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EFFECTS OF ANTIINFLAMMATORY AND IMMUNOSUPPRESSIVE MEDICINES ON FERTILITY, PREGNANCY AND LACTATION.

DR SULTAN ALMOGAIRINCONSULTANT RHEUMATOLOGIST

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Effects of antiinflammatory and immunosuppressive Medicines

on Fertility, Pregnancy and Lactation

1. Aspirin 8. Cyclosporin2. NSAID 9. MTX3. Corticosteroids 10. Leflun4. SAS 11. AZO5. HQ 12. MMF6. Gold 13. CYP7. PCA 14. Antibiologic agents

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FDA Use-in-Pregnancy ratings for drugs

Category Interpretation A Controlled studies show no risk- Adequate, well-controlled studies in preg women have failed to demonstrate risk to the fetus.

B No evidence of risk in humans- Either animal findings show risk (but human

findings do not) or, if no adequate human studies have been done, animal findings

are negative.

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Category Information C Risk cannot be ruled out –

Human studies are lacking and animal studies studies are either +ve for fetal risk or lacking as as well. However, pot. benef. may justify

the potential risk.

D Positive evidence of risk –

Investigational or postmarketing data show risk to the fetus. Nevertheless, pot. benef. may

outweigh the risk.

X Contraindicated in pregnancy- Studies in animals por humans, or investig. or

postmarketing reports have shown fetal risk which clearly outweighs any possible benef to the patient.

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Many rheumatic disease affects women of child age and meds used to treat these disease may affect

Concep – Preg – Fetal develop and lact.

Physicians who care for these women need to be aware of the poten S/E.

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In general, most of drugs however are not tested in preg women and are not labelled for use during preg.

The lack of available information presents a problem for both physician and the woman.

Safety of Drug each stage and benefit to risk ratio

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A. Fertility and conception:- remain most common drug- Asp can cross the placenta and cause

cong A (rare)- several large prosp studies failed to

confirm a significant in cleft palate or cong A.

Aspirin

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B. Preg (M) Effects

- higher dose 3 Gm/d inhibits uterine contraction and prolong labor and gestation ant and post P Hg → complicated D + anemia

- low dose Asp throughout P

ASPIRIN

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C. Preg (F)

- Possible premat closure of DA may also causes PLt aggreg and risk

of IC Hgg. - transient NEON RF and oligohy have been described

ASPIRIN

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D. LACT

- After single Asp dose of 450 mg to 650 mg 0.1 to 21% reaches the inf over 24-hours.

- Peak salicyl level in milk 2-hours after peak S. level - However, with ch. Maternal intake of antiinfl. Doses and immature NEON metab the infant can potent develop salicyl

intox. and bleed

AAP: Asp be used cautiously by the mother of nursing inf and large doses should be avoided.

ASPIRIN

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E. RECOMMEND:

- Anti inflam doses of Asp should be avoided the last (4 to 8 weeks) of preg to avoid complications and for lactation low

doses (caution)

ASPIRIN FDA (C, D3rd) BF ©

ASPIRIN

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A. Concept of F

- use in P has not been investigated in

depth for many of the newer Ag.

- NSAID not known to be teratog. in

human and prophylactic cessation of

therapy is not necessary.

- Women plan to conceive (implant)

2. NSAID

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C. Preg (F)

- 1448 newborn has been exposed to Naprox

during the 1st T. And results do not support an

assoc between the drug and Cong A.

- Another study showed only assoc with spontaneous abortion.

- There will be IC bleed + cut blood.

2. NSAID

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D. Preg (F)

- Premature closure DA

- Pulm HTN

- Impaired renal function, amniotic fluid

- The dose, duration and period of gestation are

important determinants of these effects

- Above are uncommon with D/C weeks

2. NSAID

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E. LACT

- Milk to plasman ration 0.01 trace amount of Nap, Ibup, Diclo have been reported in milk.- Some NSAID circulate entero hep (C/E) because most NSAID displace BIL they can risk of kern and are C/E in NEON J.

AAPIbup, Diclof to be comp to BF.

2. NSAID

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RECOMMEND

- When administered to preg patient NSAID should be given in

1. Lowest effective dose.

2. Intermittently, if possible

3. Tt should be D/C at least 6 to 8 weeks prior to expected delivery

NSAID FDA(B, D near term) BF ©

2. NSAID

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Flurinated prep such as dex and Betam less metabolized in placenta so greater dose to fetus so preferred for immature lung.

