Disease name and definition
Epidemiology
Clinical description of the consequences of immunosuppressive drugs on fertility and pregnancy
Immunosuppressive drugs and fertility
Immunosuppressive therapies and pregnancy
Diagnosis
Differential diagnosis
Aetiologies or effects of the different classes of immunosuppressive agents on fertility and pregnancy
Immunosuppressants | Hypothalamic–pituitary–gonadal axis | Gametogenesis | Mutagenesis | Teratogenesis | Pregnancy | NN | Management |
---|---|---|---|---|---|---|---|
A: Contraindicated drugs when pregnancy is desired | |||||||
Methotrexate | M: alteration debated, reversible after stopping for 3 months | M: mutagenic | F: teratogenic without dose effect, especially between 6 and 8 weeks | Increased frequency MC 23% | CI during pregnancy, especially during the first trimester. | ||
W: No effect: AMH the same at 6 months between treated or non-treated population but less response to ovarian stimulation the first 18 months post-MTX | >30 cases of malformation of the CNS, skull, limbs, IUGR, cardiopathy | Discontinuate at least 3 months before pregnancy in both genders | |||||
Mycophenolate | In rats: no effect on fertility | mutagenic in vivo in rats | W: clasto-carcino-teratogenic: multiple craniofacial anomalie,… | crosses placenta +++ | NN heamato monitoring if data at 2nd or 3rd trimester | Switch to another drug before pregnancy | |
M: No effect | increased risk of MC | ||||||
Le- and teri-flunomide inhibitor of de novo synthesis of pyrimidine | Total elimination of the drug may take 8 to 24 months. | No adverse effect on male or female, even in animals at high doses | neither mutagenic nor clastogenic | Teratogenic in animals: head malformations | insufficient human data | one case of congenital blindness | Stop ≥ 3.5 months before conception or Wash-out with cholestyramine (8gx3/day) or charcoal (50gx4/day) – 10 days to obtain concentration< 0.02 mg/L |
no studies in humans | |||||||
Sperm cryopreservation recommended before treatment in men | |||||||
Cyclophosphamide cytotoxic alkylating agent | W: FSH/LH increased, even with short exposures | Lasting alteration of ovarian reserve that is dose-, duration- and age-dependent: low AMH | mutagenic | embryolethal and teratogenic without dose effect, especially if early exposure: limbs, dysmorphia, eye, | CI during pregnancy and breastfeeding IUGR | more late exposure, more significant risk NN haemato | Effective contraception to be continued until end of treatment |
Wait for one ovulation cycle after discontinuation before conception | |||||||
Mitoxantrone | anomalies of the menstrual cycle or even permanent amenorrhea in 7 to 14% of treated patients in correlation with the cumulative dose and the age of exposure | deleterious effect on spermatozoïds and ovocytes leading to fertility alterations. In association with other anti-cancer drugs, | aneuploidism and azoospermia spontaneously improved after 3 to 5 months of treatment discontinuation | teratogenic in animals and humans | Contraindicated in pregnancy . | ||
A period of 6 months is required after treatment before conception | |||||||
Sperm cryopreservation recommended before treatment in men and contraception is required in women. | |||||||
Thalidomide | teratogenic in humans | ||||||
B: Drugs to be used with caution if needed | |||||||
mTOR inhibitors | M: inhibitor | M: oligoasthenosper mia, reversible if stopped (debated) | No mutagenic effect in vitro/in vivo
| embryo- and foetotoxic in animals | −16 reported pregnancies | Substitute with other drug and continue contraception for 12 weeks after stopping treatment | |
- sirolimus | Testicular atrophy | −3 MC and one child with multiple malformations (+MMF) | No information on breast feeding | ||||
- everolimus | W: menstrual disorders 1st year of graft, and 50-60% ovarian cysts, diminishing upon stopping or taking OP in 80% of cases | ||||||
temsirolimus | |||||||
anti-TNFα | M: no effect | M: no effect | non-mutagenic | W: non-teratogenic in animals and in about 50 pregnancies | 1st trimester: Few data etanercept/certolizumab ≠ inflixi/adali:mumab NTR | Crosses placental barrier ± (infliximab until 6 months in NN), less for etanercept, certolizumab | Not recommended to discontinue therapy if desire for pregnancy. |
Anti-cytokine | W: no studies | FDA: increased risk cardiac malformations – low level of proof | 2nd3rd trim: 20 cases: inflixim- adalim- certoliz- umab-: NTR | CI live vaccines | |||
etanercept | |||||||
infliximab | |||||||
adalimumab | |||||||
