high efficacy with minimal failure rate But with some adverse effects of estrogen component with increased risk of thromboembolism, hypertension, frequencies of migraine and also interfere with the metabolism of CNI so levels of CNI should be carefully assessed.
B- Depot medroxyprogesterone acetate :
It is synthetic progesterone with high efficacy and a low failure rate of 2 % despite some adverse effects such as the increased risk of thromboembolism and osteoporosis, there are no associated drug interactions with other immunosuppressants.
C-Transdermal patch :
the patch contains both estrogen and progesterone with the same risk of potential hazards like combined oral contraceptives.
D-Progesterone only pills :
Despite the avoidance of adverse effects of estrogen, there is an increased incidence of failure rate in addition to the rate of amenorrhea by 5%.
E-Intrauterine devices :
two types were identified Copper and progestin IUDs with many advantages high success rate, no drug interaction, long-lasting, easy insertion, and reversible fertility after removal of IUD.
F- The vaginal ring :
It is a ring containing both etonogestrel and low concentrations of Ethinyl estradiol so minimal adverse effects of estrogen showed in patches and the combined pills.
G- Barrier methods:
They are less effective with high failure rates and include Condoms, sponge , cervical caps, and spermicidal gel.
As regards Breastfeeding :
Breastfeeding is not contraindicated in CKD or post-transplant female patients due to the importance of breastfeeding to infants however many challenges may face both mother and fetus. The importance of breastfeeding to infants especially exclusive feeding in the first 6 months of their life as decreases the risk of infection, normal growth, decreases the risk of allergies, autoimmune diseases (DM, Celiac, and inflammatory bowel diseases), improvement of infants cognitive functions, circadian rhythm, and good psychological support. However immunosuppressed transplanted females, can produce well immunocompetent milk for infants, the importance of studying the efficacy of immunosuppressant medications on infants is very important.
Steroids:
Less than 20 % (mostly of 5%: 25 % ) of Mothers’ serum Concentrations of steroids will reach infants so it is safe to be given a dose of less than 20 mg of prednisolone so it is considered to be safe for infants breastfeeding from mothers on Prednisolone therapy. CNI :
Levels of tacrolimus decreased to a very low level to be undetectable in infants’ serum 2-3 weeks after birth on the other hand the rate of ingestion from mother milk of cyclosporine can be detected to be 0.1 mg/Kg /day to a dose of 2-10 mg/kg/day ingested by his mother so very low serum concentrations to levels that undetectable in infants serum so it is considered to be safe on infants on breastfeeding from mothers. Mycophenolate Mofetil:
There were limited data on the effect of MMF on infants during breastfeeding, till now it is contraindicated to be taken by lactating mothers.
Azathioprine:
There were no detectable levels in infants’ serum or breast milk if given up to 200 mg /day so It can be considered to be safe for breastfeeding infants.
Sirolimus, everolimus, and belatacept :
Limited data and less than enough information on these medications, so it isn’t advisable to be taken
Modification of Drugs :
Corticosteroids: prednisolone and methylprednisolone can cross the placenta and be converted to inactive form with more negligible effect on the fetus however on the mother they affect glucose metabolism so increase the risk of gestation diabetes, so can be used but with strict follow-up of blood glucose levels however in the animal studies they were associated with increased risk of cleft palate.
MMF: can cross the placenta and cause fetal adverse effects, in addition, to increasing the risk of congenital malformations by 26 % as orofacial defects and other malformations like dysplastic nails, abnormal fifth finger, corpus callosum defect, myelomeningocele, VSD, tracheal atresia, and hydronephrosis .
Also, it increased the risk of abortion to 45 %, preterm birth to 62 %, and low birth weight to 31 % after MPA exposure.
So it’s a must to stop MMF and be replaced by azathioprine.
Sirolimus: Animal studies showed an increased risk of IUGR, defect of skeletal ossification, and an increase in the rate of abortions after drug exposure. In addition, animal studies showed that mTORi may affect fertility for both males and females leading to impairment of spermatogenesis, Dysmenorrhea, and hypogonadism.
Perindopril: ACE inhibitors and Angiotensin receptor blockers are contraindicated and should be stopped before or once pregnancy is diagnosed due to these potential teratogenicities in second and third trimesters causing fetal IUGR, PDA, and oligohydramnios.
Ref :
Yousif ME, BridsonJ,Halawa AContraception After Kidney Transplantation, From Myth to Reality: A Comprehensive Review of the Current Evidence:Experimental and Clinical Transplantation (2016) 3: 252-258
Hoeltzenbein M, Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A.2012;158A:588–596.
First, the patient should be notified that fertility will be restored within 1 to 2 weeks from transplantation.
Regarding contraceptive options for transplanting ladies:
Progesterone-only pills are preferred, as estrogen-containing pills carry a high risk for thromboembolism.
IUDs carry a risk for infection.
Barriers need good compliance to be effective.
If planning for conception certain precautions should be taken:
1. Better after the first year of transplantation.
2. Steroids can be safely continued.
3. MMF and mTORi are teratogenic and should be stopped 6 months before the planned pregnancy.
4. CNI is generally safe during pregnancy but CyA dose needs to be lowered, and tac may cause neonatal hyperkalemia.
Regarding breastfeeding:
CNI is excreted in milk, better to be avoided or avoid breastfeeding if it can’t be stropped.
As general saying for counseling a patient with renal transplantation done 7 months ago:
_ pregnancy should be postponed till at least 1 year post transplant as in KDIGO guidelines
_ as transplant patients regain their fertility after transplantation so contraception should be planned soon after transplantation.
_ as regard best contraceptive
method, IUD whether old cupper or hormone releasing (progestin releasing) can be used with high efficacy and lower risk of hypertension and thromboembolic complications compared to oral contraceptive pills especially those containing estrogen.
_ as regard planning for pregnancy after 1 -2 years post transplantation, we should make sure that our patient has stable graft function ( serum creatinine less than 1.5 mg/dl together with absence or low grade protinuria less than 0.5 gm in 24 h urine collection) in addition to absence of any feto-toxic viral infections or immunosupressives therapy.
_ in this context, shift from teratogenic sirolimus to CNI ( tacrolimus) and shift from MMF to azathioprine ( at least 6 weeks prior to conception) in addition to being sure that the patient has stable graft function on the new IS regimen.
_ blood pressure control must be achieved by safe and non teratogenic drugs as ( methyl Dopa , hydralazine or labetalol ) and be sure that it is well controlled on new drugs.
_ also the patient must be fully informed about the effect of pregnancy on transplantation including hypertension and increased risk of protinuria. In addition, the risk of rejection and infections.
_ The effect of transplantation on pregnancy as preterm labour and intrauterine growth restriction should be taken into consideration.
_as regard lactation, alos CNI , azathioprine and steroids seem to be safe and with low level in breast milk so breast feeding should be encouraged as it is the best for infant growth and mother wellbeing with no harm.
_ the missing point here, why the patient is maintained on CNI free regimen, so the file of the patient should be reviewed for any previous history of infection or CNI side effects as CNI induced TMA
_ in addition, the original kidney disease must be reviewed as some diseases such as lupus nephritis and anyiphospholipid syndrome may be a catastrophic in pregnancy with higher risk of fetal loss ( recurrent abortions and still birth) so early use of aspirin is essential. Also diabetes needs special care of mother during pregnancy.
_ close monitoring of mother and fetus during pregnancy is crucial together with close monitoring of graft function every 4 weeks in 1st trimester then every 2 weeks therafter.
Contraception:
This lady is a young with 7 month of kidney transplantation . by time it is supposed that normal menstrual cycling in started, which means that patient has a chance of getting pregnancy at any time , unless the patent using contraceptive measure ( IUD in this case ).
Intrauterine devices (IUDs) are category 2 .this method carry no additional risk of pelvic infection . Advantages : easy insertion, long lasting, low failure rate (Pearl index, 1-3), no drug – drug interaction, No thromboembolism , ] cost-effective , long-lasting methods .
Contraindications : history of ectopic pregnancy and pelvic inflammatory condition. Copper IUD and the levonorgestrel-releasing IUD has both effectivity and safety. Although there is no good evidence , the immunosuppressive medication may decrease the efficacy of IUD .
Pregnancy :
The recommended time of post transplant gestation is about 1 year post transplant . As this patient is only A seven month post transplant ,therefore it recommended to postpone the pregnancy till 1 year post transplantation . after 1 year when the graft function is stable (no rejection ) the immune suppressant medication should be changed to pregnancy friendly drug ( CNI , Azathioprine,prednisolone )The mycophynolate and sirolimus are contraindicated in pregnancy should be changed before pregnancy . Graft should be remain stable for 3 month after this change in immune suppressive medication before gestation .
This patient using perindopril ( an ACE I ) for her blood pressure control , although her blood pressure is well controlled but the ACEI are contra indicated in pregnancy . This should be changed to safe drugs such as (methyldopa, labetolol ,hydralazine,calcium channel blocker).
Lactation:
The drugs that are unsafe during gestation Are unnecessarily to be unsafe during breastfeeding. Safety of each drug :
1- Steroid : In one study by Greenberger et al. report the safety of these drug in breastfeeding ,and there is very low insignificant level of steroid in milk , and showed no side effect or harm to baby .
2- Azathioprine:many researchers studies the different metabolite level in blood and found that there were either absent or it is present in a clinically insignificant amount in milk . as a conclusion this drug is safe in breastfeeding .
3- Cyclosporine (CsA).This drug is excreted in milk in a bout one sixth of mothers drug level.in another study the milk cyclosporine drug level were >2% of mother blood CsA drug level . One study found that CsA milk level was lower than detection level in 6 infants , with no any reported nephrotoxic
References :
1- Yousif ME, Bridson JM, Halawa A. Contraception after kidney transplantation, from myth to reality: a comprehensive review of the current evidence. Exp Clin Transplant. 2016 Jun 1;14(3):252-8.
2- Silvi Shah, Renganathan Lalgudi Venkatesan.Pregnancy outcomes in women with kidney transplant: Metaanalysis and systematic review.BMC Nephrology volume 20, Article number: 24 (2019).
3- Sameh M, Mohsen E k, Jon J K, Ahmed H, Ajay S. Safety of Breastfeeding by Mothers on Immunosuppressive Medication for Renal Transplantation: Obsession, Myth and Truth. JOJ uro & nephron. 2017; 3(3): 555612. DOI: 10.19080/JOJUN.2017.3.55561
· Contraception : most patients on dialysis are infertile . after transplant fertility can return quickly contraception should be planned , IUD is safe has no drug interaction compound pills have alot of complication also can be used .Pregnancy can be after 1y with stable graft function and no protienuria . pregnancy :should be planned, close flow up for the lady and the baby immunosuppression TAC and prednislone and azthioprine are safe .Change anti-hypertensive to {methyldopa , niphedipine and hydralazine } lactation :Breast feeding is not contraindicated post renal transplant , immunosuppression execrated in small amount in breast milk {TAC ,Prednislone and Azathioprine } .
·
Councilling the patient
Reproductive success following kidney transplant is common and possible outcome for recipients. However, care is needed to protect against maternal and/or fetal complications.
