III. Safety of Breastfeeding by Mothers on Immunosuppressive Medication for Renal Transplantation: Obsession, Myth and Truth
- Please address the various issues related to immunosuppressive medications and breast feeding
- Please search for new evidence not addressed by this article
The safety of immunosuppressive agents in breastfeeding in an important concern in kidney transplant women. The drugs that are not safe during pregnancy are not certainly unsafe during breastfeeding.
Maintenance low dose of prednisolone is not associated with reduction in breast milk immunoglobulins level. High dose of prednisolone (50 mg) is correlated with very low levels breast milk and no medical adverse events in infants. The safety of CNI in combination with steroids in breast feeding is also reported.
It was reported that with daily azathioprine use the levels of 6-thioguanine (6-TGN) and 6-methylmercaptopurine nucleotides (6-MP) in infant’s blood and breast milk were undetectable or negligible with no adverse events in infants. Consequently, azathioprine is safe in breast feeding.
Cyclosporine was found in low levels in breast milk and infant’s blood, and breastfed infant would receive less than 5% of an immunosuppressive dose. No nephrotoxic effect or other side effect was reported. The cyclosporine level is lower in the fore-milk in comparison to in the hind milk because of lesser fat content in fore milk than hind milk.
Tacrolimus levels was low in the infant’s blood in different studies, with normal physical and neurological development. Thus, it seems breast feeding is safe in kidney transplant patients who receive tacrolimus.
There isn’t sufficient evidence about mTOR inhibitors in breast feeding, but in a small study their use was not associated with no clinical harm.
Although serious adverse effects of MMF during pregnancy is reported, and it is contraindicated in pregnancy, but MPA in breastfeeding was not studied in humans. There isn’t enough evidence for use of belatacept in breastfeeding as well, and should not be used while breast-feeding.
Progressive increase of breastfeeding by mothers who have received transplantation was demonstrated in recent years.
Immunosuppressants medications could be continued during breastfeeding as follow15:
1. Steriods: Generally safe, with no increased risk of infection nor hematological complications in the infants. No reduced immunoglobulin levels were detected in breastfed mothers receiving steroids.
2. Azathioprine: not excreted in breast milk. No hematological complications were detected in the infants.
3. Cyclosporins: No nephrotoxic effects were detected in the infants.
4. Tacrolimus: Safe with breastfeeding.
5. Sirolimus and everolimus: Their safety profile in breastfeeding is not studied. Better to be avoided.
6. Mycophenolic acid (MPA): No available human studies, but studies over rats revealed MPA is excreted in milk. Better to be avoided.
7. Belatacept: Again no available human studies, but product information reported being excreted in milk. Better to be avoided.
Breast feeding post transplant : There are increase in nunmber in young women in dialysis also increase number of transplanted mother wishing to have a baby and preferring breast feeding .Generally breast feeding is not contraindicated and it’s safe . American guideline advised breast in the first six month in certain medication {Prednisone , TAC and Azathioprine } .We must encourage mothers to breastfeed their babies .
Any immunosuppression used during pregnancy can be used in breast feeding .
1- Steroids it secreted in the breast milk in insignificant amount no side effect reported .
2- Cyclosporine also it is secreted in very small amount about 1l6 of mother trough level so it is safe .
3- TAC infant received about 0.02% of mother dose because TAC found in breast milk in minimal amount.Also found to be safe .
4- MMF is teratogenic lead to facial abnormality and cardiac anomaly, MMF is excreted in breast milk hence it is contraindicated .
5- mTOR inhibitor there are no available data or trial to approve their use .
6- Cyclophsphamide is contraindicated in pregnancy and breastfeeding .
7- Belatacept : need more trial to investigate whether it is safe or not .
Immunosuppressive Medications and Breast Feeding
This review article observed the followings regarding immunosuppression with breast feeding:
· No trials on MMF, Sirolimus, Everolimus or Belatacept that addressing their safety with breast feeding.
· Most trials studied CNI, AZA and steroids.
· Studies evaluated the use of Steroids for auto-immune disease.
Steroids
· No harm during breast feeding for infants breastfed by females on steroids.
· A dose of 50 mg was found not having any adverse impact on the breastfed infants.
· The combination of CNI with Steroids is safe as demonstrated by some studies.
AZA
· Azathioprine and it’s metabolite were found in a very low and undectable level in the breast milk of a lactating women taking AZA.
· No increase in the rate of infection in infants breastfed by mothers on AZA therapy.
CsA
· Cyclosporin was detected in the breast-milk in a negligible level and when breastfed infants were followed up no harm or side effects were observed.
· Breastfeeding is allowable in renal transplant recipients on CsA.
Tacrolimus
· TAC level in the breast milk is very low or undetectable and doesn’t cause any harm to the infants.
· Breastfeeding is safe to a mother taking TAC.
Sirolimus and Everolimus
· Safety remains uncertain.
· Studies on 14 infants breastfed by mothers on Sirolimus and TAC, revealed no harm.
MPA(Mycophenolic acid)
· Contraindicated during pregnancy because of teratogenicity.
· MPA was not studied in breastfeeding in human.
Belatacept
· The review found no studies looking for the safety profile of Belatacept during breastfeeding.
Immunosuppressive medications and breastfeeding
Steroids :
Not detected in mothers’ milk, no adverse effects on lactating infants according to growth, risk of infection, and even hematological side effects.
Azathioprine :
Not detected on mothers milk or on infants’ blood
azathioprine is safe in mothers and on The infants of mothers receiving azathioprine with no adverse side effects on both.
Cyclosporine :
Excreted with very minimal amounts of less than 5 % of drug dose with blood levels less than 2 % of mothers blood levels.
With no effects on immunity, growth, and kidney functions of the infants.
Tacrolimus :
The maximum amount of TAC received by a baby is 0.02% of the mother’s dose.
In another study, The baby received about 0.5% of the maternal dose and was considered to be safe for infants during lactation.
Mycophenolic acid :
MPA is contraindicated during pregnancy causing abortions anf fetal abnormalities however not been studied on lactating women and in animal studies showed that its transferred in rats milk.
Sirolimus and everolimus:
no specific trials for sirolimus and everolimus and it is not known if these drugs are safe or not.
Belatacept :
Its secreted in rats’ milk and its safety has not been known till now and authors recommend that breastfeeding women not use this drug.
New evidence :
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. (27)
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. (28)
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. (29)
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. (30)
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. (31)
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. (32)
Sirolimus, everolimus, and belatacept :
Limited data and less enough information on these medications, so it isn’t advisable to be taken. (32)
27– Wall S.K., Gross J.J., Kessler E.C., Villez K., Bruckmaier R.M. Blood-derived proteins in milk at the start of lactation: Indicators of active or passive transfer. J Dairy Sci. 2015;98(11):7748–7756. .
28- Thiagarajan K.M.-F., Arakali S.R., Mealey K.J. Safety considerations: breastfeeding after transplant: Official publication of the north american transplant coordinators organization. Prog Transplant. 2013;23(2):137–146.
29- Sarkar M., Bramham K., Moritz M.J., Coscia L. Reproductive health in women following abdominal organ transplant. Am J Transpl. 2018;18(5):1068–1076.
30-Zheng S., Easterling T.R., Hays K. Tacrolimus placental transfer at delivery and neonatal exposure through breast milk. Br J Clin Pharmacol. 2013;76(6):988–996.
31- Drugs and Lactation Database (LactMed) [Internet] National Library of Medicine (US); Bethesda (MD): 2019.
32- Constantinescu S., Pai A., Coscia L.A., Davison J.M., Moritz M.J., Armenti V.T. Breast-feeding after transplantation. Best Pract Res Clin Obstet Gynaecol. 2014;28(8):1163–117.
Due to the improvement in fertility post kidney transplantation,and the consequent increase in conception rate, the demand for natural breastfeeding is increasing as well , bearing the ambivalent concern of its safety in the context of increasing list of anti-rejection medications added to the transplantation portfolio.
On the other hand incouraging the breastfeeding is undoubtedly the practice that has to be generalized to all post transplant mothers.
This study was conducted to look into this issue by surveying the published literatures dealing with this issue.
important results found :
1)MMf, Sirolimus.Everolimus and Belatacept were not studied regarding its effect on breastfeeding.
2)The novel medicines like ,cyclosporin and, Azathioprim were exceptionally investigated for safety in breastfeeding and not the other group members.
3)The Data were extrapolated from the medications used in autoimmune disease.In particular the corticosteroid.therapy.
Corticosteroid:
Several studies elucidated the safety of breastfeeding, in the term of infant growth, risk of infection, in patients on Corticosteroid, even in patient with combined Cyclsporin.
Azathioprin:
Similarly, It was shown to be safe , as its concentration (and the concentration of its metabolite 6MP) in the mothers milk and infant blood is undetected , with no reported consequences on the fetus.
Cyclosporin:
generally its level in breast milk is negligible in comparison to blood trough level , and entirely safe .
Tacrolimus:
it was found to be excreted in the mother milk and blood level in infants were reported as almost 0.5% of the mother blood level, however , infants followed for variable period of time, and they surveyed for any complications related to Tac. and all were negative. Therefore, the conclusion was , Tac is safe in breastfeeding mother, but needs follow up.
Regarding Sirolimus and Everolimus, their safety was not verified in beast feeding mothers, MMF and Belatacept were found to be excreted into the breast milk in animals . all the 4 medicines are contraindicated and have to be avoided in breastfeeding.
reference:
kristina Munos-Flores Thiagarajan et al.Safety consideration:breastfeeding after transplant.Prog Transplant. June :2013
Breast feeding is the most physiological, cheap, easy and helps to achieve better psychological wellbeing of both the lactating mother and her infant. Hence, finding the safe Immunosuppressive drugs that can be used during breast feeding is very important.
Mothers where exposed to high dose of steroids for treatment of asthma had no adverse effects documented in their breast-fed babies.
Azathioprine and its toxic metabolite (6 mercaptopurine) were not found in collected samples of breast milk or infant blood. In addition, no myelotoxic effect or higher risk of infections were observed in breast fed babies born to mothers on azathioprine treatment for IBD.
Minimal percentage of cyclosporin (mostly less than 2% of maternal serum drug level) can be excreted in breast milk that is unlikely to cause adverse effects in infants. Its amount even varies according to fat content of milk (higher in hind milk). CNI is rarely detected in significant concentration in infant blood even if it detected in breast milk.
Tacrolimus is detected in minimal concentration (0.02 up to 0.5% of maternal dose) in breast milk with no documented side effects in infants.
No evidence regard safety of sirolimus and everolimus during breast feeding, just one study with clinical follow up, but the drug level was not measured.
As regard safety of MMF and MPA, it was not tested in human. However, it is proven to be teratogenic if used during pregnancy and unsafe in animal breast feeding. No previous studies on belatacept in human, only animal studies.