certolizumab | One child of mother treated entire pregnancy, died from BCG (TB vaccine) complications | Infections without fever | |||||
golimumab | |||||||
C: Authorised drugs | |||||||
Anti-inflammatory | M and W: synthetics and high dose inhibit hypothalamic–pituitary–gonadal axis | promotes apoptosis of germ cells | not more cleft lip-palate | IUGR, premature, eclampsia > | - case of NN ACI after high doses | Possible breast feeding | |
glucocorticoids | W: In practice, no major impact on fertility | actual role of GC or underlying disease? | - predisposes to unfavourable adult metabolic profile | ||||
Anti-inflammatory | M: oligoasthenoteratospermia reversible after 2 months of stopping; 60% infertility. W: no effect | no effect | increased prematurity | No information on breast feeding | Prescribe folates | ||
Sulfasalazine Mesalazine | Prefer Mesalazine | ||||||
Anti-metabolites | M and W: no effect | few deleterious effects | mutagenic in vivo /in vitro
| M and W: Non-teratogenic | increased prematurity | Breastfeeding CI ± failure to thrive + reversible haematological NN risk | - Avoid use in a male patient wishing a conception |
Azathioprine | carcinogenic and teratogenic in animals | Mutagenic | |||||
- Discontinuation 3 months before conception | |||||||
Prodrug of 6 mercaptopurine | |||||||
- US survey of pregnancy if conception by a treated father | |||||||
- Sperm cryopreservation recommended | |||||||
- Use possible regardless of pregnancy term. | |||||||
- Possible breast feeding | |||||||
Beta interferon | increase of LH | Alterations of ovarian reserve | high molecular weight and should not cross the placenta. | no teratogenic effect | numerous reported pregnancies with either the father or the mother treated : no problem | lower birth weight and higher rate of spontaneous abortions, in the treated mother, even if the treatment is stopped as soon as the pregnancy is known | - Discontinuation not necessary in case of pregnancy |
No sperm alterations | |||||||
- No long term deleterious effects have been reported in the offspring | |||||||
Glatiramer acetate | increase of LH | Decrease of ovarian surface and number of antral follicles | high molecular weight and should not cross the placenta. | no teratogenic effect | numerous reported pregnancies with either the father or the mother treated : no problem | - Discontinuation not necessary in case of pregnancy | |
- No long term deleterious effects reported in the offspring | |||||||
Chloroquine | - No deleterious effects on pregnancy or breastfeeding | ||||||
Calcineurin inhibitors | W: no effect | M: asthenoteratospermia if dose > 2mg/kg/day | W: non-teratogenic, limited crossing to placenta (5-20%) | increased infectious risk (CMV)premature / IUGR | passes into breast milk, undetectable in newborns | Use possible during pregnancy; More experience with cyclosporine | |
Ciclosporine | |||||||
Tacrolimus | |||||||
non-teratogenic; 2 cases of congenital malformations | 30% premature/ low-birth weight | no renal repercussions in NN | Caution regarding infections | ||||
Reversible involvement of lymphocytes, without clinical repercussions. | Possible breast feeding | ||||||
rare cases of transient kidney failure in NN | |||||||
D: Drugs with limited experience (biological therapies, inductors) | |||||||
Tocilizumab Anti-IL-6 monoclonal Ab | poorly understood effects on fertility clearance: 2 weeks | Large molecule with limited crossing to placenta and breast milk | animal studies: no lethal effect. | poorly understood effects on both fertility and pregnancy | Very few pregnancies reported. | Avoid pregnancy-Limited experience- Continue contraception 3 months after stopping (FDA). | |
Rituximab anti-CD20 monoclonal Ab, B lymphocyte inhibitor | long half-life. | Very limited transplacental crossing (debated) | 150 pregnancies, some with early exposure: NTR | Prematurity 15% Haematological anomalies, sometimes infections up to 6–12 months after stopping | Avoid pregnancy less than 12 months after stopping | ||
Abatacept (anti-CD28 Ab or CTLA-4 fusion protein, inhibiting the co-stimulation pathway of the T lymphocytes (anti-T)
| clearance: 2 ½ months (half-life = 14 days) | -non-altered in animals | large molecule: | non-teratogenic in animals | Several pregnancies with early exposure: NTR | Avoid pregnancy Limited experience | |
- W: no studies | |||||||