Contraception
Optimal contraception is generally initiated before transplant in women of childbearing age. Peritransplant period is not a good time for pregnancy because of the use of potentially teratogenic medications that may harm the fetus. These drugs cannot be avoided either because of the crucial immunosuppression that is needed to protect the kidney graft. HEnce, American society of transplantation consensus conference report recommends against the usage of barrier contraceptive methods or IUD devices but instead suggests progestin only oral contraceptives or estrogen/progestin as long as hypertension is well controlled with 2 or less medications. However, this does not mean that IUD devices are not optimal methods of contraception, but simply that there is a chance of failure of contraception with this route. This I would council the patient so that she knows the risks and benefits of each method of contraception. \
Pregnancy
Next I would council the patient regarding optimal timing of pregnancy post transplant. This would depend on the circumstances, physical condition and mental conditions of the recipient.
The American society of transplantation has replaced the traditional recommendation of waiting for 2 years after successful transplantation. The current recommendation or consensus opinion suggests that if graft function is optimal then patient can proceed with pregnancy. The conditions stipulated by the American society for stable graft function include the following :
If patient conditions and required parameters are stable and within acceptable limits, then patient can plan for pregnancy as early as 6 months post transplant. The important factor to keep in mind is that pregnancy post kidney transplant should be planned according to the health condition of the recipient, and not a surprise pregnancy. This is essential for good outcome of both the mother and the baby.
Lactation and breastfeeding
Breastfeeding can be considered in this patient if it can be shown that level of exposure to immunosuppressive medications does not result in risk to newborn, either in the immediate period, or later during childhood. Informed decision has to be made regarding whether to breastfeed the infant or not.
This patient is on a regimen of Tacrolimus, prednisone and MMF. Tacrolimus and prednisolone get excreted in very small amounts in breast milk. Steroids, azathioprine and CNI are relatively safe for the recipient to breastfeed.
Drug serum levels need to be monitored and reviewed more frequently for breastfeeding mothers and blood sample of the infant may be needed to be checked. Careful and regular evaluation of the mother and the infant is crucial to achieving normal physical and mental growth. Nephrotoxocity in infant of CNI treated mothers and hematological complications in infants of azathioprine treated mothers are essential to be kept in mind and looked for.
This patient is on MMF, which has been proved to be unsafe for breastfeeding in animal studies. Further investigation is needed to consider whether this patient can breastfeed following delivery if she continues to be on MMF.
References :
Current clinical scenario:
29y old lady,
Renal transplant recipient 7 months ago
normal GFR
Maintenance IS: Sirolimus, MMF, Prednisolone
Hypertension: on Perindopril 8mg od
Counseling:
KDIGO guidelines recommend pregnancy can be planned at least 12 months after transplant with stable good graft function, no proteinuria, controlled hypertension.
European guidelines recommend planning pregnancy at least 24 months post transplant.
IUD is an acceptable, cheap effective method of contraception, I would recommend that she continue on it with regular follow up of pregnancy test.
other methods of contraception could be discussed if IUD is not tolerated or it should be removed at least after one year post Tx for planned gestation.
immunosuppressive medications:
MMF should be stopped at least 6 weeks before planned pregnancy, it should be switched to Azathioprine.
Sirolimus to be switched to CNI (tacrolimus or Cyclosporin), it is clear from the available data why she is on Sirolimus?.
for Hypertension, Perindopril should be stopped, and switched to safer anti- hypertensives like labetalol, methy dopa, calcium channel blockers and hydralazine.
breast-feeding: is encouraged, the amount of IS medication excreted in milk is very negligible.
Contraception
Although the IUD does not present drug interactions, is cheap and easily accessible, an ultrasound is important periodically to ensure its positioning.
Pregnancy
The ideal is to wait for at least one to two years after transplantation to proceed with the pregnancy. However, before ending contraception, there is a need to change medications, since MMF is potentially teratogenic and we need immunosuppression under control already in the proposed regimen (probably CNI, azathioprine, and corticosteroids).
Antihypertensive treatment should also be modified, giving priority to safer medications for pregnancy such as methyldopa or hydralazine.
Lactation
There is no need for special care beyond those already established during pregnancy. Avoid drugs that have no record of safety in newborns (such as MMF).
Council this lady regarding contraception, pregnancy, and lactation :
1. Regarding Contraception:
Fertility is usually restored few weeks up to 6 months post transplantation and contraception should be discussed prior to transplantation to avoid unplanned pregnancies in the first 1-2 years post transplantation.
This young lady is already using an IUD which is the preferred modality of contraception among many transplantation professionals being easy to use, lack of drug interactions, low failure rate around 0.5% and restoration of fertility upon its removal.
However, if complications arise like recurrent UTIs of pelvic inflammatory diseases. she can be switched to an alternative hormonal method if she continues to have a stable graft function with well controlled Bp and no evidence of thrombosis or hyper-coagulable state.
2. Regarding Pregnancy:
A .Pregnancy is encouraged with low rates of acute rejection rates and favorable long term graft and maternal survival compared to general population.
However, She requires counseling about increased maternal risks for pre-eclampsia, gestational diabetes, UTIs and other viral infections. Moreover, There is increased fetal risks for pre-term delivery, Low birth weight, fetal growth retardation and still birth. Accordingly, modifiable risk factors needs to be optimized like Bp, proteinuria and pre-pregnancy creatinine level(<133 micomol/L)
B. Timing of pregnancy:
She is still young and only 7 months post-transplant .pregnancy should be avoided in the first year post-transplant according to ACT and KDIGO guide lines and 2 years according to EBP guide lines. Additionally, she should continue to have stable graft functions with S creatinine < 133 micromol/L with no or minimal proteinuria, no rejection episodes for 1 year and no feto-toxic infections like CMV from 6 months up to 1 year.
C. Choice of immunosuppression:
she need to continue on a safe immunosuppressive regimen by introducing Tacrolimus to replace MMF (at least 6 weeks) and Sirolimus (at least 12) which are teratogenic. She need to keep on that protocol between 3-6 months and observe stability of graft function. After that contraception can be stopped and give her a chance for conceive..
D. Regarding co-morbidities including Bp control and monitoring blood sugar:
She need to stop Perindopril at least 6 weeks before pregnancy and switch it to an alternative safe drug like labetalol, methyl dopa , nifedipine or hydralazine. Blood sugar monitoring will be required as gestational diabetes increases with steroids and Tacrolimus.
3. Regarding Breast feeding:
Breast feeding is safe and encouraged on prednisolone, Tacrolimus and Azathioprine regimen which are excreted in very small amounts in breast milk, So, the exposure is less than in utero exposure. Captopril and Enalapril do not pass in breast milk and can be used post-partum to control hypertension and proteinuria.
References:
1. Lecture of pregnancy and lactation in kidney transplantation.
DR; Ghada Ankawi –Assistant professor of Medicine and consultant Nephrologist
2. And book of kidney transplantation. 6th edition
The reproductive mileu is better after renal transplantation and pregnancy should be planned with pre pregnancy counselling involving a multi disciplinary approach with obstetricians, pediatricians and the nephrologists….
Contraception:
It should be planned before transplantation and counselling should be given to the couple planning transplantation…IUD are the preferred method of contraception as it has many advantages…It is cheap, ease of use, with low failure rate, does not interact with other immunosuppressive drugs, has no side effects…The ease of restoration of fertility upon removal of the IUD makes it an easy choice for use…It has a small risk of pelvic inflammatory disease and contraceptive failure…OCP are safe after a certain period of transplantation i.e usually after 6 weeks to 2 months of surgery…The risk of thrombosis with OCP poses a risk of graft thrombosis and other thrombotic events..they should be given to patients with no risk of hypercoaguable states….Couples are encouraged to use male contraception also in addition to the IUD or the OCP…..
this patient is already using an IUD..she has to continue to use this for another 5 months till 1 year…It is recommended to post pone pregnancy till 1 year after transplant
Pregnancy:
The timing of the pregnancy should after 1 year of renal transplantation….The European guidelines mention 2 years after renal transplantation…this time frame is essential for the optimal functioning of the graft….It is crucial to ascertain that there is stable graft function with creatinine <1.5mg%, no proteinuria, no acute rejection episodes in the past year, no teratogenic drugs or fetotoxic infections….
Pre pregnancy counselling has to be done and educated about the increased risk of hyperfiltration and proteinuria in pregnancy as it is a hyperdynamic circulation….AS such there is no difference in the long term outcome of the graft after pregnancy..But renal transplantation itself is a risk for pre term delivery, pre eclampsia, IUGR, low birth weight and still birth….There is increased risk of GDM, infections…There has been increased reports of CS in renal transplant patients….
Switching of the immunosuppressive drugs should be done in the pre pregnancy counselling level itself….MMF is teratogenic and should be switched over to azathioprine aleast 6 weeks to 3 months before conception….Sirolimus is to be avoided in pregnancy and should be stopped…However there are conflicting reports on successful pregnancies after the use of mTR inhibitors….Steroids can be continued….The metabolism of tacrolimus will be altered in pregnancy due o high blood volume and high CYP3A5…Frequent monitoring is needed to prevent nephrotoxicity in the pregnant recipient….
Lactation:
Minimal levels of the drugs namey CNI, azathioprine and prednisolone have been documented and it is safe to breast feed while a patient is on the above drugs….
2.Krishna A. Agarwal, Martha Pavlakis, Sexuality, Contraception, and Pregnancy in Kidney Transplantation. Kidney Medicine. Volume 3, Issue 5, 2021,
Pages 837-847
3.Emrah Gunay, Cenk GokalpContraception and Child Birth in Kidney Transplant Patients: What Are We Missing as Physicians? Turkish Journal of Nephrology. 10.5152/turkjnephrol.2020.3980
The transplant recipient in this case scenario has multiple issues:
1) A reproductive age group female
2) Transplant done 7-month back
3) On Sirolimus and MMF, which are teratogenic
4) On anti-hypertensive perindopril, which is fetotoxic
5) Having an IUD fitted prior to transplant.
As per the KDIGO guidelines for management of transplant patients, it is suggested to wait at least 1 year after transplantation before becoming pregnant, and only attempting pregnancy when kidney function is stable with proteinuria of less than 1 gram per day.(1)
The immunosuppression should be modified with discontinuation or replacement of MMF with azathioprine before pregnancy is attempted and mTOR inhibitors are also preferably discontinued or replaced. The patient should be on stable maintenance immunosuppression with no history of graft rejection in last one year, no current or recent fetotoxic drugs and medications with have no or well-controlled hypertension.
Counselling regarding contraception:
All female transplant recipients in the reproductive age group must be counselled regarding contraceptive use in the pre-transplant period as well as post-transplant due to restoration of fertility, which may happen as early as in the first month post-transplant.
The options for contraception in transplant recipients include.
· Intrauterine devices (IUD), which could be copper or levonorgesterol based
· Progesterone only pills
· Combined hormonal contraception (oral contraceptive pills, transdermal patch, vaginal ring)
· Barrier methods: should be used as adjunct with other forms.
· Hysteroscopic sterilization and tubal ligation: As permanent measures.
The options for contraception should be discussed as per the cafeteria approach and the patient should be helped in taking a decision regarding the form of contraception best suited for her.(5)
IUDs have low failure rates. All hormonal methods are safe, but combine hormonal contraception should be avoided in patients with uncontrolled hypertension, hypercoagulable states, history of stroke or thrombosis.