Although, it seems that steroids, azathioprine and CNI are safe during breast feeding, similarly to their safety during pregnancy, the data are still lacking and derived from few observational studies on few numbers of cases. Further studies and randomized clinical trials (RCT) are required to reach solid conclusions about other IS drugs. Frequent monitoring of both maternal and infant blood levels of various drugs are needed.
new evidence not mentioned here,
Fertility is restored post transplantation and rate of pregnancy is increased, but the concern about the effect of IS on both pregnancy and lactation is raised while the data regarding their effect are limited. Corticosteroids ,azathioprine and CNI are considered safe during lactation despite being excreted in milk but their level is very low compared with intrauterine level.Corticosteroids (even high dose 50mg/day ) were not associated with adverse effects in exposed breast fed infants ,while azathioprine and its metabolites and cyclosporine were either non detectable or detected in trivial amount in breast milk anf follow up revealed no increased incidence of infection in exposed infants . Tacrolimus was detected in baby’s serum but in very small concentration.
CsA excretion in breast milk is variable depending on fat content in breast milk , it was lower in fore milk than hind milk
For other ID drugs as mycophenolate mofetil ,evirolimus , sirolimus and belatacept , data regarding their safety is limites as there were no randomizedtrials evaluating their effect on breast fed infants the data based on animal studies is rather limited and animal studies revelead that both MMF and belatacept are excretd in smallamounts in rats .
New evidence
Mycophenolate is excreted in large amounts into breast milk. However, a 2021 updated study indicates that there are infants who have presented with no adverse effects. However, alternate drugs such as azathioprine, cyclosporine and tacrolimus are still preferred over mycophenolate.
Reference
Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Mycophenolate. [Updated 2021 Sep 20]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK501638/
IS and breast feeding
IS drugs that are unsafe during pregnancy may be safe for breastfeeding. This is illustrated in the following points :
mTOR inhibitors details are not sufficient to understand safety for breastfeeding. MMF and belatacept are unsafe.
Planned pregnancy provided the patient has stable allograft function can be successful. With the right conditions, breastfeeding should be encouraged so that the recipient can lead a normal life. Careful monitoring is paramount both for the mother and the infant. Long term follow up is crucial as well. Drug levels in breast milk and infant blood need to be assessed regularly.
Important indicators to check for :
The given article concludes that patient with stable allograft function who is on a regimen of azathioprine, steroid, and CNI can safely breastfeed.
This paper handling the safety of breast feeding in mothers on immunosuppression after renal transplantation.
The data was collected electronic search from scientific papers.
Steroids :
even high doses of steroids e.g in asthmatic mothers have very low levels in breast milk.
No side effects regarding babies growth, risk of infection, hematological complications or others.
Azathioprine:
Many studies done on mothers taking azathioprine for many indications like IBD or post-transplant found that its metabolites are undetectable or insignificant in some samples of breast milk of lactating mothers with no adverse effect on babies.
Conclusion that azathioprine is safe during lactation.
Cyclosporine:
Most of the studies found that cyclosporine level in breast milk is < 5% of mothers blood level.
It is safe and without nephrotoxic effect.
Tacrolimus:
The drug level found in babies breast fed by mothers taking tacrolimus in 5 studies was found maximally as 0.5% of the maternal dose, the infants were followed in one study up to 30 month.
They concluded that tacrolimus is safe with close monitoring of the infants.
Sirolimus and everolimus:
No specific trails for them.
Mycophenolic acid(MPA) :
It is contraindicated in pregnancy.
Not studied in breast feeding in humans but in animals found in rats.
Betalacept:
No clinical studies in humans.
They recommended its unsafety.
Rituximab:
Small study suggest that women taking rituximab can breast feed their babies, because it is barely detected in breast milk.
Because of the increased number of young females transplanted successfully, breast feeding should be encouraged. This is after good contraception planning and close follow up during pregnancy.
Safety of Breastfeeding by Mothers on Immunosuppressive Medication for Renal Transplantation.
1) Steroids
2) Azathioprine
3) Cyclosporine ( CSA )
4) Tacrolimus (TAC)
5) Sirolimus and everolimus.
6) Mycophenolic acid (MPA)
7) Belatacept
New evidence not addressed by this article.
1. Cyclophosphamide.
References : Immunosuppressive Medications during Pregnancy and Lactation in Women with Autoimmune Diseases (sagepub.com).
2. Rituximab.
Reference : https://www.acog.org/-/media/project/acog/acogorg/clinical/files/committee-opinion/articles/2019/04/immune-modulating-therapies-in-pregnancy-and-lactation.pdf
-Please address the various issues related to immunosuppressive medications and breast feeding
Introduction :
There is a fact that a number of kidney transplantation increasing worldwide and the number of child bearing age women performing a kidney transplantation is increasing . there is an increasing number of mothers with kidney transplantation preferring breast feeding .
Generally it is important for a doctors to encourage breast feeding because
1- Increase the number of childbearing age women with renal transplantation.
2- Increased the number of mothers that prefer breast feeding .
3- Studies report the safety of CNI,Prednisolone,Azathioprine , in kidney transplant patient .
Long term large size study is needed in this field as regarding some immune suppressant medication there is scanty of studies, or there is very small number with short term follow up.
In these patients the drug level needs to checked frequently.the milk and blood level of these medication may needs to be monitored .the mother and the baby may need to be monitored for both physical and mental growth.
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 effect and any other side effect report in infants.
Another study , demonstrate that CsA concentration in milk varies from 16 micro g /L to 596 micro g/L. again it is safe in breastfeeding .
4- Tacrolimus (TAC).
The studies found that tacrolimus is excreted in amothers milk .
In one study , Milk concentration was 0.42 Nano gram /milliliter.the auther mentioned that infant receiving about 0.02% of the mothers dose .
In a case report , the milk to tacrolimus blood concentration ratio was 0.23.they advised that tacrolimus is safe in breast feeding .
Another study also report that infants receiving less than 0.23 % of the mother,s dose .
5- Sirolimus and everolimus
There is no study studying specific the safety of sirolimus and everolimus .
No study measuring Sirolimus and everolimus milk level during breastfeeding.
Therefore the safety of these drug during lactation in unknown.
6- Mycophenolic acid (MPA)
It is not studied in human. but animal studies demonstrate that MMF can be excreted in rat milk.
7- Belatacept
There is no clinical study about this drug . the manufacturer mention that this drug secreted in a milk , it should be avoided during lactation .
-Please search for new evidence not addressed by this article
According to the guideline ( American academy of pediatrics ) , It is advised for breast feeding only within first sith month of life . there was no any report for side effect of infant whose mother on prednisone, azathioprine, cyclosporine, and tacrolimus . (1)
MPA, sirolimus/everolimus are contraindicated during pregnancy , because of these concerns and limited studies addressing the safety in lactation , it is recommended to avoid during .(2)
Baby expose to drug is very little as compared to its exposure during gestation , for example Tac and prednisolone level in milk is about or less than 1% and 0.1% of maternal dose respectively .
Breast milk reduces the risk for infections and necrotizing enterocolitis and can increase mental, motor, and behavioral development at ages 18 and 30 months in preterm infants.(3)(4)
It is common practice to encourage breastfeeding post transplantation, because its benefit is more higher than its risk . .
Reffernces
1) Moritz MJ, Constantinescu S, Coscia LA, et al. Transplant Pregnancy Registry International (TPRI) 2019 Annual Report. Transplant Pregnancy Registry International (TPRI); 2020.
2) Constantinescu S, Pai A, Coscia LA, Davison JM, Moritz MJ, Armenti VT. Breast-feeding after transplantation. Best Pract Res Clin Obstet Gynaecol. 2014;28(8):1163-1173.
3) Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr. 2010;156(4):562-567.
4) Vohr BR, Poindexter BB, Dusick AM, et al. Persistent beneficial effects of breast milk ingested in the neonatal intensive care unit on outcomes of extremely low birth weight infants at 30 months of age. Pediatrics. 2007;120(4):e953-e959.
Steroid
AZATHIOPRINE
• studies showed no haematological abnormalities I’m neonates with breastfeeding mother .
The infants of mother received azathioprine didnot shown any significant increase risk of infection when compared to controls group .
CYCLOSPORINE:
studies showed cyclosporine level in infant blood is 2% of mother serum level.
•
the infants was followed for 2 years without any evidence of growth retardation or reported side effects of cyclosporine affecting infants .
Tacrolimus
studies showed infants whose mother received tacrolimus are physical and neurological development were normal
studies showed TAC level in infants was less than 0.9 ug/L , they advices that lactation in TAC treated patients safe with close monitoring to patients.
SIROLUMUS AND EVERLOIMUS:
it remains uncertain if breastfeeding by mum on sirolumus or everloumus safe or not
MMF
It is contraindicated in pregnancy as causes spontaneous abortion and foetal abnormalities
and studies showed that MMF can be transferred to breast milk
BELATACEPT
It shouldn’t be used while breastfeeding
Immunosuppression use and breast feeding in renal transplant recipient:
Fertility and pregnancy outcome are improved in renal transplant recipients. All drugs that are contraindicated in pregnancy need not be contraindicated in lactation…The recommendations are based on few studies and expert opinions. Other recommendations are extrapolated based on animal studies. There are no controls available in most of these studies so definite conclusion was not possible.
we could discuss the effect of the individual drugs on breast feeding
There are no recommendations of the use of ATG, basiliximab after renal transplantation in the breastfeeding women recipient.
Lactation has alot of benefits also can gives physical and psychological support for the mother and her baby it should be encouraged by the clinicians even for kidney recipient women, there are few studies that show the benefits of lactation on kidney recipient women and the effect of different immunosuppressants medications on the baby .
Some medications that are considered unsafe during pregnancy can be used safely in lactating women with undetectable concentration in breast milk .
Immunosuppressants medications and their effect on breast feeding:
Steroids have no significant medical effect and no side effects on the infants with mother who receiving steroid even with high dose up to 50 mg.
Azathioprine metabolites are undetected in breast milk with no side effect on the baby.
Cyclosporin some studies show that maternal milk has one sixth of the CSA blood level other show 2% from mother’s serum and most studies show that there is no growth restrictions and side effect of CSA on the baby .
Tacrolimus can be considered as a safe drug that can be used during lactation with no effect on the baby.
Sirolimus and everolimus there is lack of studies and data for these drugs during lactation so it remains unclear.
Mycophenolic acid which is contraindicated in pregnancy but there is no study for its effect during lactation.
Belatacept there is no study for drug safety in lactation but some animal studies show that MMF and belatacept are unsafe .
A] Please address the various issues related to immunosuppressive medications and breast feeding
B] Please search for new evidence not addressed by this article
REFERENCES
Safety of Breastfeeding by Mothers on Immunosuppressive Medication for Renal Transplantation: Obsession, Myth and Truth
The drugs that are not safe during pregnancy are not necessarily unsafe during breastfeeding. On reviewing non-transplant patients,
Steroids
the levels of prednisolone are at very low levels in breast milk and have no any significant medical effect on infants who were breastfed by mothers receiving steroids even in a high dose of prednisolone 50mg/day.
