Table 1 Consequences of the main immunosuppressor on fertility and pregnancy

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 2^nd or 3^rd 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

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 1^st 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

1^st 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

2^nd3^rd 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

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

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 1^st trimester since limited crossing of placenta ± end of the 2^nd trimester when its crossing increases.

<5 pregnancies reported: NTR

Administration in 3^erd 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