Counselling regarding pregnancy:
Patients should be counselled regarding the risks of pregnancy to the graft, to the baby as well as maternal risks. These include:
Risks to graft: Data has shown that there is no significant effect of pregnancy on risk of rejection as well as the long term graft outcomes. The graft outcomes depend on the graft function prior to pregnancy, with increased risk in patients with higher baseline creatinine, prior rejection episodes, proteinuria and hypertension.(6)
Risk to the baby: There is increased risk of pre-term delivery (40-50%), fetal growth restriction, low birth weight spontaneous abortion and stillbirth in transplant recipients. (7) The risks are more with serum creatinine >1.7mg/dl, presence of hypertension and proteinuria.
Risks to the mother: There is increased risk of pre-eclampsia by 6-7 times, gestational diabetes mellitus and UTI by 2 times and the incidence of caesarean section for delivery is more than 50% in these patients.(7)
So, the pregnancy of the patient should be planned by following certain rules:
· Wait minimum one year on stable graft function
· Change immunosuppression: sirolimus to Tacrolimus, MMF to azathioprine prior to conception.
· Plan to conceive only 12 weeks after changing these immunosuppressive medications.
· Change Perindopril to labetalol or alpha methyldopa
· Use barrier methods as an adjunct to the IUD in the meantime
· Prior to pregnancy, get evaluation of infections: CMV, BK virus
· Vaccination prior to pregnancy: HBV, HPV, Tetanus, Influenza, pneumococcal
· Once pregnant: Close follow up with CBC, renal function, liver function, urine routine, urine culture if pus cells present (treat asymptomatic bacteriuria), CNI drug level, blood sugars and blood pressure.
· Mode of delivery: Vaginal preferred, but caesarean section as per indication.
Counselling regarding lactation:
Mothers on immunosuppression should be encouraged to breastfeed the child. Corticosteroid, cyclosporine and tacrolimus secretion in breastmilk is very low and the exposure of these drugs through breastmilk is much less as compared to the in-utero exposure.
References:
1) Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
2) McKay DB, Josephson MA, Armenti VT, August P, Coscia LA, Davis CL, Davison JM, Easterling T, Friedman JE, Hou S, Karlix J, Lake KD, Lindheimer M, Matas AJ, Moritz MJ, Riely CA, Ross LF, Scott JR, Wagoner LE, Wrenshall L, Adams PL, Bumgardner GL, Fine RN, Goral S, Krams SM, Martinez OM, Tolkoff-Rubin N, Pavlakis M, Scantlebury V; Women’s Health Committee of the American Society of Transplantation. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant. 2005 Jul;5(7):1592-9. doi: 10.1111/j.1600-6143.2005.00969.x. PMID: 15943616.
Dear Dr Farag
This is a copy and paste from a colleague’s reply (Amit Sharma). This is very unethical; therefore, you have been referred to the Academic Integrity Officer for investigation
See below
Contraception
It should be maintained firmly for at least 1 year post Tx ( or 2 years according to European guidelines ) .
IUD being a favourable choice as it has low failure rate , no interaction with medications , rapid restoration of conceivability after removal, with no increase in the rate of infections .
We may need to consider usind another method of contraception besides IUD .
Pregnancy
Allowed after 1 year of Tx ( 2 years in European guidelines ) , so pregnancy is not advised at this given time but can be prepared for later on
Chech the vaccination status and update it ( if not already done pre Tx ) , give the following : influenza , pneumococcal , HBV , HPV and Tetanus Vaccines
fetal effects also to be discussed as there is increased rate of preterm delivery , spontaneous abortion , still births , IUGR & low birth weights
Lactation:
🍁contraception:
Post tx women should undergo a strict contraceptive method to ensure no pregnancy for at least 1 year and preferred 2 years as in European guide lines
IUD is one of the safest methods with excellent contraception and minimal interactions with the immunosuppressive drugs , or double contraceptive methods can be used .
🍁Pregnancy:
*at least 1 year post Tx ، preferred 2 years .
*stable RFTS creat less than 1.5 , minimal or no proteinuria
*off nephrotoxic medications
MMF (8 weeks) and sirolimus (3 months) should be be stopped and replaced by CNIs and steroids .
*infection free especially CMV ,BK
*vaginally delivery is preferred unless obstetric contraindications
🍁Lactation :
Lactation should be encouraged and Immunosuppressive medications are minimally excreted in milk but MMF and Balatacept should not be used during Lactation.
Council this lady regarding contraception, pregnancy, and lactation.
*regarding contraception:
The incidence of pregnancy associated risks after transplantation are more in the first year so she should be advised to wait till the end of the first year.
Adverse pregnancy outcomes of induced abortion rates and neonatal deaths were highest in the 2–3 year interval following kidney transplant as compared to 3 year interval.
The ideal time of conception in women with renal transplant is between 1 and 2 years after transplantation according to guidelines by American Society of Transplantation, whereas European best practice guidelines recommend delaying pregnancy for a period of 2 years after transplantation.
-IUD is already present before transplantation its safe and effective with no drug interaction with immunosuppressive medication and minimal risk of thromboembolism with very low failure rates.
But i will advised her for another non Hormonal method of contraception as condom or vaginal ring
*regarding pregnancy ;
Timing of transplantation is crucial post transplantation periods 3years are associated with more risk.
Before planning of pregnancy she must have stable graft function s creat < 1.4 mg/dl ,24 hour urine protein < 500mg ,controlled BP.
History of rejection episodes, viral infections must be discussed before pregnancy.
*Regarding immunosuppression
-Steroid is safe with pregnancy
-She is on CNI free protocol but no data available about the cause.
-Immunosuppression treatment should be changed 6 weeks before pregnancy
-Sirolimus is not safe with pregnancy and should be switched to tacrolimus.
-MMF is teratogenic
– at time of pregnancy switch prindopril to methyl dopa with close monitoring of Bp
The recommended maintenance immunosuppression in pregnant women is calcineurin inhibitors (tacrolimus/cyclosporine), azathioprine, and low dose prednisone; and it is considered safe.
* regarding lactation;
Breastfeeding is not contraindicated after transplantation .
Some immunosuppressive medication heve little or no secretion in the breastmilk
Steroid, CNI, and azathioprine are safe with lactation
Reference
Silvi Shah, Renganathan Lalgudi Venkatesan.Pregnancy outcomes in women with kidney transplant: Metaanalysis and systematic review.BMC Nephrology volume 20, Article number: 24 (2019).
Silvi Shah et al.Overview of Pregnancy in Renal Transplant Patients.Int J Nephrol. 2016.
Free PMC article
Sexual dysfunction improves after the transplantation and contraception should be planned prior to transplantation.
Contraception:
Pregnancy:
Lactation:
This patient is only 7 month post kidney transplantation, so a suitable contraceptive method should be discussed with her and the different ways of contraceptions regarding its saftey, accuracy, interactions with immunusuppression drugs, advantages and disadvantages : oral combined hormones, depot medroxyprogestrone acetate, etonogestrel implant, transdermal patch, progestin-only pills, intrauterine deviceses, the vaginal ring and barrier methods.
The planning for pregnancy should be after 1 year post transplant with a sstable graft fuction of a creatinine less than 1.5 mg/dl.
Drug adjustment : the minimal peroid of stopping MMF is 6 weeks and for Sirolimus is 12 weeks before attempting pregnancy. So contraception can only be stopped after these peroids.
MMF can be changed to AZA, and Sirolimus can be changed to tacrolimus at the lower therapeutic level.
The anti hypertensive drug also need to be changed to Methyldopa, labetolol or calcium channel blocher.and to have a good control.
Vaccination before pregnancy for influenza, pneumococcus, Hepatitis B and tetanus.
Meticulous follow up during pregnany is mandatory with obsteterician and transplant unit.
Dicussion for the mode of delivery, that normal vaginal delivery is possible if no obstetrical indications.
Breast feeding should be encouraged.
Female patients especially in child bearing age with ESRD will presented with a lot of multiple hormonal disturbances that affect their reproductive functions and pregnancy rates and it’s complications so the only chance for giving normal pregnancy or with less complications is by getting kidney transplantation and for those patients the decisions of pregnancy,timing, risks , possible complications and even the type of contraceptive all should discussed with the patient even before kidney transplantation.
After transplantation by 1-2 months reproductive functions are restored so contraception should be started immediately after transplantation especially for well functioning graft women.
Intrauterine device is the safest and effective method for contraception but pelvic infection should be taken in consideration, another types like oral preparations,patch and vaginal ring can be used in transplant recipient women with specific precautions like CNI level monitoring,hormonal preparations can cause hypertension and thromboembolism so in these situations progesterone only preparations are preferable.
Most of the studies and recommendations go with that conception can be occurs after 1-2 years post transplant with specific criteria to decrease the pregnancy risk , some of these criteria in addition to the pregnancy time post transplant are: graft function should be normal or near normal,absence of proteinuria , normal blood pressure or well controlled hypertension,normal aalograft doppler ultrasound, safe immunosuppressants regimen and no acute rejection attack.
There are a higher rate of complications and risks associated with pregnant women with history of kidney transplantation like :
Urinary tract infections and pyelonephritis
Preeclampsia and preterm birth
Spontaneous abortion and ectopic pregnancy
Pre maturity and intrauterine growth restrictions.
So for this lady she has to wait 1 year post transplant to get pregnant and her IS should be adjusted.
She is on MMF should be stopped few months before conception, she is on sirolimus also should stopped 6 wks before conception and she is on perindopril that should be switched to methyldopa ,so her medications can be changed to CNI ,azathioprine and keep her on prednisolone with methyldopa.
Lactation can be encouraged after delivery and can be kept on the same regimen.
Reference
_ Danovitch GM. Handbook of kidney transplantation. 6th ed Philadelphia,P A :Lippincott Williams and Wilkinson;2017.
the discussion should include
Ø Assessment of a woman’s desire to achieve or avoid pregnancy,
Ø discussion of fertility
Ø education regarding pregnancy risks
Ø ideal timing of pregnancy( she has been transplanted only 7 months ago and the guidelines recommend to wait at least one year after transplantation, have stable allograft function with no proteinuria, no recent episodes of rejection or infection, and well-controlled medical conditions (hypertension, diabetes) to achieve optimal pregnancy outcomes)
Ø the potential teratogenic effects of immunosuppression and review medications several months before attempting conception. she is on:
1- mycophenolate mofetil which is contraindicated in pregnancy as it causes spontaneous abortion in 50% and fetal malformations in 26% including microtia, cleft palate, and esophageal, cardiac, and kidney
abnormalities .she must discontinue mycophenolate and start Azathioprine at least 6 weeks preconception. So she need to keep her IUD and use another method with to guarantee no conception
2- sirolimus which has limited data on its safety during pregnancy and lactation . Prednisone, azathioprine, and calcineurin inhibitors are generally considered safe)
3- her perindopril need to be stopped and changed into other non teratogenic antihypertensive with close follow up of her blood pressure
Ø during pregnancy monitoring of blood pressure and glucose, urine culture, and calcineurin inhibitor trough levels. Follow-up is recommended every 2–4 weeks during the first and second trimesters, and every 1–2 weeks thereafter. Increased activity of the drug-metabolizing enzyme cytochrome P4503A, increased maternal blood volume, and decreased albumin and hemoglobin concentrations during pregnancy can result in lower whole-blood calcineurin-inhibitor concentrations, with relatively unchanged unbound (active) drug concentrations. Clinically, tacrolimus concentrations are measured in whole blood; dose increases required to maintain therapeutic levels may result in elevated unbound concentrations and possible toxicity in women with significant hypoalbuminemia or anemia. Trough concentrations should be followed postpartum, particularly for those in whom tacrolimus dose increases were made during pregnancy
Ø contraceptive options.