Azathioprine
regarding metabolites of azathioprine, 6-thioguanine (6-TGN) and 6-methylmercaptopurine nucleotides (6-MP), in the infant’s blood. Both the 6-TGN and 6-MMPN were undetectable It was undetectable in collected mothers’ milk samples and there was no side effect noted in their infants. The infants sof mothers receiving azathioprine did not show any significantly increased rate of infection when compared to the control group (n=12)
Cyclosporine (CsA)
a breastfed infant would receive less than 5% of an immunosuppressive dose .The infant was followed up for 2 years without any evidence of growth retardation or any reported side effects of CsA affecting the child
Tacrolimus (TAC)
maximum amount of TAC that will be received by the baby was 0.5% to 0.02% of the mother’s weight-adjusted dose with no adverse effects so breastfeeding is safe to another receiving tacrolimus
Sirolimus and everolimus
no current studies
Mycophenolic acid (MPA)
It is well known that MPA is contraindicated during pregnancy. It could cause spontaneous abortion and other fetal anomalies. MPA in breastfeeding was not studied in humans. Animal studies have demonstrated that MPA can be transferred to breast milk in rats
Belatacept
There is no any clinical studies
A) Steroids
No side effect or any harm has been observed in infants who were breastfed by mothers receiving steroid.
B) Azathioprine
azathioprine is safe in mothers who are breastfeeding.
C) Cyclosporine (CsA)
CsA level in human milk varies from 16 micrograms/L to 596 micrograms/L. No side effects were noted in infants in regards to growth and renal function.
D) Tacrolimus (TAC)
It is safe during breastfeeding
E) Sirolimus and everolimus
still need more studies
F) Mycophenolic acid (MPA)
Although it is contraindicated in pregnancy but its effect in breastfeeding still uncertain and needs more studies
G) Belatacept
Product information revealed that belatacept secreted in breast milk of rats. They recommended that belatacept should not be used while breast-feeding
I didn’t get your point Prof.
Fertility starts to improve about 6 months after transplantation.
Advantages of breastfeeding to maternal and infants health is well known, encouraging safe breastfeeding is important
Few studies addressing the safety of immunosuppression medication in lactating mothers.
no specific trials on MMF, sirolimus, everolimus or belatacept that addressed their safety during breastfeeding.
●Analytical Review
▪︎Steroids
Effect of Steroids level in the breastmilk of lactating monthers on oral maintenance doses of prednisolone and azathioprin was studied and there was no effect on growth, no increase of incidence of infections or hematological complications or decrease in immunoglobulin levels in the breast milk.
Even in higher doses up to 50 mg there no significant medical effect on infants .
Use of stetoids in combination with CNI or azathioprine also didn’t show any significant side effects to infants.
▪︎Azathioprine
metabolites of Azathioprine at a dose of 2-2.1mg/kg/day of were not detected in the infant’s blood and there was no side effect noted in infants.
With no hematological abnormalities or increasein incidence of infection
So authors concluded that azathioprine is safe in mothers who are breastfeeding.
▪︎Cyclosporine (CsA)
CsA levels in the infant blood were 2% of mothers’ serum level.
In an observational study, Thiru et al. demonstrated that the CsA dose was less than 0.1mg/kg in the infant while the mother was receiving 3mg/kg.
infants of CNi receiveing mothers showed no evidence of growth retardation or any side effects of CsA .
Nyberg et al. Showed that in combination of prednisolone, azathioprine and CsA , CsA levels were below the detection limit of 30ng/ml in all infants and serum creatinine ranged from 25 to 54µmol/L at 1 week after birth and 23-52µmol/L after breastfeeding.
And there was no nephrotoxic effect .
▪︎Tacrolimus
Studies showed milk to blood TAC levels ratio was 0.23. The baby received about 0.5% of the maternal dose.
lactation in TAC-treated patients was safe with close monitoring of the infant.
▪︎Sirolimus and everolimus
No specific trials for sirolimus and everolimus.
one infants was breastfed by a mother receiving sirolimus in addition to TAC reported and no clinical harm occurred,
Its uncertain if breastfeeding by mums on sirolimus or everolimus is safe or not. ▪︎Mycophenolic acid (MPA)
MPA is contraindicated during pregnancy
MPA in breastfeeding was not studied in humans and it was found to be transferred to breast milk in rats.
▪︎Belatacept
No clinical studies that looked at safety profile of balatacept in infants.
Product information revealed that belatacept secreted in breast milk of rats.
▪︎Rituximab
Rituximab is a humanized monoclonal antibody targeted at CD20 antigen on B lymphocytes. Safety data of use during pregnancy and the 6 months before pregnancy are limited, although published reports are reassuring,
Safety of rituximab during lactation has not been studied.
A single report on women exposed to rituximab described B-cell lymphocytopenia in the neonates months after birth .
This finding has not been confirmed by other studies.
In conclusion
it is safe for mothers to breastfeed while on immune suppression that includes steroids, cyclosporine, tacrolimus or azathioprine. Nonetheless, a close follow-up of these infants is of paramount importance.
Immune Modulating Therapies in Pregnancy and LactationCommittee OpinionCONumber 776April 2019
As pregnancy increases in tx, here are some facts regarding immunosuppressive drugs during breastfeeding-
1.steroid safe to use
2.azathioprine attained max level in breastmilk 4hr post oral intake, but safe to use
3.cyclosporine attained (15-70%) in brestmilk of serum level, but no effect on child.
4.tacrolimus safe to use.
5.Belatacept and mmf secreted in breast milk in animal studies hence unsafe to use.
6.mtori no data available.
Pregnancy or fertility has been improved post-transplant due to early access to transplant and invention of newer immunosuppressive drugs results in good patient and kidney outcome.
Breastfeeding has been real concern in KTR:
1) Steroids
a. no significant medical effect, no effect on growth, infections, or haematological complications.
b. safe if used in combination with calcineurin inhibitors.
2) Azathioprine
a. Maximum level of azathioprine in breast milk is at 4 hours post ingestion
b. the exposure to the infant is limited
c. safe to use in breastfeeding.
3) Cyclosporine
a. Cyclosporine levels in breast milk are 15-90% of the serum levels (with lower concentration in foremilk and higher concentration in hind-milk)
b. exposure to the infant is low
c. safe to breastfeed while on cyclosporine.
4) Tacrolimus
a. Tacrolimus levels in the infant breastfed by a patient on tacrolimus are limited
b. safe to breastfeed while taking tacrolimus.
5) Sirolimus and everolimus
a. No specific trials have been conducted, but a case report has shown no harmful effects.
6) Mycophenolic acid
a. Human studies have not been done to assess effect on breastfeeding although the drug transfer to infants through breastmilk has been shown in rats.
7) Belatacept
a. Human studies have not been done to assess effect on breastfeeding although the drug gets secreted in breastmilk of rats
b. recommended not to use it while breast-feeding.
Breastfeeding should be encouraged if on CNI, Azathioprine and steroids. There is no clear evidence on mTOR inhibitor, while MMF and belatacept use has been proved hazadous in animal studies.
Please search for new evidence not addressed by this article
Studies showed use of CNI, Azathioprine and steroids is safe in breastfeeding. Evidence for mTOR inhibitor, belatacept, Basiliximab, rituximab and ATG is limited, so should assessed case based and institution protocols
Please address the various issues related to immunosuppressive medications and breast feeding
Steroids
study was conducted upon the effect of prednisolone and azathioprine in 2 lactating mothers showed there is no effect on growth, risk of infections or hematological complications in the infants. also immunoglobulin levels in the breast milk did not decrease. and demonstrated that the levels of prednisolone are at very low levels in breast milk and have no any significant medical effect on infants.
Azathioprine
studied four cases of women receiving from 1.2-2.1mg/kg/day of azathioprine daily.
They looked for metabolites of azathioprine, 6-thioguanine (6-TGN) and 6-methylmercaptopurine nucleotides (6-MP), in the infant’s blood and mother milk Both were undetectable, and there was no side effect noted in their infants.
So azathioprine is considered safe in mothers who are breastfeeding
CYCLOSPORINE
Study found that CsA levels in the infant blood were 2% of mothers’ serum level, while others reported that maternal milk contains one-sixth of cyclosporine blood level of lactating mothers.
In study conducted showed that milk cyclosporine levels ranged from 15 to 90% higher than simultaneous serum levels. However, a breastfed infant receives less than 5% of an immunosuppressive dose. The infant was followed up for 2 years without any evidence of growth retardation or side effects of CsA affecting the child. This study concluded that no nephrotoxic effect or other side effect was occurred with mother taking prednisolone, azathioprine and CsA
TACROLIMUS:
Tacrolimus levels in the infant breastfed by a patient on tacrolimus are very low and it is safe to breastfeed while taking tacrolimus.
Sirolimus or Everolimus
investigators did not check sirolimus level in infant’s blood. Therefore, it remains uncertain if breastfeeding by mums on sirolimus or everolimus is safe or not.
Mycophenolic acid (MPA)
It is well known that MPA is contraindicated during pregnancy. It could cause spontaneous abortion and other foetal anomalies. A higher incidence of structural malformations was
Human studies have not been done to assess effect on breastfeeding although the drug transfer to infants through breastmilk has been shown in rats
Belatacept:
Human studies have not been done to assess effect on breastfeeding although the drug gets secreted in breastmilk of rats and it has been recommended not to use it while breast-feeding.
In conclusion breastfeeding should be encouraged if mothers on Calcineurin inhibitors, Azathioprine and steroids. There is no clear-cut data on mTOR inhibitor use, while MMF and belatacept use has been proved unsafe in animal studies.
Please search for new evidence not addressed by this article
Steroids;
breast milk transfer is 0.1% of the total maternal dose.
Tacrolimus:
No detectable Tac in the serum of the infant 2-3 weeks postpartum.
Cyclosporine:
Detectable amount <0.1% mg/kg/day
MMF:
There are limited data on the effects on breastfed infants of mothers taking mycophenolic acid.
Azathioprine:
No clinically observed adverse effects.
In general:
CNI, Steroids, and Azathioprine are safe, MMF is contraindicated.
No data about the use of sirolimus, everolimus, and belatacept.
REF:
1. Singh M. Breastfeeding and medication use in kidney disease. Adv. Chronic Kidney Dis. 2020;27(6):516-524.
immunosuppression medications and breast feeding :
A- Steroids
it is safe to be used either during pregnancy and breast feeding
and it is safe if used in combination with CNI .
B- Azathioprine
safe to be used in breastfeeding.
C- Cyclosporine
Cyclosporine levels in breast milk are 15-90% of the serum levels and it is safe also
D- Tacrolimus
Safe to be used also
E- Sirolimus and everolimus
Need more study
F- Mycophenolic acid
it is contraindicated during pregnancy but still need more study to assess its safety in breast feeding
G-Belatacept
It is not recommended to use it while breast-feeding.
