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Table 1 Consequences of the main immunosuppressor on fertility and pregnancy

From: Immunosuppressive drugs and fertility

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
  1. Note the significant impact of cyclophosphamide on fertility If emergency use needed, start the treatment if possible after the 1st trimester
  2. The website of the French Teratogenic Agent Information Centre [Centre de Référence sur les Agents Tératogènes (CRAT)] (http://www.lecrat.org/) can provide more information
  3. Ab antibodies, CI contraindicated, MC miscarriage, FDA Food and Drug administration, W women, M men, HAS French National Authority for Health [Haute Autorité de Santé], ACI adrenocortical insufficiency, Ig immunoglobulin, IL-2 interleukin-2, MMF mycophenolate, MTX methotrexate, NN neonatal, OP oestrogen-progestin contraceptive pills, NTR nothing to report, IUGR intrauterine growth restriction), US United States
  4. teratogen substance that causes malformations in the foetus when administered to the mother, mutagen substance that increases the number of mutations in the genome, mutations that are likely to promote malformations or an increased carcinogenesis risk, clastogen substance likely to induce chromosomal breaks and thus aberrations