Ø Other options of surrogate pregnancy, and adoption.
Ø risks for mother, baby, and graft that are specific for each woman.
Ø Outcomes are affected by maternal age, genetic causes of kidney failure, sensitization, maternal comorbidities and life expectancy, infection history, medications, social support, and medical resources available.
Ø She can nurse her child as most of the immunosuppressant are not or little expressed in the mother milk.
What are the missing pieces in her data you ned to know to make a proper counseling?
We need to know why she is on m TORi as she might have CNI toxicity at low dose, viral infection or malignancy.
Christina L. Klein, Michelle A. Josephson, Post-Transplant Pregnancy and Contraception, CJASN Jan 2022, 17 (1) 114-120; DOI: 10.2215/CJN.14100820
Timing of pregnancy ?
At least one to two years post transplant .
Recommendation :
stable graft Cr less than 1.5 mg /dl.
CMV and PK virus screening and pretransplant virological state .
Teratogenic drug nee to be stop :
MMF stop for six week before pregnancy
sirolimus 3 month before pregnancy
azathioprine safe alternative to MMF
patient should be 3 month follow up stable graft after change immunosuppressive drug .
patient should know that risk of preeclampsia and gestational hypertention higher than general population .
There is risk of preterm labor ,low ,birth weight and abortion.
long term graft and patient survival the same for general population .
Contraception:
CDC recommendation for contraception were divided according to stable versus complicated graft function (complicated graft function was defined as acute or chronic graft failure or rejection).
In women with stable graft function all hormonal methods are categorized as safe.
Estrogen –containing therapy should be avoided for 6 weeks’ post-surgery due to high risk of thrombosis
Combined hormonal contraception is not recommended in women with complicated graft function, uncontrolled hypertension, history of stroke, thrombosis, or hypercoagulable state diabetes, lupus, and prior deep venous thrombosis.
The IUD are preferred among many transplant professionals because it has many Advantages (including low failure rate, ease of use, and lack of immunosuppressive drug interactions and systemic side effects), along with restoration of fertility upon removal. (2)
In this case IUD is the best choice
Counselling for pregnancy
Patients should be counselled about all risks of pregnancy to her health, the baby as well as the graft
Effect of pregnancy to the mother: diabetes mellitus, hypertension, pre-eclampsia, UTI delivery by caesarean section is more than 50% in these patients
Effect to baby: increased risk of spontaneous abortion, induce abortion, stillbirth pre-maturity, fetal growth restriction, low birth weight.
Effect on graft no significant effect of rejection and the long-term graft outcomes unless with certain condition such as higher baseline creatinine, prior rejection episodes, proteinuria and hypertension have been shown determinant of graft outcome.
Pregnancy planning should start after one-year post transplantation
They should not conceive until they meet the following criteria
1.otimal graft function defined as s creatinine less than 33umol/l(less than1,5mg/DL) with no or minimal proteinuria.
2.No rejection episodes for one year
3, No concurrent fetotoxic infections such as CMV (min 6 month -1 year)
4.No teratogenic or fetotoxic medication.
5.immuno suppression is stable at maintenance level. (1)
In this case Change of immunosuppression maintenance from sirolimus to Tacrolimus, MMF to azathioprine
Change Perindopril to, labetalol or alpha methyldopa
Close follow up for IS and keep in the lower limit on trough level in non-pregnant women
All vaccines should have been given pre-transplant. If not, it should be given before pregnancy these include:
• Influenza
• Pneumococcus
• Hepatitis B
• HPV
• Tetanus
Breastfeeding
Considered safe on prednisone, Azathioprine, & CNI as minimal transfer into breastmilk is documented. Overall, infant’s exposure to immunosuppression with breastfeeding is lower than in utero exposure
REF:
1.Lecture of pregnancy and lactation in kidney transplantation by
DR; Ghada Ankawi –Assistant professor of Medicine $ consultant Nephrologist
1. Post-Transplant Pregnancy and ContraceptionChristina L. Klein and Michelle A. Josephson, CJASN January 2022, 17 (1) 114-120; DOI: https://doi.org/10.2215/CJN.14100820
CONTRACEPTION
The patient is already on intrauterine devices which is an effective method of contraception and should be considered as a safe, long lasting ,had low failure rate and an effective method after transplant with no evidence for increased infection rate in kidney transplant recipients. Also the effect is reversible after IUD removal, and no drug interaction with immunosuppression.
Other methods which can be used in transplant patients include:
· Progesterone only pills
· Combined hormonal contraception (oral contraceptive pills, transdermal patch, vaginal ring)- has been shown to cause uncontrolled hypertension, hypercoagulable states, history of stroke or thrombosis.
· Barrier methods
Pregnancy
Kidney transplantation offers a better quality of life and providing the possibility of successful pregnancy for women of childbearing age. All her drugs should be reviewed several months before attempting conception, patient should be advised to avoiding pregnancy for at least 1 year after receiving kidney transplant beside having stable allograft function with no proteinuria, no recent episodes of rejection or infection, and well-controlled medical conditions (hypertension, diabetes) to achieve optimal pregnancy outcomes ,prednisone is safe during pregnancy while MMF is contraindicated and should be substituted with azathioprine at least 6 weeks before conception. There is limited data about mTORi and better to be replaced with CNI. ACEi are teratogenic and should be replaced with safe drugs as methyldopa or, beta blockers (particularly labetalol), hydralazine, and dihydropyridine calcium channel blockers are all safe in pregnancy and can be used. Nondihydropyridine calcium channel blockers (such as diltiazem) are better avoided during pregnancy because of an increment in the CNI levels. Low dose aspirin decrease risk of gestational HTN and preeclampsia. She should know that there is an increase in GFR in the first trimester and sustained during pregnancy, absence of this increase may indicate poor prognosis. She should know she will need intensified clinical and lab. monitoring with follow up every 2-4 weeks in first and second trimester and every 1-2 weeks thereafter. Acute rejection rates are similar to that in general population. The recommended maintenance immunosuppression regimen in pregnant transplant recipients is the combination of a CNI (either tacrolimus or cyclosporine), azathioprine, and low-dose prednisone Kidney transplantation doesn’t affect vaginal delivery and caesarian section is not routinely indicated, during surgery care should be taken to avoid injury of transplanted ureter.
Breastfeeding:
Emotional, nutritional, and immunologic benefits of breastfeeding have been well-documented and valuable for these newborns.
Breast feeding is safe in kidney transplant recipients who is taking prednisolone, azathioprine, and tacrolimus or cyclosporine.
REFERENCES:
1-Chandra A, Midtvedt K, Åsberg A, Eide IA. Immunosuppression and reproductive health after kidney transplantation. Transplantation. 2019 Nov 1;103(11):e325-33.
2-Sameh M, Elkossi M, Kim JJ. Safety of breastfeeding by mothers on immunosuppressive medication for renal transplantation: Obsession, myth and truth. JOJ Uro and Nephron. 2017;3(3):1
Council this lady regarding contraception, pregnancy, and lactation.
*regarding contraception:
It should be discussed before transplant as she will regain her fertility post transplant.
So pregnancy must be postponed at least 1-2years post transplant .
Methods of contraception :
-IUD :
It is preferred method as it is safe and effective with no drug interaction with IS medications , minimal risk of thromboembolism
-Barrier methods : Condom , vaginal ring
– All other hormonal methods are safe with stable graft function, it’s important to avoid estrogen-containing contraception for six weeks post-surgery because it’s thrombogenic effect.
combined methods are preferred as IUD + Condom or vaginal ring
*regarding pregnancy ;
as mentioned above the ideal time of pregnancy after 1- 2 years post transplant and stable graft function s cr less than 1.4 and proteinuria less than 500 mg with no rejection episode in the last 1 year or infection and controlled Bp and after proper time of IS modifications as follow :
Immunosuppression treatment should be changed 6 weeks before pregnancy
-Steroid is safe with pregnancy
-Sirolimus is not safe with pregnancy and should be switched to tacrolimus.
-MMF is teratogenic and should be replaced by Azathioprine .
– Change prindopril to methyl dopa with close monitoring of Bp.
* regarding lactation;
Breastfeeding is not contraindicated after transplantation .
Some immunosuppressive medication heve little or no secretion in the breastmilk
Steroid, CNI, and azathioprine are safe with lactation
Council this lady regarding contraception, pregnancy, and lactation.
Regarding the pregnancy councilling,I well tell her it is better to wait until complete one year post transplant without any complication like rejection or infection then we will shift from MMF to azathioprine and mTOR to CNI,and wait for another 6 month to make sure you had stable graft function in this new regimen and if you had no proteinurea and good control of blood pressure after changing the ACE inhibitors to beta blocker or methyldopa we can prepare you to conceive
Regarding pregnancy
Follow up should be in a close manner with to control the blood pressure and to prevent the proteinuria but she should know about the risk of pre eclampsia,gestianal diabetes,preterm labour and c/section and the fetal complication like low birth weight,congenital anomalies,abortion
Regarding the Brest feeding
No risk of breastfeeding with this new regime it consider safe
Contraception:
It is advised that women in the childbearing age receive counseling about contraception before and after kidney transplantation since sexual function improves in a few weeks after transplantation.
This is important because some immunosuppressive drugs, for example MMF, seems to decline in serum estrogen level and may reduce the efficacy of estrogen containing contraceptives. On the other hand, it is recommended that female transplant recipients should avoid pregnancy during the first posttransplant year. The optimal form of contraception is not clear now, and so women should be informed about various contraceptive methods and their advantages and limitations.
Long-acting reversible contraception methods include IUDs and the progestin-releasing implant. Women with kidney transplants can use either copper or levonorgestrel-releasing IUDs, the progestin-only methods, or estrogen-containing methods. although it is preferred to delay the start of estrogen-containing contraceptives until six weeks posttransplant because of the increased risk of thromboembolic events and to avoid progestin injection because long-term use is associated with reduced bone density. In women with complicated KT, IUDs can continue, not initiate it. They can use progesterone only methods, not estrogen containing contraceptive.
For this patient, IUD is the appropriate contraceptive method until the time of decision for pregnancy.
Pregnancy:
She should be informed that the pregnancy in KT recipients is high risk and it needs close observation and management with a high-risk obstetrician in conjunction with a transplant nephrologist.
The pregnancy during the first year after transplantation is considered a high risk (higher risk of rejection and infection), so the pregnancy is better to postpone to the second posttransplant year.
The patient should be evaluated about the history and presence of CMV infection. If it is present, pregnancy is advised 1 year after CMV infection.
If the patient is not vaccinated against influenza, pneumococcus, hepatitis B, HPV, and tetanus, she should receive them.