Conclusion :
CNI, Azathioprine and steroids are safe during breast feeding .
There is no clear evidence on mTOR inhibitor
MMF and belatacept use are hazadous in animal studies
Various issues related to immunosuppressive medications and breast feeding.
Steroids:
Even in a high dose of prednisolone 50mg/day is safe.
Azathioprine:
Levels were undetectable in breast milk or in infant blood and were not associated with
increased risk of infection on a long-term follow-up.
Cyclosporine:
Levels are undetectable or at insignificant levels in infants breastfed by mothers on this
drug.
Tacrolimus:
Detected in infants’ serum but at insignificantly low levels.
Mycophenolate mofetil and belatacept:
The data based on animal studies is rather limited. There are no specific trials on MMF,
Sirolimus, Everlimus or belatacept that addressed their safety during breast feeding
.
Please search for new evidence not addressed by this article:
Review by Committee on Obstetric Practice and Society for Maternal-Fetal Medicine,divide biological agents into :
1- Low-Risk Medications:
CS, CSA and Azathioprine considered low risk medication during both pregnancy and
lactation.
2- High Risk Medication: MMF considered high risk medication.
Review of National institute of medicine Drugs and Lactation Database, (LactMed), last
Revision: September 20, 2021. (2)
Mycophenolate:
Information from one patient indicates that relatively large amounts
of mycophenolate are excreted into breastmilk, with peak milk levels at about 2 hours
after a dose of the delayed-release formulation (Myfortic).
Because little information is available on the use of mycophenolate during
breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or
preterm infant.
Sirolimus :
Because almost no information is available on the use of Sirolimus during
breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or
preterm infant.
Abatacept:
If is required by the mother, it is not a reason to discontinue breastfeeding. However, an
alternate drug may be preferred, especially while nursing a newborn or preterm infant.
In general, immunomodulating drugs that are not contraindicated in pregnancy are
compatible with breastfeeding.
It is safe for mothers to breastfeed while on immune suppression that includes steroids,
cyclosporine, tacrolimus or azathioprine.
Nonetheless, a close follow-up of these infants is of paramount importance.
References:
1-Committee on Obstetric Practice and Society for Maternal-Fetal Medicine. Immune
Modulating Therapies in Pregnancy and Lactation.
2- National Library of Medicine (US).
Breastfeeding is of well-known importance for infants and for their mothers.
Transplantation as a renal replacement therapy offers ESRD a better quality mimicking the normal life, including pregnancy with a satisfactory outcome compared to ESRD.
Fortunately, the number of breastfeeding solid organ transplant recipients increased since 2016, and we also should do encourage them naturally live and breastfeed their babies
As regards breastfeeding, this analytical review of literature addresses the reported safety profiles of different immunosuppressive drugs used in transplantation.
The mother and her infant must be carefully followed especially
a. growth monitoring for the infants
b. checking their drug levels
c. hematological side effects of Aza and CNI nephrotoxicity should be evaluated
· Steroids appears to be safe in lactating mothers wither being on oral maintenance doses of prednisolone or in higher doses.
· Similarly azathioprine did not affect growth, the risk of infections or hematological complications in the breast feeding infants. Moreover, Aza was undetectable in collected mothers’ milk samples and there was no side effect noted in their infants.
· Cyclosporine (CsA): Lewis et al. found that CsA levels in the infant blood were 2% of mothers’ serum level. Similarly, Nyberg et al., Morreti et al., and Bramham et al. demonstrated the safety of CNI in combination with steroids in breastfeeding mothers. Arakali et al. reported no side effects in infants of breastfeeding mothers
· Sirolimus and everolimus: there are no specific trials for sirolimus and everolimus. However, one of the fourteen infants was breastfed by a mother receiving sirolimus in addition to TAC in a trial reported by Bramham et al. No clinical harm occurred, but the investigators did not check sirolimus level in infant’s blood. Therefore, it remains uncertain if breastfeeding by mums on sirolimus or everolimus is safe or not.
· Mycophenolic acid (MPA) It is well known that MPA is contraindicated during pregnancy. However, MPA in breastfeeding was not studied in humans.
· Belatacept The author did not find any clinical studies that looked at safety profile in infants being breastfed by mothers on belataccept. Product information revealed that belatacept secreted in breast milk of rats.
In conclusion, Transplant clinicians should encourage breastfeeding whenever it is possible.
Steroids
Studies showed that the level of prednisolone is very low in breast milk and it did not cause any harm to the infant.
No side effects or any harm has been observed in infants who were breastfed by mothers receiving steroids.
Azathioprine
Studies looked at the metabolites of azathioprine in the infant and in the breast milk, They were undetectable in both.
No side effects were noted in the infants of mothers treated with azathioprine, also, they did not show any increased risk of infection.
Cyclosporine
Studies showed that:
Cyclosporine levels in the infant blood were 2% of mothers’ serum level.
Maternal milk contains one-sixth of the cyclosporine blood level of the lactating mothers.
A breastfed infant would receive less than 5% of an immunosuppressive dose.
No nephrotoxic effect or other side effects was occurred or noticed in these infants.
Tacrolimus
A study showed that:
Milk to blood TAC levels ratio was 0.23. The baby received about 0.5% of the maternal dose.
Physical and neurological development was normal.
They advised that lactation in TAC-treated patients was safe with close monitoring of the infant.
Sirolimus and everolimus
There are no specific trials for sirolimus and everolimus.
In one study:
infant was breastfed by a mother receiving sirolimus in addition to TAC, No clinical harm occurred, but the investigators did not check the sirolimus level in the infant’s blood. Therefore, it remains uncertain if breastfeeding is safe or not in this case.
Mycophenolic acid
It is not studied in humans. Animal studies have demonstrated that MPA can be transferred to breast milk in rats.
Belatacept
Product information revealed that belatacept was secreted in the breast milk of rats.
There are no clinical studies about its safety in humans.
Steroids;
breast milk transfer is 0.1% of the total maternal dose.
Tacrolimus:
studies showed that total Tac ingestion by the infant is <0.5% of the total adult weight-adjusted dose, no detectable Tac in the serum of the infant 2-3 weeks postpartum.
No difference in Tac concentration between breastfed and bottle-fed infants.
Cyclosporin:
Rate of ingestion is <0.1% mg/kg/day. Cyclosporine level was undetectable in the infants.
MMF:
Limited data suggested that there is no discernible adverse effects in 7 infants from breastfeeding, it is currently not advised.
Azathioprine:
No clinically observed adverse effects.
In general:
CNI, Steroids, and Azathioprine are safe, MMF is contraindicated.
No data about the use of sirolimus, everolimus, and belatacept.
Reference:
Singh M. Breastfeeding and medication use in kidney disease. Adv Chronic Kidney Dis. 2020;27(6):516-524.
Issues related to immunosuppressive medications and breast feeding:
Steroids:
Oral maintenance doses of prednisolone did not affect growth, the risk of infections or hematological complications in the infants.
Levels of prednisolone are at very low levels in breast milk and have no any significant medical effect on infants.
Azathioprine:
Undetectable in the infant blood and mothers’ milk. Safe in mothers who are breastfeeding.
No side effect noted in their infants or hematological abnormalities were found or
increased risk of infections.
Cyclosporine (CsA):
CsA levels in the infant blood were 2% of mothers’ serum level. It is estimated that a breastfed infant would receive less than 5% of an immunosuppressive dose.
Follow up: no evidence of growth retardation or any reported side effects of CsA affecting the child.
Tacrolimus (TAC):
Lactation in TAC-treated patients was safe with close monitoring of the infant. Physical and neurological development was normal.
Sirolimus and everolimus:
It is uncertain if breastfeeding by mums on sirolimus or everolimus is safe or not. No specific trials were found.
Mycophenolic acid (MPA):
MPA in breastfeeding was not studied in humans. Animal studies have demonstrated that MPA can be transferred to breast milk in rats.
Belatacept:
Product information revealed that belatacept secreted in breast milk of rats. They recommended that belatacept should not be used while breast-feeding. No clinical trials were performed.
New evidence:
Long-term follow up on breastfed infants is not well-documented.
Tacrolimus:
50% of maternal serum concentration was detected in colostrum within the immediate postpartum period, associated with a 36% risk of transient hyperkalemia and mild kidney impairment in the infant.
Azathioprine:
Longer follow-up data are lacking. It is likely to be safe if given 4 hours before breastfeeding. The manufacturer does not recommend use during breastfeeding.
No enough information on sirolimus, everolimus, and belatacept.
Tocilizumab:
Little information is available on the clinical use of tocilizumab during breastfeeding. Only small amounts of tocilizumab were detected in breast milk after intravenous doses in several mothers. It is also likely to be partially destroyed in the infant’s gastrointestinal tract and absorption by the infant is probably minimal. A few mothers have breastfed their infants with undetectable infant serum levels and no reported adverse effects. If tocilizumab is required by the mother, it is not a reason to discontinue breastfeeding. Until more data become available, tocilizumab should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant.
Mycophenolate
Information from one patient indicates that relatively large amounts of mycophenolate are excreted into breast milk, with peak milk levels at about 2 hours after a dose of the delayed-release formulation (Myfortic). A few infants have reportedly been breastfed during mycophenolate therapy, with no adverse effects reported. Because little information is available on the use of mycophenolate during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
References
1. Overview of pregnancy in renal transplant patients
[Published online November 30, 2016]
Int J Nephrol, 2016 (2016), p. 4539342, 10.1155/2016/4539342
2. K.M.-F. Thiagarajan, S.R. Arakali, K.J. Mealey, et al.
Safety considerations: breastfeeding after transplant: Official publication of the north American transplant coordinators organization
Prog Transplant, 23 (2) (2013), pp. 137-146
3. B. Kociszewska-Najman, N. Mazanowska, B. Pietrzak, et al.
Low transfer of tacrolimus and its metabolites into colostrum of graft recipient mothers
Nutrients, 10 (3) (2018), p. E267
4. Drugs and Lactation Database (LactMed) [Internet], National Library of Medicine (US), Bethesda (MD) (2020)
Tocilizumab Available at:
https://www.ncbi.nlm.nih.gov/books/NBK500589/, Accessed 4th May 2020
5. Drugs and Lactation Database (LactMed) [Internet], National Library of Medicine (US), Bethesda (MD) (2019)
Mycophenolate Available at:
https://www.ncbi.nlm.nih.gov/books/NBK501638/, Accessed 4th May 2020
6. K. Bramham, G. Chusney, J. Lee, L. Lightstone, C. Nelson-Piercy
Breastfeeding and tacrolimus: serial monitoring in breast-fed and bottle-fed infants
Clin J Am Soc Nephrol, 8 (4) (2013), pp. 563-567
7. Breastfeeding and Medication Use in Kidney Disease
ManishaSingh Published: May 10, 2020DOI:https://doi.org/10.1053/j.ackd.2020.05.007
Safety of Breastfeeding by Mothers on Immunosuppressive Medication for Renal Transplantation: Obsession, Myth and Truth
Steroids
Grekas et al. ,Greenberger et al. ,Nyberg et al. ,Morreti et al., Arakali et al.all found that steroid present at very low levels in breast milk and have no any significant medical effect on infants .It is also noted No side effect or any harm has been observed in infants who were breastfed by mothers receiving steroid.