Anankira anti-IL-1 receptor | little teratogenicity in the 1st trimester since limited crossing of placenta ± end of the 2nd trimester when its crossing increases. | <5 pregnancies reported: NTR | Administration in 3erd trimester with increased risk of NN immunosuppression, and CI live vaccines for at least the first 6 months following birth. | Avoid pregnancy Limited experience | |||
Dimethyl fumarate | inhibitor of immune cells and an anti-oxidant | consequences on fertility not known. | consequences on pregnancy not known. | ||||
Natalizumab | Fertility alterations in female but not male animals | No teratogenic effects - effects not fully known yet | Discontinuation of treatment recommended 2 months before conception in men. | ||||
Fingolimod or FTY 720 or Sphingosine 1-phosphate receptor modulator | Effects on fertility not well known, − Would have a protective effect on ovarian function at least in vitro
| teratogenic effects, in animals | Recommended to stop the treatment 2 months before the conception in men and women. | ||||
Induction | Unknown effects on both fertility and pregnancy | Avoid pregnancy within 12 months of stopping | |||||
- anti-human thymocyte Ig | |||||||
- IL-2 receptor inhibitors daclizumab | |||||||
- belatacept fusion protein (Fc fragment of human IgG1+extracellular CTLA-4 |
Contraindicated drugs when pregnancy is desired (Table 1)
Methotrexate
Mycophenolate (purine synthesis inhibitor)
Leflunomide and teriflunomide
Cyclophosphamide
Mitoxantrone
Drugs to be used with caution (Table 1)
Anti-TNF-α (tumour necrosis factor alpha) (anti-cytokine)
mTOR inhibitors: sirolimus, everolimus, temsirolimus
Treatments associated with a low risk of deleterious effects on fertility and pregnancy (Table 1)
Glucocorticoids
Sulfasalazine
Mesalazine
Azathioprine (purine analog, precursor of 6- mercaptopurine)
Ciclosporine (calcineurin inhibitor)
Tacrolimus (calcineurin inhibitor)
Beta interferon and glatiramer acetate
Chloroquine
Recent drugs in which the effects are not fully known (Table 1)
Biological therapies
Immunomodulators in multiple sclerosis
Induction immunosuppressive treatments
Management of patients using immunosuppressive drugs
A: Management prior to starting immunosuppressive treatment |
1. Patient information to clarify the consequences of the planned treatment on future fertility and the couple desire for subsequent fertility (”Bioethics Law of 2004 and 2011 France (Art. L. 2141-)11) |
2. Verify the absence of pregnancy. |
3. Send to a fertility preservation centre, particularly if cyclophosphamide (see Table 3). |
4. Effective contraception until desire for pregnancy, even in case of supposedly already altered ovarian reserve if the treatment is teratogenic and/or pregnancy would be at risk due to the underlying disorder. The metabolic effects of calcineurins and mTOR inhibitors as well as glucocorticoids will require the prescription of a progestin-only rather than a combined oestrogen-progestin contraceptive. |
5. Screening for potential gynaecological neoplasias (cervical-vaginal smear, mammography) that could be worsened by immunosuppressive treatment |
B Pre-conception management of a parent treated with immunosuppressive agent |
1. Pre-conception consultation to discuss stopping/changing immunosuppressive drug with referring team. |
2. Preconception consultation with the couple: an explanation will be offered concerning the possible strategies and obligations in order to minimise the maternal-foetal risks if pregnancy is possible; these include the need for a stable disease, multidisciplinary management, a possible period of weaning from the treatment or immuno-suppression switch, the risk of organ rejection and/ or reactivation of an underlying disease, the risk of transmitting a genetic disorder causing organ failure (Wilson’s disease, polycystic kidney disease, etc.). |
3. The pregnancy will need to be planned, and the treatment will need to be modified if necessary in a pre-conception time period adapted to its half-life (See Table 1, last column). |
4. If pregnancy inadvertently occurs while taking immunosuppressive treatment, reassure the patient, test for known complications (ultrasound fetal examination) and consider stopping or replacing the treatment according to the context. |
5. During a planned pregnancy while on authorised treatment, the dosages of immunosuppressive agents should be closely monitored in order to avoid overdose situations that are shared with the foetus, but also to avoid underdosing, which would compromise the control of the disease or the function of the graft. During pregnancy there are variations in absorption and metabolism of the drugs. |