If there is not an obstetrical indication, she can have vaginal delivery without significant risk for her allograft.
Because of good kidney function (Cr< 1.5), absence of proteinuria, controlled hypertension, and no history of previous rejection, her pregnancy may be associated with good outcomes.
Kidney allograft outcomes in pregnant transplant recipients with a well-functioning allograft appear to be comparable with that of nonpregnant transplant recipients.
Drugs:
Immunosuppressive drugs, particularly CNIs should be monitored closely and should be kept stable at the maintenance level and similar to prior transplantation levels.
Fetotoxic and teratogenic drugs should be discontinued before transplantation, so in this patient, MMF, sirolimus, and perindopril should be discontinued and substituted with safe drugs in pregnancy.
The use of MMF and mTOR inhibitors (sirolimus and everolimus) is contraindicated in pregnancy. MMF should be discontinued at least six weeks prior to conception because of its association with severe structural malformation. In addition, MMF exposure in the first trimester of pregnancy has been associated with spontaneous abortion.
Sirolimus should be discontinued at least 12 weeks prior to conception.
The recommended maintenance immunosuppression regimen in pregnant transplant recipients is the combination of a CNI (either tacrolimus or cyclosporine), azathioprine, and low-dose prednisone.
After adjustment of immunosuppressive drugs, it is better to postpone pregnancy for a few weeks for close monitoring of graft function because of the increased risk of rejection following modification of immunosuppression.
Because of significant fetal risk, ACEi and ARB, should be discontinued as soon as is planned for pregnancy, and at least 6 weeks prior to conception.
Methyldopa, beta blockers (particularly labetalol), hydralazine, and dihydropyridine calcium channel blockers are all safe in pregnancy and can be used. Nondihydropyridine calcium channel blockers (such as diltiazem) are better avoided during pregnancy because of an increment in the CNI levels.
Breastfeeding:
Breastfeeding can be suggested in kidney transplant recipients taking prednisolone, azathioprine, and tacrolimus or cyclosporin.
Dear All
There was a brain storming question raised by Professor Ala earlier please look into it and give your comments this is because you all gave your well organized answers and looking into this question would train you to be decision makers.
We need to know more information about her ethnic back ground as we learned that specific ethic background associated with poor maternal and fetal outcome also the primary disease in particular APL , SLE , HUS , comorbidity ( HTN , DM , Obesity)
CMV , EBV viral status of D/R and the risk of reactivation if D+VE /R- Status , Induction type ( ATG , alemtuzumab likely as she is CNI free protocol and any recent rejection episodes ? why she is on CNI free protocol ? and low dose MMF in less than 1 year , any recent active viral infection in particular CMV , or PTLD ? or CNI induced TMA ?
regardless she is only 7 months post transplantation with effective IUD i would advised against pregnancy till rule out any possibility of above mentioned risks and consider waiting for at least 1-2 years as she is still young and planned her pregnancy with the lowest risk from all aspects ( maternal , fetal , graft outcome ).
Regarding contraception:
This lady being 29 yr. old in child bearing period, with history of 7 months renal transplantation is advised to avoid pregnancy till the passage of at least 1 or 2 years post transplantation.
Best method of good efficacy, least drug interactions, maintaining patient’s adherence would be IUD.
Regarding pregnancy:
Timing: one or two years would be better to wait after renal transplantation provided that the patient’s renal functions are stable of sCr less than 1.5 mgldcl. , stable immunosuppression regimen, no proteinuria, no history of rejection episodes, no history of infections as CMV or other infections that may be encountered by fetal or graft complications.
Vaccinations: should be provided properly with special concern to Influenza, Pneumococcus, Hepatitis B, HPV, and Tetanus.
Modification of immunosuppression: both sirolimus and MMF should be replaced by CNI and azathioprine being more safe to mother, graft and fetus with almost no teratogenic side effects and less rejection incidences. This switch should also be done before pregnancy is expected by at least 3 to 6 months to be considered safe and with close monitoring of renal functions and drug level status.
Modification of hypertensive medication: ACEI and ARBS are contraindicated in pregnancy, methyl dopa is best tolerated with the advice of minimal salt intake to keep her blood pressure controlled.
Counselling the patient and her partner:
They should be informed by all the risks of pregnancy (incidence of rejection, fetal complications as premature labor, preeclampsia, and increased risks of pregnancy associated conditions as HTN, gestational diabetes, urinary tract infections or obstruction).
They should also be aware of shifting the medications, the mode of delivery, breast feeding options after delivery.
Frequent monitoring during pregnancy is a must :Every 2–4 weeks during the first and second trimesters, and every 1–2 weeks thereafter, with special concern to: BP control, Graft function, UA, CNI level,FBS ,GTT , CBC, Liver function tests and CMV PCR once every trimester.
Regarding lactation period:
Breast feeding is considered safe on the same immunosuppressive regimen of pregnancy which should be encouraged for its advantages as less financial burden on the family, high immunological value for the fetus, establishing good maternal fetal relationship and convenience.
Also the doses of immunosuppression may be increased after delivery, requiring close monitoring of renal functions, patient’s adherence to treatment and drug level.
Monitoring of complications of pregnancy if existed as gestational DM or other new complications or events.
Thank you
◇Women who receive transplants require
contraception counseling because of the teratogenicity of immunosuppressant medications and the risks posed by pregnancy after transplant [1].
◇When counseling this lady:
_____________________________
Regarding contraception and pregnancy I will tell her that:
▪︎She hould wait at least 1 year before attempting to become pregnant, and then should do so only when cleared by the transplant team and obstetrician, with close monitoring.
▪︎Fertility often returns within a few months after transplant [2],
▪︎A successful pregnancy outcome is most likely when a minimum of 1 year intervenes between transplant and conception [1].
▪︎She should use 2 contraceptive methods concurrently. So, it is better to keep the IUD in place and use condoms until she complete more than one year from the time of transplantation.( an advantage of IUD is that the effect is reversible after removal, and immunosuppression drug interaction
is not a concern and it is not associated with increased risk of thromboembolism) [4].
▪︎She should meet certain clinical prerequisites after transplant before she conceive, as outlined by the American Society of Transplantation [5].These include:
– No rejection within the previous year
– Adequate and stable graft function (eg,
serum creatinine < 1.5 mg/dL and urinary
protein excretion < 500 mg/24 hours)
– No acute infection that might affect the
fetus.
– Maintenance immunosuppression at
stable dosages.
▪︎Careful planning is a must if she wants to get pregnant.
▪︎ She must meet with their transplant team and obstetricians early to allow time for the care team to adjust the type and dosing of immunosuppressant drugs, to ensure stable graft function, and to optimize any current chronic medical conditions before conception.
▪︎Before she get pregnant she must control her blood pressure with no or low proteinuria (≤500 mg) [6].
☆Concerning her medication:
▪︎The teratogenic risk of mycophenolate mofetil is well established in studies documenting specific congenital malformations and fetal loss in the first trimester [3]. So, at least 3 to 6 months before conceiving, she needs to change MMF to azathioprine .
▪︎The antihypertesive drug Perindopril is not recommended in pregnancy. It can affect her baby's kidneys, therefore should be changed to another medicine (The drugs most commonly used—methyldopa, labetalol, and nifedipine—are widely accepted as safe in pregnancy).
2. Lactation
▪︎ It is safe for her to breastfeed while on immune suppression that includes steroids, cyclosporine, tacrolimus or azathioprine.
▪︎Little information is available on the use of mycophenolate and sirolimus during breastfeeding.
▪︎The amounts of prednisolone in breastmilk are very low and no adverse effect have been reported in breastfed infants with maternal use of any corticosteroids ( for eg prenisolone) during breastfeeding.
▪︎Finally I will tell her that the blood levels of the immunosuppression drugs which she is taking should be checked more frequently during breastfeeding.
_______________________________
Ref:
[1]Mina Al-Badri, Juliana M. Kling, et al. "Reproductive planning for women after solid organ transplant ". Cleveland Clinic Journal of Medicine. Sept 2017, 84 (9) 719-728; DOI: https://doi.org/10.3949/ccjm.84a.16116
[2] McKay DB, Josephson MA." Pregnancy in recipients of solid organs: effects on mother and child". N Engl JMed 2006; 354:1281–1293.
[3] Hoeltzenbein M, Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A 2012; 158A:588–596.
[4] Mohamed E. A.Yousif. Julie M. Bridson, Ahmed Halawa. "Contraception After Kidney Transplantation, From Myth to
Reality: A Comprehensive Review of the
Current Evidence"
[5] Deshpande NA, Coscia LA, et al." Pregnancy after solid organ transplantation: a guide for obstetric management. Rev Obstet
[6] Silvi Shah and Prasoon Verma. "Overview of Pregnancy in Renal Transplant Patients".
Thank you
1-Counseling regarding contraception ;
This lady should be counseled that , the intrauterine devices is an effective method of contraception and should be considered as a safe and an effective method after transplant with no evidence to suggest increased infection rate in kidney transplant recipients.
2-Counseling regarding pregnancy ;
This lady should be counseled about appropriate time to conceive . 1 to 2 years following successful transplantation is considered to be the best time to conceive. Graft function is considered to be optimum when serum creatinine was <1.5 mg/dl, with <500 mg/24-h protein excretion.
Also she should be counseled about the associated risks. Pregnancy in renal transplant recipients is associated with increased risk of graft rejection leading to renal damage and also at risk of developing gestational hypertension, preeclampsia, infections, preterm deliveries and premature rupture of membranes.
Her immunosuppressive medication should be modified prior to conception . Sirolimus should be switched to CNI and mycophenolate should be switched to azathioprine at least 3 months before conceveive .The other none immunosuppressive agent should be reviewed .In this patient perindopril should be switched to none teratogenic anti hypertensive agent .
3-Counseling regarding lactation;
Emotional, nutritional, and immunologic benefits of breastfeeding have been well-documented and could be valuable for these newborns.
Concern must be directed at the effects of the child’s exposure to immunosuppressive agents excreted into the breast milk.
Breastfeeding could be considered in transplant recipients if it can be shown that the level of exposure does not result in risks to the newborn, immediately and throughout childhood.
Sirolimus should be switched to CNI and mycophenolate should be switched to azathioprine
Reference ;
1- Christina L. Klein and Michelle A. Josephson et al.Post-Transplant Pregnancy and Contraception.CJASN January 2022, 17 (1) 114-120.
2- McKay D, Josephson M. Reproduction and transplantation: report on the AST consensus conference on reproductive issues and transplantation. Am J Transplant. 2005;5:1–8. doi: 10.1111/j.1600-6143.2005.00969.x.
3- Pezeshki M, Taherian AA, Gharavy M, et al. Menstrual characteristics and pregnancy in women after renal transplantation. Int J Gynaecol Obstet. 2004;85(2):119–125. doi: 10.1016/j.ijgo.2003.09.013.
Thank you
Contraception planning
Contraceptive methods:
1-permanent:
a-Female tubal ligation
b-male Vasectomy
2-Temporary:
a-IUD- preferred among many transplant professionals
Advantages
• Low failure rate
• Ease of use
• Lack of IS drug interactions and systemic side effects
• Restoration of fertility upon removal
b-All hormonal methods are categorized as safe in women with stable graft function (CDC contraception recommendations were separated by stable vs “complicated” graft function), but not complicated graft function, uncontrolled HTN, history of stroke, thrombosis, or hypercoagulable state.