Azathioprine
Gardiner et al. They looked for metabolites of azathioprine, (6-TGN) and (6-MP), in the infant’s blood. Both the 6-TGN and 6-MMPN were undetectable.
Morretti et al. ,analyzed breast milk to detect 6-MP, a metabolite of azathioprine. It was undetectable in collected mother’s’milk sample
and there was no side effect noted in their infants.
The authors concluded that azathioprine is safe in mothers who are breastfeeding.
Angelberger et al. ,studied the risk of infection in babies who were breast-fed by mothers with inflammatory bowel diseases (IBD) on azathioprine. The infants of mothers receiving azathioprine did not show any significantly increased rate of infection
Cyclosporine
the authors estimated that a breastfed infant would receive less than 5% of an immunosuppressive dose.
Onstensen et al. ,demonstrated that serum CsA level in infants were less than 2% of the mother CsA serum level. without any evidence of growth retardation or any reported side effects.
Nyberg et al. concluded that no nephrotoxic effect or other side effect was occurred or noticed in these infants.
There was variability in breast milk drug levels, ranging from lower concentration in the fore-milk in comparison to higher concentration in the hind milk.
Tacrolimus
French et al. reported that maximum amount of TAC that will be received by the baby was 0.02% of the mother’s weight-adjusted dose.
Also they found the physical and neurological development was normal.
Another case reported by Gardiner et al. They advised that lactation in TAC-treated patients was safe with close monitoring of the infant.
Sirolimus and everolimus
it remains uncertain if breastfeeding by mums on sirolimus or everolimus is safe or not .
Mycophenolic acid
It is well known that MPA is contraindicated during pregnancy. It could cause spontaneous abortion and other foetal anomalies. A higher incidence of structural malformations was seen .
MPA in breastfeeding was not studied in humans. Animal studies have demonstrated that
MPA can be transferred to breast milk in rats.
Belatacept
The author did not find any clinical studies that looked at safety profile in infants being breastfed by mothers on belat accept. Product information revealed that belatacept secreted in breast milk of rats. They recommended that belatacept should not be used while breast-feeding .
*** Safety of Breastfeeding by Mothers on
Immunosuppressive Medication for Renal Transplantation: Obsession, Myth and Truth
#Please address the various issues related to immunosuppressive medications and breast feeding
# Steroids :
* Study conducted that the use of prednisolone in lactating mothers did not affect growth, infections or hematological complications in the infants.
* CNI in combination with steroids were safe in breast feeding mothers, with no side effects in infants of breastfeeding mothers.
# Azathioprine
* It was undetectable in collected mothers’ milk samples, so the study concluded that azathioprine is safe in mothers who are breastfeeding.
# Cyclosporine (CsA)
*Study found that CsA levels in the infant blood were 2% of mothers’ serum level, while others reported that maternal milk contains one-sixth of cyclosporine blood level of the lactating mothers.
* Behrens et al. showed that milk cyclosporine levels ranged from 15 to 90% higher than simultaneous serum levels.
However, a breastfed infant receive less than 5% of an immunosuppressive dose.
* The infant was followed up for 2 years without any evidence of growth retardation or side effects of CsA affecting the child.
*This study concluded that no nephrotoxic effect or other side effect was occurred with mother taking prednisolone, azathioprine and CsA
*CsA level was undetectable in an infant blood who was breastfed for 10.5 months.
*There was lower concentration in the fore milk in comparison to higher concentration in the hind milk but with side effects were noted in both infants in regards to growth and renal function.
# Tacrolimus (TAC) :
* Tacrolimus level in infant breastfed of transplanted mother are very low,
and it was safe during taking tacrolimus
# Sirolimus and everolimus :
There are no specific trials for sirolimus and everolimus, but it was reported by Bramham et al. no clinical harm occurred.
# Mycophenolic acid (MPA)
*It is well known that MPA is contraindicated during pregnancy.
*It could cause spontaneous abortion and other foetal anomalies.
* A higher incidence of structural malformations was found in the use of MPA during pregnancy
*MPA in breastfeeding was not studied in humans. Animal studies have demonstrated that MPA can be transferred to breast milk in rats.
# Belatacept:
*They did not find any clinical studies that looked at safety profile in infants being breastfed by mothers on belat accept.
*They found belatacept secreted in breast milk of rats.
*They recommended that belatacept should not be used while breast-feeding.
# Please search for new evidence not addressed by this article
* Tacrolimus:
Are low in breast milk with no adverse effect to the breast fed infant, clinician from Transplantation Pregnancy Registry and other experts consider tacrolimus acceptable to use during breastfeeding after transplantation.
*Cyclosporine:
In combination with corticosteroid and azathioprine no reports of adverse effect on infant growth, development or kidney function.
Transplantation Pregnancy Registry and other experts consider Cyclosporine to be safe during breastfeeding after transplantation.
* MMF:
It is contraindicated in pregnancy, however because of little information is available on the use of MMF during breastfeeding most sources recommend avoiding it.
* Azathioprine:
Most experts consider breast feeding during azathioprine therapy to be acceptable
Breastfeeding After Organ Transplantation
Philip O. Anderson
Published Online: 12 Feb 2020
Doi: https://doi.org/10.1089/bfm.2019.0280
References
1. Transplant Pregnancy Registry International. 2017 Annual Report. Transplant Pregnancy Registry International (TPR) Gift of Life Institute Philadelphia, PA, 2018. Google Scholar
2. Armenti VT, Moritz MJ, Davison JM. Breastfeeding and tacrolimus: Is it a reasonable approach? Expert Rev Clin Immunol 2013;9:623–626. Crossref, Medline, Google Scholar
3. Constantinescu S, Pai A, Coscia LA, et al. Breast-feeding after transplantation. Best Pract Res Clin Obstet Gynaecol 2014;28:1163–1173. Crossref, Medline, Google Scholar
4. Krysko KM, LaHue SC, Anderson A, et al. Minimal breast milk transfer of rituximab, a monoclonal antibody used in neurologic conditions. Neurol Neuroimmunol Neuroinflamm 2020;7:e637. Crossref, Medline, Google Scholar
Please address the various issues related to immunosuppressive medications and breast feeding
Steroids
oral maintenance doses of prednisolone and azathioprine in 2 lactating mothers did not affect growth, the risk of infections or hematological complications in the infants. They found that immunoglobulin levels in the breast milk did not decrease.
50mg of prednisolone cause a very low levels in breast milk and have no any significant medical effect on infants. No side effect or any harm has been observed in infants who were breastfed by mothers receiving steroid. combination of CNI with steroids in breastfeeding mothers showed no side effects in infants of breastfeeding mothers.
Azathioprine
1.2-2.1mg/kg/day dose showed undetectable metabolites of azathioprine, 6-thioguanine (6-TGN) and 6-methylmercaptopurine nucleotides (6-MP), in the infant’s blood. Breast milk analysis of 6-MP, was undetectable in collected mothers’ milk samples and there was no side effect noted in their infants. .Only 2 samples had a very low level (1.2-7.6ng/ml) compared to mother’s blood level (50ng/ml). The risk of infection in babies (age 3.3-4.7years) who were breast-fed by mothers with inflammatory bowel diseases (IBD) on azathioprine was comparabl to the control group.
Cyclosporine (CsA)
CsA levels in the infant blood were 2% of mothers’ serum level. Maternal milk contains one-sixth of cyclosporine blood level of the lactating mothers. Although the milk cyclosporine levels ranged from 15 to 90% higher than simultaneous serum levels, breastfed infant would receive less than 5% of an immunosuppressive dose. serum CsA levels in 6 infants were less than 2% of the mother CsA serum level. CsA dose was less than 0.1mg/kg in the infant while the mother was receiving 3mg/kg. The infant was followed up for 2 years without any evidence of growth retardation or any reported side effects of CsA affecting the child.
Studies showed that breastfeeding can be allowed in the renal transplanted mothers( prednisolone, azathioprine and CsA ). Blood CsA levels were below the detection limit of 30ng/ml in all infants.
Excretion of CsA in breast milk varies from 16 micrograms/L to 596 micrograms/L. There was variability in breast milk drug levels, ranging from lower concentration in the fore-milk in comparison to higher concentration in the hind milk. That is explained by lesser fat in foremilk than in hind-milk.
Tacrolimus (TAC)
A dose of 0.1mg/kg/day produced mean concentration of tacrolimus in milk of 0.429ng/ml. TAC intake infant was estimated at 0.06 microgram/kg/day. The maximum amount of TAC that will be received by the baby was 0.02% of the mother’s weight-adjusted dose. In one case report, a mother milk to blood TAC levels ratio was 0.23. The baby received about 0.5% of the maternal dose. In 6 infants with follow-up of 30 months,TAC level in infants was less than 1.9μg/L. So,lactation in TAC-treated patients was safe with close monitoring of the infant.
Sirolimus and everolimus
There are no specific trials for sirolimus and everolimus.
Mycophenolic acid (MPA)
MPA in breastfeeding was not studied in humans. Animal studies have demonstrated that MPA can be transferred to breast milk in rats.
Belatacept
No clinical studies involving safety profile in infants being breastfed by mothers. As belatacept is secreted in breast milk of rats it is recommended that belatacept should not be used while breast-feeding.
Please search for new evidence not addressed by this article
A recent CJASN paper published in 2022 is consistent with this 2017 paper. Corticosteroid was considered safe with infant exposure of 0.35%–0.58% of maternal prednisone dose. infant would receive at most 2% of the mother’s weight-adjusted dose of Cyclosporine which is not detectable in the infant’s blood, although rarely has it been . For tacrolimus, estimates of the ingested dose are 0.06%–0.5% of maternal weight-adjusted dose . Blood levels of tacrolimus in bottle- and breastfed infants are comparable. Data are lacking for breast milk concentration and infant exposure to mycophenolate products and mammalian target of rapamycin inhibitors.
Christina L. Klein, Michelle A. Josephson,Post-Transplant Pregnancy and Contraception, CJASN Jan 2022, 17 (1) 114-120; DOI: 10.2215/CJN.14100820
The immunosuppressants taken by transplanted mothers may be secreted in mothers’ milk, but for most drugs, it was of low levels. all studies are limited by the low number and short follow-up, but it seems safe to breastfeed while on steroid, AZA, CsA and TAC. MPA/MMF as contraindicated in pregnancy is not studied, and data is limited. Batalacept is not widely used, and data is limited. mTOR inhibitors, although seemingly not harmful, they are not well studied (according to the below-mentioned study: Breastfeeding is not recommended due to delayed wound healing and lack of evidence demonstrating safety)
I did not find a clinical trial but this review published in 2021 summarizes similarly what we learned from our journal club.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515073/pdf/main.pdf
(Sexuality, Contraception, and Pregnancy in Kidney Transplantation)
Agarwal, K. A., & Pavlakis, M. (2021). Sexuality, Contraception, and Pregnancy in Kidney Transplantation. Kidney Medicine, 3(5), 837-847.