Estrogen-containing therapy should be avoided for 6 weeks post surgery due to high risk of thrombosis.
c-Barrier methods.
Women should not conceive until at least one year post- transplantation while meeting the following criteria:
1. Optimal graft function defined as serum creatinine < 133 umol/L (< 1.5 mg/dl) with no or minimal proteinuria.
2. No rejection episodes for a year.
3. No concurrent fetotoxic infections such as CMV (min 6 months – up to a year).
4. No teratogenic or fetotoxic medications.
5. Immunosuppression is stable at maintenance level.
Consistent with KDIGO guidelines, whereas European guidelines recommend 2 years
MMF should be switched to Azathioprine for a few months (minimum 3 months, but preferably 6 months)
Women may attempt to conceive only if graft function remains stable on the new regimen
-All vaccines should have been given pre-transplant. If not, it should be given before pregnancy these include:
• Influenza
• Pneumococcus
• Hepatitis B
• HPV
• Tetanus
Follow-up is recommended every 2–4 weeks during the first and second trimesters, and every 1–2 weeks thereafter
• BP control
• Graft function- U/E, HCO3, UA, PCR & CNI level
• Comorbidities- FBS every visit + GTT every trimester • Complications (anemia/ preeclampsia)- CBC, LFT
• CMV PCR once every trimester
Breastfeeding
Considered safe on prednisone, Azathioprine, & CNI as minimal transfer into breastmilk is documented
Overall, infant’s exposure to immunosuppression with breastfeeding is lower than in utero exposure
Thank you
Excellent
I will advise this patient to avoid pregnancy for a period of more than a year post kidney transplant as recommended by KIDGO guidelines. I have to make sure that graft function is normal. There is optimal renal function with no proteinuria and patients medical conditions like hypertension in this case is well controlled . This patient already has a IUD in situ and I will advise her to continue with that though failure rate can be around 0.5%. I will advise her to see contraception councillor as a multimodality approach.
As regards immunosuppressant, MMF and Sirolimus should be avoided as they are teratogenic. MMF and Sirolimus should be stopped at least 3 months before planning a conception . I will shift the patient on CNI, Azathiapime and prednisolone at that time.
I will stop perinidopril and start a safer antihypertensive like methyldopa , nifedipine or labetalol. steroids are safe , however I will keep an eye on sugar levels.
I will encourage her for breast feeding after successful completion of pregnancy. The above mentioned immunosuppressive agents and antihypertensive agents will not cause any harm to baby by breast feeding as their levels will be very low in breast feed
Thank you
Excellent
Council this lady regarding contraception, pregnancy, and lactation :
contraception :
– Patient has IUD fitted before her renal transplantation: she can continue with the IUD method and there is no increased risk of infection.
-The advantages of the IUD include easy insertion, long-lasting, low
failure rate, the effect is reversible after IUD removal, and immunosuppression drug interaction is not a concern in women with kidney transplants.
-It is not associated with an increased risk of thromboembolism.
-Copper IUD has an effective duration of 10 years, and the levonorgestrel-releasing intrauterine system lasts for 5 years .
Pregnancy:
– The ideal time of conception in women with renal transplant is between 1 and 2 years after transplantation according to guidelines by the American Society of Transplantation, whereas European best practice guidelines recommend
delaying pregnancy for 2 years after transplantation to minimize the risk of adverse events due to pregnancy, as possible risks of acute rejection and graft loss and prematurity will be less after this time.
-Adequate graft function before conception (no proteinuria and well-controlled blood pressure) is the key factor toward a safe pregnancy because these 2 conditions are associated with poor outcomes for the fetus and pregnant mothers after kidney transplants.
– Her maintenance immunosuppression should be switched to CNI, Azathioprine, and Prednisolone under careful supervision and monitored for 3months.
Hypertension control:
-Drugs that have been consistently shown to be safe should be used;
these include methyldopa, hydralazine, and labetalol.
-perindopril should be switched to one of these drugs if she is pregnant.
Lactation:
-She can lactate her baby with the same maintenance immunosuppression( CNI, Azathioprine, and Prednisolone .)
Thank you
The lady has issues regarding:
It was never mentioned about her previous pregnancy and child, so I assume its first pregnancy. So, its understandable that patient might be desperate to get pregnant. So, we need to keep this at the hind of mind.
KDIGO guidelines suggested to wait at least 1 year after transplantation before becoming pregnant, and only attempting pregnancy when kidney function is stable with proteinuria of less than 1 gram per day. BSH guideline suggest even longer 2 years post Tx prior to pregnancy planning
The immunosuppression should be modified with changing MMF with azathioprine at least 6 weeks before pregnancy is attempted and mTOR inhibitors are also preferably discontinued at least 8-12 weeks prior to pregnancy.
The patient should be on stable maintenance immunosuppression with stable graft function for at least one year.
Counselling regarding contraception:
Transplant recipients in the reproductive age group must be counselled regarding contraceptive use in the pre-transplant period as well as post-transplant due to restoration of fertility, which may happen as early as in the first month post-transplant.
The options for contraception in transplant recipients are:
· Intrauterine devices (IUD), which could be copper or levonorgesterol based
· Progesterone only pills
· Combined hormonal contraception (oral contraceptive pills, transdermal patch, vaginal ring)- has been shown to cause uncontrolled hypertension, hypercoagulable states, history of stroke or thrombosis.
· Barrier methods: should be used as adjunct with other forms.
· Hysteroscopic sterilization and tubal ligation: As permanent measures.
The patient chose IUDs which is good choice because of low failure rates.
Counselling regarding pregnancy:
Patients should be counselled regarding the risks of pregnancy to the graft, to the baby as well as maternal risks. These include:
Effect on graft: Generally no significant effect on risk of rejection and the long-term graft outcomes. Graft function prior to pregnancy, with increased risk in patients with higher baseline creatinine, prior rejection episodes, proteinuria and hypertension have been shown determinant of graft outcome.
Effect to baby: increased risk of pre-term delivery (40-50%), foetal growth restriction, low birth weight spontaneous abortion and stillbirth in transplant recipients. The risks are more with serum creatinine >1.7mg/dl, presence of hypertension and proteinuria.
Effect to the mother: risk of pre-eclampsia by 6-7 times higher, gestational diabetes mellitus and UTI by 2-fold and the incidence of caesarean section for delivery is more than 50% in these patients.
Plan for the patient
· Pregnancy planning should start after one year post transplantation
· Change immunosuppression maintenance: sirolimus to Tacrolimus, MMF to azathioprine
· Change Perindopril to CCB,labetalol or alpha methyldopa
· Continue the IUD for now, barrier methods has high failure rate
· Prior to pregnancy, get evaluation of infections such as CMV, BKV
· Vaccination prior to pregnancy: HBV, HPV, Tetanus, Influenza, pneumococcal
· Close follow up with after the change in IS
· Mode of delivery: as per indication at the time of birth or complications
Counselling regarding lactation:
encouraged to breastfeed the child.
Corticosteroid, cyclosporine, and tacrolimus secretion in breastmilk is negligible
Klein CL, Josephson MA. Post-transplant pregnancy and contraception. Clinical Journal of the American Society of Nephrology. 2022 Jan 1;17(1):114-20.
Ong SC, Kumar V. Pregnancy in a kidney transplant patient. Clinical Journal of the American Society of Nephrology. 2020 Jan 7;15(1):120-2.
Yousif ME, Bridson JM, Halawa A. Contraception after kidney transplantation, from myth to reality: a comprehensive review of the current evidence. Exp Clin Transplant. 2016 Jun 1;14(3):252-8.
Chandra A, Midtvedt K, Åsberg A, Eide IA. Immunosuppression and reproductive health after kidney transplantation. Transplantation. 2019 Nov 1;103(11):e325-33.
Sameh M, Elkossi M, Kim JJ. Safety of breastfeeding by mothers on immunosuppressive medication for renal transplantation: Obsession, myth and truth. JOJ Uro and Nephron. 2017;3(3):1.
Thank you, Excellent
Fertility rate improved after kidney transplant within months and there’s high risk effects of pregnancy on graft and may lead to graft loss due to increase incidence of uncontrolled hypertension and develops of preeclampsia; also evidence of teratogenic effects of immunosuppressive drug on foetus with high risk of prematurity.
So ladies with kidney transplant should counselling regarding conception from one to two years after transplant to avoid unplanned pregnancy and should monitoring her blood pressure and her medication 3 months before pregnancy to avoid teratogenic effects of immunosuppressive agents.
Methods of contraception:
Permanent by tubal ligation but still history of ectopic pregnancy.
Another permanent option is male vasectomy
Temporary method is combined oral hormonal therapy (oestrogen & progesterone ); but there is risk of hypertension and arterial and venous thrombosis and exacerbation of migraines.
Progesterone only pills but still risk of thrombosis
vaginal ring
intrauterine contraception device (IUCD) safe and effective method but there’s risk of infection and bleeding.
Male and female condoms but high risk of failure rate
it’s not safe and not effective.
Lactation:
All immunosuppressive agents excreted in breast milk in small level and not side effects on babies.
But cellcept should shift to azathioprine during pregnancy and lactation because it’s effects on foetus
Sirolimus contraindicated in pregnancy and lactation.
Rituximab should be avoiding in pregnancy and lactation.
References:
Mina Al-Badri, MBCHB, Juliana M. Kling, MD, MPH and Suneela Vegunta, MD; Reproductiveplanning for women after solid-organ transplant:Cleveland Clinic Journal of Medicine September 2017, 84 (9) 719-728; DOI: https://doi.org/10.3949/ccjm.84a.16116
Thank you
Council this lady regarding contraception, pregnancy, and lactation :
1- for contraception :
2- for pregnancy :
3- for lactation :
Thank you, WELL DONE
1.She had IUD in situ, and this is one of the safest birth control method in trans
plants patient with low failure rates
2.IUD can be remove once pregnancy is planned
3.She should continue with IUD at the moment because pregnancy is not recomm
ended now
Planned pregnancy is associated better outcomes.Many transplant ladies had succ
essful transplant. At the same time risk associated with pregnancy must be disscus
s ;
1.Pregnancy outcomes ; live births, miscarriages, induced abortion,still birth,and ecto
ptic pregnancy
2.Maternal outcomes ; Preeclampsia, pregnancy induced hypertension, gestational
diabetes, and CS
3.Fetal outcomes ; preterm birth, low birth weight, neonatal deaths
4.Graft outcomes ; acute rejection, graft failure post-pregnancy
Once pregnancy is agreed on ; Perindoperil should stop and change to safest anti
hypertensive e.g. Nifedipine at least 6 to 8 weeks prior to conception
MMF must be stop at least 3 to 6 months prior to conception and replaced by
azathioprine
Siruolimus must be stop and change to CNIs e.g. Tacrolimus
Low dose aspirin 75 mg should be use before 16 weeks to protect against
preeclampsia
Steroids needs may go up the time of delivery
Close monitoring and follow up
Screening for UTIs & treatment of asymptomatic bacteruria
Fetal monitoring & surveillance
The need for MDT team around her
Prednisolone, CNIs, & Azathioprine are known to be safe during lactation and she
should continue to take them
CMV status has to checked as high risk patients(D+,R-) may requires regular PCR level
Thank you
Pre-pregnancy counselling Should take place before transplantation
1*Women should not conceive until at least one year posttransplantation while meeting the following criteria:
1-Optimal graft function defined as serum creatinine < 133 umol/L ( 140/90 & target 120- 140/ 80-90 mmHg
Stop fetotoxic anti-HTN 6 weeks prior to pregnancy
Safe drugs during pregnancy are
Methyldopa
Bblocker (labetalol)
Non-DHP CCB, amlodipine
Hydralazine
*Gestational DM
GTT should be performed every trimester
*Infections- UTI
Urine analysis done every 2-4 weeks. If positive, urine culture should be sent.
Treatment should be for 2 weeks followed by prophylactic antibiotics for the rest of the pregnancy (European best practice guidelines).
*Infections- CMV
Donor +ve to Recipient –ve caries the highest risk.
Screen every trimester with maternal CMV PCR as indicated
If positive, fetal surveillance using ultrasound should be done
Reported cases on successful treatment with ganciclovir in combination with IVIG.
*Anemia
Treatment is the same as non-pregnant transplant recipients
4*Delivery
Vaginal delivery if possible, C-section only if there’s an indication
Stress dose steroids only in Complicated pregnancy or higher prednisone dose
Typical regimen
– IV Hydrocortisone 50 mg before the surgery followed by 25 mg q 8 hours for 24 hours post
5*Breastfeeding
Breastfeeding is Considered safe on prednisone, Azathioprine, & CNI as minimal transfer into breastmilk is documented and In CNI absorption from breast milk was negligible
6*contracetion
IUD- preferred method among many transplant professionals
Because of it’s low failure rate and easy to use
Inaddtion there is no IS drug interactions and the mother can restore fertility after removal of the IUD
Other hormonal methods are considered as safe in women with stable graft function but we can’t use in complicated graft function, like uncontrolled HTN, history of stroke, thrombosis, or hypercoagulable state and estrogen -containing therapy should be avoided for 6 weeks post surgery due to high risk of thrombosis.
Reference
Lecture of
GhadaAnkawi, Assistant Professor of Medicine & Consultant Nephrologist KAU, Jeddah, Kingdom of Saudi Arabia. Pregnancy and lactation in Kidney Transplantation.
Thank you
Contraception and pregnancy:
·
· IUD to be kept for 1 to 2 years from time of transplantation.
· 3 to 6 months before conceiving, some medication changes are needed ; change MMF to azathioprine so as to avoid its side effects on the
fetus, Perindopril not recommended in pregnancy to be replaced e.g by methyldopa.
· Graft function stability to me maintained by blood pressure control ,with minimal or no proteinuria before pregnancy.
Lactation
Breast feeding with intake of azathioprine, steroid, & tacrolimus, is safe,with frequent blood level monitoring
· Rarely, the drug level in breast milk & in the infant’s blood may need to be
checked.
· Sirolimus ; mTOR inhibitor safety during breastfeeding is not well established
Reference
Shah, S., Venkatesan, R.L., Gupta, A. et al. Pregnancy outcomes in women with kidney transplant: Metaanalysis and systematic review. BMC Nephrol 20, 24 (2019). https://doi.org/10.1186/s12882-019-1213-5
. Sameh Morgan et al. Safety of Breastfeeding by Mothers on Immunosuppressive Medication for Renal Transplantation: Obsession, Myth and Truth
JOJ uro & nephron 3(3): JOJUN.MS.ID.555612 (2017)
Thank you
one up to six months postrenal transplant fertility resume so the patient should be counselling before transplantation and initiation of contraceptive should take place timely and safely.
partner should attend counselling as to share appropriate contraceptive method with his partner
before conception should have some criteria as to avoid complication for mother and foetus such as:.
1-stable graft function and serum creatinine 133umol/l(less than 1.5mg/dl) and no or mild proteinuria..
2-no rejection for one year.
3-no infection as CMV(6 month to one year).
4-time of conceive is after postrenal transplant is one year(2 years by European Best practise guidelines).
medication
mycophenolate need to be stop 6 week before conception.
convert sirolimus to CNI 12 week before conception.
converted ACE to calcium channel blocker 6 week before conception
IUD is suitable contraception
breast feeding Azathioprine ,prednisolone all these medication are safe during pregnancy .
Thank you
1- Contraception after kidney transplantation
Early concealing is very important as fertility is rapidly restored to normal within 1- 6 months post transplantation so contraception is needed to
A- avoid unplanned , unadvised pregnancies
B- improve pregnancy out come and decrease maternal complications
Methods of contraception
I- permanent methods
a- female tubal ligation :
SE : increase risk of ectopic pregnancies
b- male vasectomy .
II- Temporary methods
a- IUD ( copper and progestin ) :
Advantages : effective contraceptive method , no drug interaction with IS and no increased risk fo HPN , thromboembolism
SE : increased risk for pelvic infections specially immediately after insertion
b- Hormonal methods
1- compined estrogen and progesterone oral pills
advantages : low failure rates
SE : increased risk for HPN , thromboembolism and migraine , drug interaction with IS as they are metabolized by CYP 450 3A4
2- Depot medroxy progesterone acetate : intradermal injection every 3 months , no interaction with IS
3- Transdermal patches
4- Vaginal rings
5- Etonogesterol implant
c- Barrier methods
a- Male condom
b- Female condom
c- Diaphragm with spermicide
d- Cervical cap with spermicide
2- Pregnancy postransplantation
Pregnancy should be avoided during fisrt year post transplant as there is increased risk for graft rejection and dysfunction
Best timing for pregnancy
1- After fisrt year posttransplantation with stable graft function ( no rejection episodes for at least 1year , Sc r <1.5 mg/dl )
2- No proteinuria
3- Well controlled BP
4- Replace teratogenic and fetotoxic IS with more safe ones. Replace MMF and sirolimus with azathioprine and CNI
Pre pregnancy preparation
1- Vaccination status : all following vaccines should be given before pregnancy ( influenza , pneumococcal , hepatitis B , HPV and tetanus).
2- Bp ; should be well controlled and replace teratogenic drugs as ACEI with safe ones as non dihydropyridines
3- IS; replace teratogenic drugs (MMF , sirolimus) with azathioprine and CNI
4- US assessment of the graft
5- Base line investigations include : CBC , KFT , FBS and HbA1C
Urine analysis , C& S and proteinuria level , PCR for BK and CMV
During pregnancy follow up
Regular checking every 2-4 weeks during 1 st and 2 nd trimester and every 1- 2 weeks after that
Breast feeding
Is considered safe as milk excretion of IS is lower than the mount that crosses placenta.
Thanks Fatima
# Council this lady regarding contraception, pregnancy, and lactation.
** contraception:
* IUDs are an ideal option for transplanted women
* Early concerns of IUD failure and theoretic risk of pelvic inflammatory disease was not been supported by observational studies.
#Advantages
*Low failure rate
*Ease of use
*Lack of IS drug interactions and
systemic side effects
*Restoration of fertility upon removal
*levonorgestrel IUD Mirena has the additional advantage of reducing heavy menstrual bleeding
** pregnancy:
* Kidney transplantation offers a better quality of life and providing the possibility of successful pregnancy for women of childbearing age.
* The fertility can be efficiently reverted within 1 to 6 months after KT, so early counselling involve the husband and using of contraception is need to reduce the risk of unplanned pregnancies, maternal complications and improve the outcomes after KT.
* A period of 1 – 2 year after KT is sufficient to minimize the risk of adverse events of pregnancy wich are:
# Maternal Risk
*Preeclampsia 24 – 36 %
*Gestational DM 8%
*UTI 14.6% – 42%
*Other infections, including CMV
*C-section (> 50%)
# Fetal Risk
*Higher rates of preterm delivery 40 – 50%
(Risk factors: maternal HTN & sCr > 1.7)
*Higher rates of FGR
(Risk factors: maternal HTN, proteinuria & CNI use)
*Higher rates of low birth weight (average 2.4 Kg)
*Spontaneous abortion: 13-26%
(Risk factors: MMF exposure)
*Higher rates of still birth
#To minimize these risk we need:
1) Timing of pregnancy
Women should not conceive until at least one year posttransplantation while meeting the following criteria:
1. Optimal graft function defined as serum creatinine < 133 umol/L (< 1.5 mg/dl)
with no or minimal proteinuria.
2. No rejection episodes for a year.
3. No concurrent fetotoxic infections such as CMV (min 6 months – up to a year).
4. No teratogenic or fetotoxic medications.
5. Immunosuppression is stable at maintenance level.
Consistent with KDIGO guidelines, whereas European guidelines recommend 2 years
2) Switching immunosuppression to pregnancy safe regimen effectively
*Immunosuppressive drugs carry risks for the fetus, but the risks of prednisone, azathioprine, cyclosporine, and tacrolimus are surprisingly low.
* MMF is teratogenic should be switched to
Azathioprine for a few months
(minimum 3 months, but preferably
6 months)
*Perindopril should be change to methyldopa to control her blood pressure
3)Proper follow up before, during, & after pregnancy
• BP control
• Medications review
• Vaccination status
• US with Doppler for kidney/graft.
Graft function
CNI level
Comorbidities & Complications (anemia/ preeclampsia /CMV )
** lactation:
* Breast feeding is not considered to be absolutely contraindicated
* It is safe with prednisone, Azathioprine & CNI as minimal transfer into breastmilk is documented
*Infant’s exposure to immunosuppression with breastfeeding is lower than in utero exposure
*Breast fed infants did not have higher tacrolimus levels compared
with bottle-fed infants
# References
Dr/ Ghada's Ankawi Lecture
Shah S, Verma P. Overview of pregnancy in renal transplant patients.
International journal of nephrology. 2016;2016:4539342.
2. Saha MT, Saha HH, Niskanen LK, Salmela KT, Pasternack AI. et al. Time course of
serum prolactin and sex hormones following successful renal
transplantation. Nephron. 2002;92(3):735–7.
Thank you
Dear all, with such maintenance therapy, just 7 months post-transplant, do you think it would be easy to plan for conception after 1 year of transplant ?
What are the missing pieces in her data you ned to know to make a proper counseling?
Yes, thanks dr:ALa.
I think the question here .
Is the patient started Siroliums as de novo protocol or shifted from tacrolimus for any cause?
History should cover all side effects of tacrolimus specially if patient developed TMA or history of biopsy before.
Over all we should wait at least 1year or as KDIGO after 2 years.
European guidelines recommend 2 years
For me,I think the question about conception is straightforward because she already had a an IUD fitted in & she is 7 months postransplant with stable graft function,& possibly had regained her fertility.
And importantly no mention about any problems with her IUD,so I would simply advice her to keep it in place to complete 1 to years from time of transplantation.
Thank you Dr ALa
she is in first year post transplant on CNI free protocal we need to know is its planned for CNI free protocal from the begining ? WHY ? Primary disease like HUS ,APL ,SLE , comorbidities like DM , uncontrolled HTN , metabolic syndrome or just shifted to mTOR based with MMF based on complications with CNIs including CNI toxcity or drug induced TMA , PTDM , uncontrolled HTN , BKV ?