Immunosuppressive medications and breast feeding
Safety immunosuppression during breastfeeding is a concern with the increasing of transplant women in childbearing period.
Breastfeeding with receiving CNI, AZA and steroids is considered safe.
More frequent drug level monitoring in those mothers is needed.
Drug level in breast milk and infant blood may be checked.
No available trials addressed safety of MMF, sirolimus, everolimus or belatacept in case of breastfeeding.
The mother and infant should be regularly evaluated to follow up mental and physical growth.
Mothers receiving CNI or azathioprine, their infants should be checked for nephrotoxicity and hematological side effects respectively.
Safety of mTOR inhibitors is not yet established. Animal studies showed that MMF and Belatacept were unsafe.
New evidence not addressed by this article
Corticosteroids: patients on doses >20mg prednisolone can delay feeding for 3-4 hours decreasing baby’s exposure to the drug.
Azathioprine: very small amount is excreted in breast milk with highest concentration 1-2 hours after drug ingestion ;could be used with breastfeeding.
Mycophenolate: not recommended in breastfeeding due to the limited data,
Rituximab: is suggested to be safe according to its pharmacological properties inspite of limited data during breastfeeding
mTORi and belatacept: it is recommended to be avoided
Paizis K. Immunomodulatory drugs in pregnancy and lactation. Australian prescriber. 2019 Jun;42(3):97.
Chandra A, Midtvedt K, Åsberg A, Eide IA. Immunosuppression and reproductive health after kidney transplantation. Transplantation. 2019 Nov 1;103(11):e325-33.
☆Safety of Breastfeeding by Mothers on
Immunosuppressive Medication for Renal
Transplantation: Obsession, Myth and Truth
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
▪︎This review is aimed to critically appraise current evidence to answer with a focus on
immune suppress. for renal transplantation.
☆Results:
1) There are no specific trials on MMF, sirolimus, everolimus or belatacept that addressed their safety during breastfeeding.
2) Most of the trials explored breastfeeding in patients treated with CNI , azathioprine and steroid.
3) Studies that looked at usage of steroids for autoimmune diseases.
☆Analytical Review:
Steroids:
_________
▪︎ The levels of prednisolone are at very low in breast milk and have no any significant medical effect on infants.
▪︎Some studies reported the safety of CNI in combination with steroids in breastfeeding mothers
Azathioprine:
______________
▪︎Is safe in mothers who are breastfeeding.
▪︎It’s metabolites is not detected in the infant’s blood.
▪︎In the infants of mothers receiving azathioprine no side effect is noted, no hematological abnormalities , and no increase in the rate of infections were found.
Cyclosporine (CsA):
____________________
▪︎Cyclosporine levels are undetectable or at insignificant levels in infants breastfed by mothers on this drug.
▪︎No evidence of growth retardation, nephrotoxic effect or any reported side effects of CsA affecting the child.
Tacrolimus (TAC):
___________________
▪︎Tacrolimus levels were detected in infants’ serum but at insignificantly low levels
▪︎Breastfeeding is safe.
Sirolimus and everolimus:
_____________________________
▪︎There are no specific trials for sirolimus and everolimus.
▪︎It remains uncertain if breastfeeding is safe or not.
Mycophenolic acid (MPA):
___________________________
▪︎Is contraindicated during pregnancy.
▪︎It could cause spontaneous abortion, foetal anomalies & structural malformations
▪︎MPA in breastfeeding was not studied in humans and the data based on animal studies is rather limited.
Belatacept:
____________
▪︎No clinical studies that looked at safety profile in infants being breastfed by mothers on belataccept.
▪︎Product information revealed that belatacept secreted in breast milk of rats and they recommended that it should not be used while breast-feeding.
☆Discussion:
_______________
▪︎Planning conception when the allograft function is stabilised.
▪︎Transplanted mothers who breastfeed while they are on immunosuppression
medications are increasing progressively over the last 20 years
▪︎Transplant clinicians should encourage breastfeeding whenever it is possible for many reasons.
1) The increasing number of women in childbearing age group deserves a normal life after transplantation.
2) Most of the cases that have been published show that breastfeeding while
receiving CNI, azathioprine and steroids are relatively safe.
3) Although there is no clear guidelines, a large percentage of mothers, as shown in the annual report of NTPR30, have
preferred to breastfeed their infants.
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
☆Please search for new evidence not addressed by this article:
▪︎Long-term follow up on breastfed infants is not well-documented
▪︎Rituximab: no long term safety data
▪︎The exposure in utero to immunosuppression is greater than via breast milk [2].
▪︎No lingering effects due to breast-feeding have been found to date in infants who were breast-fed while their mothers were taking prednisone, azathioprine, cyclosporine, and/or tacrolimus.
▪︎Except for those medications where clinical information is inadequate (mycophenolic acid products, sirolimus, everolimus, and belatacept),the recommendation for transplant recipients regarding breast-feeding has evolved into one that is cautiously optimistic [2].
_____________________
Reference
[1] Ghada Ankawi. Lecture:Pregnancy and lactation in Kidney
Transplantation. ASNRT.
[2]Serban Constantinescu et al. Breast-feeding after transplantation.Best Pract Res Clin Obstet Gynaecol. 2014 Nov.
levels of prednisolone are at very low levels in breast milk and have no any significant medical effect on infants
azathioprine is safe in mothers who are breastfeeding.
CSA is relatively safe as well
lactation in TAC-treated patients was safe with close monitoring of the infant.
no specific trials for sirolimus and everolimus.
MPA in breastfeeding was not studied in humans. Animal studies have demonstrated that MPA can be transferred to breast milk in rats
belatacept should not be used while breast-feeding
most of the cases that have been published show that breastfeeding while receiving CNI, azathioprine and steroids are relatively safe.
the drug level in breast milk and in the blood samples of the infant may need to be checked
Safety of Breastfeeding by Mothers on Immunosuppressive Medication for Renal Transplantation: Obsession, Myth and Truth.
Please address the various issues related to immunosuppressive medications and breast feeding.
Breastfeeding is encouraging in post kidney transplant female after delivery .
It has many organic and psychological benefits for mother and baby but still there is an obstacle regarding the immunosuppressive medications safety in this situation.
Breastfeeding by mothers (who are allograft recipient and are on steroid, azathioprine and CNI) is safe and no risk or harmful affect the infants of these mothers.
It is still not clear if mTOR inhibitors are safe during breastfeeding.
MMF and belatacept have been proved to be unsafe in animal studies.
Please search for new evidence not addressed by this article.
Gonzalez Suarez ML, Kattah A, Grande JP, Garovic V. Renal Disorders in Pregnancy: Core Curriculum 2019. Am J Kidney Dis. 2019 Jan;73(1):119-130. doi:10.1053/j.ajkd.2018.06.006. Epub 2018 Aug 16. Erratum in: Am J Kidney Dis. 2019 Jun;73(6):897. PMID: 30122546; PMCID: PMC6309641.
Women of childbearing age who wish to conceive after a successful kidney transplant is growing and with this comes the most valid question
Doc can I breast feed my baby?
The authors of this mini review have tried to address this issue on the basis of published literature.The most commonly used immunosuppressive drugs like
Steroids
CNI
Azathioprine
are considered SAFE
Safety of MMF, Sirolimus, belatacept and Everolimus remains questionable as there was no available human data according to this review.
Couldn’t find any new evidence regarding this issue🙏🏽
Female patients who received renal allograft , deserve normal life post transplantation , so peri transplant counseling is very important regarding the conception , contraception & breastfeeding.
Encouragement of Breast feeding is advised as The side effects of immunosuppressive medications was taken in consideration and its exposure on the infants & excretion in the breastfeeding was studied.
The following immunosuppressive medications are excreted in mother`s milk in very small amount & are safe :
Most of the trials explored breastfeeding in patients treated with calcineurin inhibitors (CNI), azathioprine and steroid.
1-Steroids . studies demonstrated the safety of steroids in breastfeeding kidney transplanted mothers with no side effects in their infants .
1- CNI ( cyclosporine & tacrolimus ) follow up of the drug level is important .
3-Azathioprine.
There are no specific trials on MMF, sirolimus, everolimus or belatacept that addressed their safety during breastfeeding.
Data for mTOR inhibitor, belatacept, Basiliximab, rituximab and ATG is very limited.
. There is an increase in the numbers of young female patients who are coming through successful solid organ transplantation so that transplanted mothers who breastfeed while they are on immunosuppression medications are increased.
Steroids
– Oral maintenance doses of prednisolone did not affect growth, immunoglobulin
levels in the breast milk, the risk of infections, or hematological complications in the infants.
-The levels of prednisolone are at very low levels in breast milk and have no significant medical effect on infants .
-Combination of CNI and steroid are safe in breastfeeding mothers.
Azathioprine
– Azathioprine metoblites ( 6-TGN and 6-MMPN )were undetectable in the infant’s blood.
-6-MP was undetectable in collected mothers’ milk samples and there was no side effect noted in their infants.
-No hematological abnormalities were found in neonates.
-The maximum level of 6-MP in the breast milk was at 4 hours post administration of the azathioprine .
-azathioprine is safe in mothers who are breastfeeding and there is no significantly increased rate of infection.
Cyclosporine (CsA)
– CsA levels in the infant blood were 2% of mothers’ serum level.
-There is no evidence of growth retardation or t nephrotoxic effect or other side effects was occurred or were noticed in infants.
-CsA was undetectable in the blood of a breastfed infant (<10ng/L).
Tacrolimus (TAC)
-Milk to blood TAC levels ratio was 0.23. The baby received about 0.5% of the
maternal dose.
-TAC level in infants was less than 1.9μg/L.
– Lactation in TAC-treated patients was safe with close monitoring of the infant.
Sirolimus and everolimus
-There are no specific trials for sirolimus and everolimus.
-It remains uncertain if breastfeeding by mums on sirolimus or everolimus is safe or not.
Mycophenolic acid (MPA)
-It is well known that MPA is contraindicated during pregnancy.
– It could cause spontaneous abortion and other fetal anomalies.
Belatacept
-There are no clinical studies that looked at the safety profile in infants being breastfed by mothers on belatacept.
-It was recommended that belatacept should not be used while breast-feeding Rituximab
–There are limited data on breastfeeding. The pharmacological properties of rituximab suggest it should be safe.
Reference:
-Kathy Paizis.Immunomodulatory drugs in pregnancy and lactation. Aust Prescr. 2019 Jun; 42(3): 97–101.