Dear Dr. Mohammed Saad, Dr. Mohamed Mohamed, and Dr. Saja
Thank you for the valid points about the primary cause and looking why she is on two antiproliferative drugs without CNI.
Still there is other missing piece of data that can change the decision and may avoid endagering the patient unnecessary risky endavour of pregnancy!
Thanks a lot Dear Prof.Alaa
In addition to what mentioned by Dr. Saja above, I add these few points:
# mTOR‐I regimens are associated with a reduced risk of CMV infections.
# mTOR‐I with an anti-metabolite increases the risk of graft loss & acute rejection compared with CNI & an anti-metabolite.
# If pregnancy planned, the MMF needs to be changed to AZA( a weaker antimetabolite compared to MMF specially early postransplant)
# Concerns about safety of sirolimus in pregnancy
Reference
Hahn D, Hodson EM, Hamiwka LA, Lee VWS, Chapman JR, Craig JC, Webster AC. Target of rapamycin inhibitors (TOR‐I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database of Systematic Reviews 2019, Issue 12. Art. No.: CD004290. DOI: 10.1002/14651858.CD004290.pub3. Accessed 11 May 2022.
We need to know why she is on mTOR based regimen( is there any problems with CNI as in this case choosing a safe maintenance IS medications during pregnancy will be difficult).
We need to know if she completed her family, in this case the counselling will be just for contraception.
CMV status not known, may be important regarding pregnancy talk & counselling
we need to know the CMV and EBV serology status of the donor and recipient in case of D+VE/ R-vE prior to transplant this is high risk for reactivation and associated with increased maternal and fetal risk .
in addition to the induction type and increased risk viral infection like CMV , BKV and PTLD (ATG , alemtuzumab )
The clinical and laboratory data missing in this scenario:
1) Basic disease causing ESRD?
2) Any history of sensitization including blood transfusion, pregnancy or prior transplant?
2) Type of donor (living/ deceased) and HLA matching.
3) Induction used?
4) Why patient is on sirolimus? Is it due to a de-novo protocol or changed from CNI due to any specific reason?
5) Is there any specific reason to use ACE inhibitor in this patient?
6) Past obstetric history is also important. Is she mother to any live child at present?
Considering everything favorable (first transplant, low risk of recurrence, no history of sensitization, living and good HLA match donor and sirolimus use due to a de-novo protocol), we still have to wait for 1 year before advising making efforts to conceive.
ACE inhibitors can be changed even at 7 months itself if no specific indication (no history of proteinuria).
Only after completion of one year, we should think of changing MMF to azathioprine
Regarding changing Sirolimus to Tacrolimus, it would be tough if there were compelling indications to start sirolimus initially.
any indication for omit CNI which consider back bone of transplant ?? and put patient on 2 antiproliferative drug ? either CNI toxicity or TMA
Its recommended to have conception after 1 year post transplantation giving the allograft function is normal and there is no proteinuria .
Meanwhile contraceptives are advisable to ensure no conception in the first year. Contraceptive has to be barriers and IUCD rather than hormonal medications to avoid suppressing the recovering Hypothalamic-pituitary -adrenal axis. Anti rejection therapy has to be changed 6 weeks prior to conception with CNi [Tacrolimus and Cyclosporin], Mycophenolate should be changed to Azathioprin 2 mg/kg , mTORi should be stopped as well , small dose of cortison can be continued.
Similarly anti hypertensive RAAS inhibitors should be changed to methyl dopa, Labetalol or Ca channel blocker prior to conception.
The patient has to be counselled about the complications related to post transplant pregnancy
pregnancy after transplantation is a high risk pregnancy as its associated with:
1]pre eclampsia
2]Adversely affecting allograft function.
3] pre mature delivery , low birth weight and intra uterine growth retardation.
4] Anecdotally reported cases of obstructive nephropathy , acute allograft failure and acute rejection.
so it needs close observation . Aspirin low daily dose can prevent the complications of pre eclampsia and intra uterine growth retardation.
Monitoring of renal function is essential as the GFR is increasing by 30-40 percent during pregnancy with reduction of serum creatinine and uric acid blood level, failure of that is predictive of adverse outcome.
There is no contraindication for normal vaginal delivery in kidney transplanted pregnant patient.
Cs is indicated if there is obstructive uropathy with pressure on the ureter by gravid uterus.or other fetal related indications.
special precaution has to be experienced during the CS not to damage the ureter of the transplanted kidney which is located above the uterine artery.
Lactation is safe in transplantation patient
Reference:
Silvi Shah and Prasoon Verma .Overview of Pregnancy in renal transplant patients.Int. J Nephrology. 2016
Council this lady regarding contraception, pregnancy, and lactation.
Pregnancy:
Patient should be advised to avoiding pregnancy for at least 1 year after receiving kidney
transplant beside having stable allograft function with no proteinuria, no recent episodes
of rejection or infection, and well-controlled medical conditions (hypertension, diabetes)
to achieve optimal pregnancy outcomes.
Others option of motherhood should be discussed post-transplant surrogate pregnancy,
and adoption.
Contraception:
Patient can continue her IUD device, with explanation that there’s still risk of pregnancy.
(0.2% for Levonorgestrel.0.6% for cupper)
Preferred contraception: methods are listed in order from most effective to least
effective (1)
Levonorgestrel intrauterine device.
Copper intrauterine device.
Progestin-only implant.
Progestin-only injectable.
Progestin oral contraceptive.
Combined hormonal contraception
(combined oral contraceptive pill,
vaginal ring, and transdermal).
Immunosuppression:
Prednisone, azathioprine, and Calcineurin inhibitors are generally considered safe.
Mycophenolate mofetil and mycophenolic acid (mycophenolate products) are
contraindicated.
Maternal exposure to mycophenolate may result in structural malformations in the
offspring.
Mycophenolate, which is considered a potentially teratogenic medication and should
Women should be counseled to discontinue mycophenolate products at least 6 weeks
not be taken without concurrent use of highly effective contraception.
Azathioprine is commonly substituted for mycophenolate products in women attempting
conception.
There are limited data on safety and outcomes with the mammalian target of rapamycin
inhibitors, belatacept, basiliximab, anti-thymocyte globulin, and rituximab. (2).
Hypertension medication:
ACE , should be discontinued before or at time of pregnancy confirmation. Nifedipine or
labetalol or methyldopa can used during pregnancy to control hypertension.
Breastfeeding :
Corticosteroid use has been deemed safe.
For tacrolimus, estimates of the ingested dose are 0.06%–0.5% of maternal weight-
adjusted dose.
Data are lacking for breast milk concentration and infant exposure to mycophenolate
products and mammalian target of rapamycin inhibitors.
Quotes from the 2003 American Society of Transplantation (AST) consensus conference
issued the opinion that “breast feeding need not be viewed as absolutely
contraindicated” (3).
.
References:
1-Sally Rafie et al.Contraceptive use in female recipients of a solid-organtransplant.Prog
Transplant. 2014 Dec; 24(4): 344–348.
2-3- Christina L. Klein and Michelle A. Josephson et al.Post-Transplant Pregnancy and
Contraception.CJASN January 2022, 17 (1) 114-120.
Thank you, Dr. Mohammed
Concise and well organized response
Contraception:
Fertility improves within 6 months after kidney transplantation and it is recommended to postpone pregnancy until 1-2 years post transplant.
She should know that stable graft function with no recent episode of rejection, no proteinuria, well controlled BP and no recent infections increase possibility of having optimal pregnancy outcome
Major complications to the fetus include prematurity, intrauterine growth retardation and low birth weight
She should know that there is an increased risk of preeclampsia, HTN and gestational DM
Contraception will help to avoid unplanned pregnancy, decrease possibility of those complications and allow optimizing immunosuppression and reviewing all her drugs before attempting conception.
It is better to keep IUD as it is effective, long lasting and reversible with no drug interaction with immunosuppressive agents.
Other available methods include combined hormonal contraceptives (not recommended in uncontrolled HTN), depot medroxyprogesterone (cause reversible decrease in bone density), etonogestrel implant (long lasting and reversible but decrease bone density), Progestin only pills (should ensure compliance to decrease failure rate and may interact with immunosuppressive agents), and barrier methods which are less effective and should be used in combination with other methods
Pregnancy:
All her drugs should be reviewed several months before attempting conception, prednisone is safe during pregnancy while MMF is contraindicated and should be substituted with azathioprine at least 6 weeks before conception.
There is limited data about mTORi and better to be replaced with CNI
ACEi are teratogenic and should be replaced with safe drugs as methyldopa or labetalol
Low dose aspirin decrease risk of gestational HTN and preeclampsia.
She should know that there is an increase in GFR in the first trimester and sustained during pregnancy, absence of this increase may indicate poor prognosis.
She should know she will need intensified clinical and lab. monitoring with follow up every 2-4 weeks in first and second trimester and every 1-2 weeks thereafter
Acute rejection rates are similar to that in general population
Kidney transplantation doesn’t affect vaginal delivery and caesarian section is not routinely indicated, during surgery care should be taken to avoid injury of transplanted ureter
Lactation
Breast feeding has several physical and psychological benefits especially in first six months.
Tacrolimus, Azathioprine and prednisolone are safe, although little amounts may be detected in breast milk.
She should have frequent drug level monitoring
Drug level in breastmilk and blood sample of infant may need to be checked
The mother and infant should be regularly evaluated to follow up mental and physical growth.
Klein CL, Josephson MA. Post-transplant pregnancy and contraception. Clinical Journal of the American Society of Nephrology. 2022 Jan 1;17(1):114-20.
Ong SC, Kumar V. Pregnancy in a kidney transplant patient. Clinical Journal of the American Society of Nephrology. 2020 Jan 7;15(1):120-2.
Yousif ME, Bridson JM, Halawa A. Contraception after kidney transplantation, from myth to reality: a comprehensive review of the current evidence. Exp Clin Transplant. 2016 Jun 1;14(3):252-8.
Chandra A, Midtvedt K, Åsberg A, Eide IA. Immunosuppression and reproductive health after kidney transplantation. Transplantation. 2019 Nov 1;103(11):e325-33.
Sameh M, Elkossi M, Kim JJ. Safety of breastfeeding by mothers on immunosuppressive medication for renal transplantation: Obsession, myth and truth. JOJ Uro and Nephron. 2017;3(3):1.
Thank you
The fertility is suspected to return six months after kidney transplantation. So; women of childbearing age should be counselled about the increased risk of pregnancy complications, the effect of pregnancy on the graft function, the immunosuppressive drugs and their impact on the fetus. Also, inform these women about the best possible time to conceive which is one year after transplantation. They need good graft function with control of the blood pressure before becoming pregnant. Different types of contraceptive methods should be discussed. Their efficiency and side effects, in order to help them make an informed decision.
These women should be emphasized not to get unplanned pregnancies, as the medications used by them need to be modified and should be on them with stable graft function for at least 3 months before conception.
they need to have regular follow up during the pregnancy. and the delivery needs to be at the hospital.
fetal outcomes such as preterm delivery, and low birth weight.
increased risk of UTI, CMV and other infections
beast feeding can be carried as a negligible amount excreted in the breast milk.
Thank you Jamila for the hard work