Rates of pregnancy post-transplant are increasing due to increased and early access to transplant as well as newer immunosuppressive drugs giving good graft outcomes.
The most important issue associated with immunosuppressive medications in breastfeeding is the exposure and effect of these drugs on the infant, which can be enumerated as follows:
1) Steroids: They have no significant medical effect, no effect on growth, infections or hematological complications. They are safe if used in combination with calcineurin inhibitors.
2) Azathioprine: Maximum level of azathioprine in breast milk is at 4 hous post intake, but still the exposure to the infant is very less and it is safe to use azathioprine in breastfeeding.
3) Cyclosporine: Cyclosporine levels in breast milk are 15-90% of the serum levels (with lower concentration in fore-milk and higher concentration in hind-milk) but the exposure to the infant is very low and it is safe to breastfeed while on cyclosporine.
4) Tacrolimus: Tacrolimus levels in the infant breastfed by a patient on tacrolimus are very low and it is safe to breastfeed while taking tacrolimus.
5) Sirolimus and everolimus: No specific trials have been conducted, but a case report has shown no harmful effects.
6) Mycophenolic acid: Human studies have not been done to assess effect on breastfeeding although the drug transfer to infants through breastmilk has been shown in rats.
7) Belatacept: Human studies have not been done to assess effect on breastfeeding although the drug gets secreted in breastmilk of rats and it has been recommended not to use it while breast-feeding.
So, it is safe to conclude that breastfeeding should be encouraged if on Calcineurin inhibitors, Azathioprine and steroids. There is no clear-cut data on mTOR inhibitor use, while MMF and belatacept use has been proved unsafe in animal studies.
Data has reinforced that use of CNI, Azathioprine and steroids is safe in breastfeeding. Data for mTOR inhibitor, belatacept, Basiliximab, rituximab and ATG is very limited, hence should be avoided.(1,2)
Reference:
1) Chandra A, Midtvedt K, Åsberg A, Eide IA. Immunosuppression and Reproductive Health After Kidney Transplantation. Transplantation. 2019 Nov;103(11):e325-e333. doi: 10.1097/TP.0000000000002903. PMID: 31397802.
2) Singh M. Breastfeeding and Medication Use in Kidney Disease. Adv Chronic Kidney Dis. 2020 Nov;27(6):516-524. doi: 10.1053/j.ackd.2020.05.007. Epub 2020 May 11. PMID: 33328068; PMCID: PMC7211684.
The benefits of normal lactation, physical and psychological elements, for the infant as well as the mother, are well established and well known. There are only a few studies performed to address the safety of immune suppression, especially the novel immunosuppressive drugs, from the point of view of breastfeeding by a transplanted mother.
Steroid:
prednisolone are very low levels in breast milk and did not affect growth, the risk of infections or hematological complications in the infants. Immunoglobulin levels in the breast milk did not decrease in patients receiving immunosuppression.
Azathioprine
Azathioprine metabolites, 6-thioguanine (6-TGN) and 6-methylmercaptopurine nucleotides (6-MP), were undetectable in the breast milk and there was no side effect noted on the infants. The infants of mothers receiving azathioprine did not show any significantly increased rate of infection when compared to the control group.
Cyclosporine
It is excreted in minimal amount in breast milk (less than 2% of the mother CsA serum level) but study showed no nephrotoxic or other adverse effects on the baby. Another study demonstrated undetectable Cyclosporine levels in the breastfed babies from mothers on Cyclosporine.
Tacrolimus (TAC)
The levels of tacrolimus in infants were undetectable and reach 0.5% of the mother’s dose. Studies advised that lactation in TAC-treated patients was safe but needs close monitoring of the infant.
m-TORS- Sirolimus and everolimus
There are no studies that report the effect of mTORi on babies. It is uncertain if breastfeeding by mothers receiving mTOR inhibitors is safe or not.
Mycophenolic acid
MPA is contraindicated during pregnancy. It is well known that MPA associated with fetal anomalies. MPA in breastfeeding was not studied in humans. Animal studies revealed that MPA can be excreted in rats’ milk. A higher incidence of structural malformations was seen with MMF exposures during 28 pregnancies in 18 kidney transplant recipients.
Belatacept
Authors recommend that belatacept should not be used while breast-feeding as there is no study evaluated the effect of belatacept on enfants breastfed from transplanted patients.
2.AZATHIOPRINE,
3.CYCLOSPORINE,
4.TACROLIMUS ,
5.SIROLUMUS AND EVORLIMUS ,
6.MYCOPHENOLATE MOFETIL,
7.BELATACEPT,
Thank you for the update
There is still a considerable fear of breast-feeding to infants when their mothers are immunocompromised and on immunosuppressive medicines .
Steroids:The levels of prednisolone are at very low levels in breast milk and have no any significant medical effect on infant. Other studies revealed the safety of CNI use with steroids in breastfeeding mothers.
Azathioprine: AZA ,and its metabolite 6-thioguanine (6-TGN) and 6-methylmercaptopurine nucleotides (6-MP) level in breast feeding milk is very low nearly undetectable and azathioprine is safe in mothers who are breastfeeding.
Cyclosporine (CsA): The breastfed infant can receive less than 5% of an immunosuppressive dose. CsA had no nephrotoxic nor other evident side effect on infants, so it is safe for mothers on CsA to do breastfeeding.
Tacrolimus (TAC):Low level of Tac in infant’s blood .Lactation in TAC-treated patients was safe with close monitoring of the infant.
Sirolimus and Everolimus:No specific trials conducted on their safety with breast feeding
Mycophenolic acid (MPA):It is contraindicated in pregnancy due to fetal anomalies and spontaneous abortion risk.No studies in breast feeding in humans
Belatacept: Better avoided in breastfeeding mothers as no studies are available.
Corticosteroids: Less than 0.1% of the maternal prednisolone dose is excreted in breast milk, patients on doses >20mg prednisolone can delay feeding for 3-4 hours decreasing baby’s exposure to the drug.
Azathioprine: Safety in lactating women is well documented, with only a small fraction of maternal AZA dose and 6-mercaptopurine detected in breast milk with highest concentration 1-2 hours after drug ingestion.
CNIs: are excreted in breastmilk, but it’s absorption in the infant is limited. Tac excretion into breast milk was 0.2% of the maternal dose.
Mycophenolate: It is highly protein-bound and unlikely to be excreted in breast milk in high concentrations ,But data limited so not recommended for use in breast feeding .
Rituximab: Rituximab absorption from the infant gastrointestinal tract is likely very low due to its large molecular weight. there are limited data and studies conducted in breastfeeding patients.
mTORi and belatacept: it is recommended to avoid these drugs due to scarce data.
REFERENCES:
1-Paizis K. Immunomodulatory drugs in pregnancy and lactation. Australian prescriber. 2019 Jun;42(3):97.
2-Chandra A, Midtvedt K, Åsberg A, Eide IA. Immunosuppression and reproductive health after kidney transplantation. Transplantation. 2019 Nov 1;103(11):e325-33.
Thank you for the update
Please address the various issues related to immunosuppressive medications and breast feeding
This article address in depth the safety profile of the different known immunosuppression medication use by kidney transplant mothers during lactation ,in general they found Limited data about the breast-feeding safety in kidney transplant recipient on immunosuppression and we should completely enlighten the lactating mother about the unknown and possible risks of breast feeding while on immunotherapy in this review they found there is no enough evidence to support the use of MMF , sirolimus eveolimus belatocept and better to avoid during breast feeding while the use of steroids , CNI , azathioprine considered safe with negligible excretion in breast milk with no increased risk of infections or hematological toxicity with azathioprine also did not affect the growth with CNIS and steroid best on the available evidence from different observational studies , pilot and case reports from different populations with short fu
Please search for new evidence not addressed by this article
TPR 2016 report they encourage the practice of breast feeding among transplant recipients since 1994-2016 with reassuring data about the safety use of prednisolone, azathioprine, CNI tacrolimus, cyclosporine) as maintenance IS during breast feeding as the exposure of these medication is low due to less excretion in the breast milk with no side effects reported
Prednisolone daily dose of 5-10 mg daily is safe
Azathioprine 1.2-2.1 mg /KG /day safe with undetectable level in breast fed fetus
Tacrolimus and cyclosporine same safety profile with negligible drug exposure
Belatocept , sirolimus , everolimus and MMF better to avoid due to inadequate data
So with the increased number of the young recipients at the reproductive age ,the breastfeeding should be encouraged based on the available evidence and known that infant immunosuppressive drug exposure via breastmilk is very low in addition the rate of breast feeding among solid organ transplant patients increased progressively but still large studies with long-term follow up are needed to address the long term safety profile on physical and mental fetal growth and nephrotoxicity
Still the safety of MMF , SIROLIMUS EVEROLIMUS ,BELATOCEPT uncertain
The prevalence of congenital malformations in children fathered by male recipients, including patients on mycophenolic acid therapy at the time of conception, is at level with the general population (2).
However, the MMF associated with the risk of organ malformation up to 23% and miscarriage in > 50% (3,4).
References:
1-Kidney transplantation in adults: Sexual and reproductive health after kidney transplantation up-to-date medicine 2022.
2-Chandra A, Midtvedt K, Åsberg A, Eide IA. Immunosuppression and Reproductive Health After Kidney Transplantation. Transplantation. 2019 Nov;103(11): e325-e333.
3-Boulay H, Mazaud-Guittot S, Super vielle J, et al. Maternal, foetal and child consequences of immunosuppressive drugs during pregnancy in women with organ transplant: a review. Clin Kidney J. 2021;14(8):1871-1878. Published 2021 Mar 3. doi:10.1093/ckj/sfab049
4-Shah S, Verma P. Overview of pregnancy in renal transplant patients. Int J Nephrol 2016; 2016: 4539342
5-Combs J, Kagan A, Boelkins M et al. Belatacept during pregnancy in renal transplant recipients: two case reports. Am J
Transplant 2018; 18: 2079–2082
Thank you for the update
o The purpose of this article is to discuss the safety of immunosuppressive drugs during breastfeeding in women who have had kidney transplants.
Steroids: No negative effects were seen with the use of a steroid, even at high doses, and no changes in immunoglobulin levels in breastfeeding women were observed with the use of steroids.
Lactating women with kidney transplants are not at risk of infection or having their haemoglobin levels altered by azathioprine or its metabolites (6-thioguanine and 6-methyl mercaptopurine), and there is no indication of infection risk or haematological alterations in newborns.
Cyclosporine: Indication from research indicates that maternal milk contains 1/6 of the cyclosporine found in the blood of nursing women and that the drug is undetectable in the blood of newborn newborns, with no evidence of nephrotoxic effects on neonates.
-Tacrolimus has a measurable quantity in babies, however, the amount is minimal.
– MPA has been shown to be transferred to breast milk in rats; however, there have been insufficient studies conducted in humans; however, it has been observed that there is no significant adverse effect on the baby who is breastfed by the mother while exposed to MPA; therefore, an alternative drug should be used.
– Sirolimus lacks adequate evidence, and although it has been shown to be safe in a few trials, it is preferable to switch to an alternate medication.
Despite the fact that everolimus is rather safe, particularly in the first few days after childbirth when colostrum is present and the amount of everolimus is not excessive, other medications should be considered since there are insufficient studies and data.
-Azathioprine: Studies have shown that the amount of AZA, (6MP) in breast milk is very low, almost undetectable and that it has not been discovered in baby blood, leading to the conclusion that it is safe for babies and that it is connected with a low infection risk for neonates.
Belatacept: While there are no studies available, it is best to avoid nursing in the meanwhile.
Update Weam?
Safety of breastfeeding while on immunosuppression is a concern with the increasing number of young transplant women in childbearing period.
Breastfeeding has several physiological and psychological benefits.
Few studies investigated the safety of immunosuppressive agents especially novel therapy during breastfeeding.
Breastfeeding while receiving CNI, azathioprine and steroids are considered safe with no harmful effects on the infants.
Drug level monitoring in those mothers should be more frequent.
Drug level in breast milk and blood sample of infant may be checked.
No specific trials addressed safety of MMF, sirolimus, everolimus or belatacept during breastfeeding.
The mother and infant should be regularly evaluated to follow up mental and physical growth.
Mothers receiving CNI or azathioprine, their infants should be checked for nephrotoxicity and hematological complications respectively.
Safety of mTOR inhibitors is not well established
MMF and belatacept were unsafe in animal studies.
Corticosteroids: small amount are found in breast milk, patients on doses >20mg prednisolone can delay feeding for 3-4 hours decreasing baby’s exposure to the drug.
Azathioprine: compatible with breast feeding, very small amount is excreted in breast milk with highest concentration 1-2 hours after drug ingestion.
Mycophenolate: Breastfeeding is not recommended due to the limited data,
Rituximab: there are limited data on breastfeeding but is suggested to be safe according to its pharmacological properties.
mTORi and belatacept: although limited data is available, it is recommended to avoid these drugs.
Paizis K. Immunomodulatory drugs in pregnancy and lactation. Australian prescriber. 2019 Jun;42(3):97.
Chandra A, Midtvedt K, Åsberg A, Eide IA. Immunosuppression and reproductive health after kidney transplantation. Transplantation. 2019 Nov 1;103(11):e325-33.
Thank you for the update
III. Safety of Breastfeeding by Mothers on Immunosuppressive Medication for Renal Transplantation: Obsession, Myth and Truth
Please address the various issues related to immunosuppressive medications and breast feeding
There are limited studies that looked into the safety of breast feeding by a transplanted mother using IS medications, especially the novel agents.
Steroids
· Prednisolone plus azathioprine in lactating mothers caused no problems in
infants (Grekas et al)
· A 50mg of prednisolone used asthmatic mothers caused no problems in
infants (Greenberger et al).
· CNI combined with steroids was safe in breast feeding mothers (Morreti et al &
Bramham et al).
· Arakali et al. reported no S/Es in infants of breastfeeding mothers.
Azathioprine
· Metabolites (6-TGN & 6-MP) undetectable in the infant’s blood(Gardiner et al).
· Metabolites undetectable in mothers’ milk & there was no S/E in infants(Morretti
et al.).
· In 2 out of 29 breast milk samples, a very low level of metabolites was
detected compared to mother’s blood level (Sau et al.).
· Christensen et al., studied 6 lactating mothers with IBD & concluded that
azathioprine is safe in mothers who are breastfeeding.
· Infants of mothers receiving azathioprine did not show any significantly
increased rate of infection when compared to the control group (Angelberger
et al.).
Cyclosporine (CsA)
· Levels in the infant blood were =<2% of mothers’ serum level(Lewis et al &
Onstensen et al).
· Maternal milk contains one-sixth of blood level of the lactating mothers
(Ziegenhagen et al.).
· Behrens et al. showed that milk cyclosporine levels are 15-90% higher than
simultaneous serum levels; however breastfed infant receive less than 5% of
an IS dose.
· No growth retardation or any reported side effects of CsA affected children
followed for 2 years (Thiru et al).
· No nephrotoxic effect or other S/Es was noticed in infants breastfed by
mothers taking prednisolone, azathioprine & CsA (Nyberg et al.).
· CsA level was undetectable in an infant blood who was breastfed for 10.5
months.
· Moretti et al concluded that CsA level in milk varies from 16 (fore milk) to 596
(hind milk) micrograms/L. The levels variability is explained by lesser fat in
fore-milk than in hind-milk.
· Osadchy et al & Morton et al. failed to detect CsA in the blood of infants.
Tacrolimus (TAC)
· TAC intake by infants of liver transplanted mothers was negligible, & physical
& neurological development was normal.
· Gouraud et al advised that lactation in TAC-treated patients was safe with
close monitoring of the infant.
· Zheng et al. concluded that breast feeding is safe in a mother receiving
tacrolimus.
Sirolimus and everolimus
· No specific trials for sirolimus & everolimus.
· No harm occurred in in 1 of 14 infants breastfed by a mother receiving
sirolimus in addition to TAC (Bramham et al); ho clinical harm occurred, but
the investigators did however sirolimus level was not checked in infant’s
blood.
· It is uncertain if breastfeeding while taking sirolimus or everolimus is safe or
not.
Mycophenolic acid (MPA)
· MPA is contraindicated during pregnancy.
· It causes spontaneous abortion & fetal anomalies.
· Malformations were seen with MMF exposures pregnancy.
· MPA in breastfeeding was not studied in humans.
· Animal studies showed that MPA can be transferred to breast milk in rats.
Belatacept
· No clinical studies are available.
· Belatacept is secreted in breast milk of rats.
· Not recommended for use while breast-feeding.
Recommendations:
Breast feeding should be encouraged because:
1. The increasing number of women in childbearing age group deserves a normal
life after transplantation.
2. Most published data show that breastfeeding while receiving CNI, azathioprine
& steroids are relatively safe.
3. A large percentage of mothers, as shown in the annual report of NTPR 30, have
preferred to breastfeed their infants.
========================================
Please search for new evidence not addressed by this article
Breastfeeding
Considered safe on prednisone, Azathioprine, & CNI as minimal transfer into breast milk is documented
• Long-term follow up on breastfed infants is not well-documented
• Other agents: no enough data
• Overall, infant’s exposure to immunosuppression with breastfeeding is lower than in utero exposure
Clin J Am Soc Nephrol. 2021 Mar 17;CJN.14100820
================================
Sirolimus
• May cause lower sperm counts, dysmotility, and reduced spontaneous pregnancy rates
Tranplantation 2017 Jul; 101(7): e214–e217
Clin J Am Soc Nephrol. 2021 Mar 17;CJN.14100820
========================================
MMF
Anomalies include, microtia or anotia, with external
auditory canal atresia & other craniofacial malformations
First trimester exposure is associated with miscarriages in > 50%
Birth defects in up to 22.9%
All women of childbearing potential must be advised to use either an IUD or two alternative contraceptive agents while on it
Am J Med Genet A. 2009 Jun;149A(6):1241-8
Clin J Am Soc Nephrol. 2021 Mar 17;CJN.14100820
Reference
Ghada Ankawi. Lecture:Pregnancy and lactation in Kidney
Transplantation. ASNRT. Fellowship in Clinical Transplantation
Thank you for the update
1. There are no specific trials on MMF, sirolimus, everolimus or belatacept that addressed their safety during breastfeeding.
2. Most of the trials explored breastfeeding in patients treated with calcineurin inhibitors (CNI), azathioprine and steroid.
3. Studies demonstrated the safety of steroids in breastfeeding kidney transplanted mothers with no side effects in their infants .
4. Studies did not detect the metabolites of azathioprine in the collected kidney transplanted mothers’ milk samples and there was no side effect noted in their infants.
5- Studies demonstrated the safety of azathioprine in mothers who are breastfeeding
6- Studies found that,There was variability in breast milk CsA levels, ranging from lower concentration in the fore-milk in comparison to higher concentration in the hind milk.
7.Studies reported no CsA related nephrotoxic effect or other side effect was occurred or noticed in infants of breastfeeding kidney transplanted mothers.
8- In conclusion of these studies, CsA is safe for mothers to do breastfeeding .
9- Studies reported that ,It is safe for mothers on TAC to do breastfeeding.
10-There are no specific trials for sirolimus and everolimus. No clinical harm occurred, but the investigators did not check sirolimus level in infant’s blood. Therefore, it remains uncertain if breastfeeding by mums on sirolimus or everolimus is safe or not.
11- It is well known that MPA is contraindicated during pregnancy. It could cause spontaneous abortion and other foetal anomalies.
12-There is no any clinical studies that looked at safety of belataccept profile in infants being breastfed by mothers on belataccept. Product information revealed that belatacept secreted in breast milk of rats. They recommended that belatacept should not be used while breast-feeding
Thank you for the update, but where are the references?
Please address the various issues related to immunosuppressive medications and breast feeding :
1- Steroids :
– no adverse effects even in high doses of up to prednisolone 50 mg/day. however, these studies were on non-transplant mothers treated with steroids for other medical disorders.
2- Azathioprine :
– drug levels were not detected in breast milk or infant blood. also, there was no an increase in the risk of infection.
3- CNIs ( Cyclosporin and Tacrolimus) :
– drug levels were very low in infant blood.
4- MMF, Sirolimus and Belatacept :
– there were no specific trials addressing the safety of these drugs. however, based on small studies, there was no conclusive evidence of any delay in physical development of infants.
Thank you for the update, but where are the references?
Safety of Breastfeeding by Mothers on Immunosuppressive Medication for Renal Transplantation: Obsession, Myth and Truth.
1- Steroid:
prednisolone are very low levels in breast milk and have no any significant medical effect on infants.
2- Azathioprine
Azathioprine metabolites were undetectable in the breast milk and has no side effect on the infants.
3- Cyclosporine (CsA)
It is excreted in minimal amount in breast milk but, it has no nephrotoxic or other adverse effects on the baby.
4- Tacrolimus (TAC)
The infants of mothers on tacrolimus receive 0.5% of the mother’s dose, although studies advised that lactation in TAC-treated patients was safe with close monitoring of the infant.
5- Sirolimus and everolimus
It is still uncertain if breastfeeding by mothers receiving mTOR inhibitors (sirolimus or everolimus) is safe or not.
6- Mycophenolic acid (MPA)
It is well known that MPA associated with fetal anomalies. And contraindicated in pregnancy. MPA in breastfeeding was not studied in humans. Animal studies revealed that MPA can be excreted in rats’ milk.
7- Belatacept
It should not be used while breast-feeding, it is proved to be unsafe in animal studies.
In conclusion:
Breastfeeding seems to be safe and should be encouraged by the clinician in the mothers who are no steroids, CNI and azathioprine.