Agent such as Pred and Methyl Pred only 10% of maternal dose to F so preferred for maternal dis.

3. Cortecosteroid

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A. Concept and F:CST in high doses have causes cleft P in experimental animals and low birth weight in human.No evidence that pred or methyl pred are teratog in humans.

B. Preg (M) as non-preg, DM, HTN, AVN. Premature rupture of membrane

3. Cortecosteroid

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C. Preg (F)

Small % of maternal dose of prednisone, prednisolone, + methyl Pr reaches F and NEON monitoring for incidence of Adr. Supp and infection (very low).

Several large studies have not found incidence of cong A.

3. Cortecosteroid

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D. Lact

Small amount of CST in BrM For maternal doses of 20 mg once or twice daily. The nursing infant would be exposed to minimal amount of steroid. At higher dose they recommended waiting at least 4 hours. However, even at 80 mg ld. The nursing infant would have <0.1% of the dose which corresponds to <10% of the infant’s end of cortisol product.

AAP Compatible with BF

3. Cortecosteroid

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E. RECOMMEND

Routine use of POCa + Vitamin D supp is recommended

Stress dose for any stressful event such as surgery

Lactation (four hours)

CST FDA (B/C) BF ©

3. Cortecosteroid

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30% of oral dose is absorbed in small intestine. The test passes into the colon. SAS will be cleared into 5 AM SA and Sulfa

+ fetal conc. are approx. the same as maternal conc. but 5 AM SA has very limited placental transfer.

Sulfasalaz

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A. Concept + FIn (W) no reports of problem to F.In (M) SAS induces oligosp., impaired

sperm motilits.Temporary and reversible infertility

with D/C drug.

B. Preg (F) most experience in IBD patients no in fetal abortion or spontaneous

abortion

Sulfasalaz

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C. LactDrug is excreted in Br M (45% of maternal S.

level). No adverse effects in 16 nursing infants. An exclusively Br Fed infant developed bloody diarrhea attributed to his mother SAS and mother was slow acetylator who has relatively high S. level. Based on this report.

AAP Classifies SAS as a drug should be given with caution to nursing W because substantial S/E may occur in same inf. It may be the first choice in treat RA in child age who are planning to get preg.

SAS FDA (B, D near term) BF © caution

Sulfasalaz

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A. Concept + F

No adverse effects on F

B. Preg (F)

No report of cong malf in children exposed to the drug used to treat RA and SLE.

9 preg in 8 SLE patient on HQ Tt thought preg.

9 livebirths with no cong malf. And F/U 33 Ms

Conclusion: it is safer to continue Tt with HQ than to D/C it during preg + risk aflare up of the dis.

HYDROXY CH

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Retrospec

36 preg in 33 patients (SLE) exposed to HQ and compared them with preg in 53 control W.

The obstetric outcome of two groups were similar. There was no evidence of teratogenic effect of HQ.

HYDROXY CH

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27 preg in 23 W with M to mod SLE

In 17 of the preg the drug was used at a dose 200-400 mg OD through gestation. The outcome of these cases included two abortion, two prenatal, one infant with CHB

Six patient HQ was started during the 1st trimester and in the remaining four therapy was stopped after dx of preg resulting in a worsening of the dis and higher dose of CST and preg termination in one because of severe renal lupus F/U of 20 newborn (healthy + no S/E) so benefit of continu of HQ risks and dis exac

HYDROXY CH

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Preg (M)

Available data suggest that HQ can be continued safely throuh preg. It seems that because of the risk of SLE flare, discontinuing therapy during preg represent a greater danger to the fetus and mother than continuing H. Moreover, cessation of therapy at the time preg is detected would not stop exposure of the embryo and fetus to the drug because of the very long elimination half life.

HYDROXY CH

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Preg (L)

Low conc. of HQ are found in Br milk because of slow elimination rate and potential of accummul of atoxic amount in the infant, breast feeding during daily therapy with HQ should be undertaken cautiously.

AAP classified the drug as compatible with breast feeding.

HYDROXY CH

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RECOMMEND

HQ does not seem to pose a significant risk to the fetus especially with low doses. It may be most prudent to avoid its use during preg in patient with RA since the patient can be managed safely with CST.

However, with patients with SLE already taking HQ, the benefit of continuing Tt with this medication, though preg seem to outweigh the risk associated with its use.

HQ FDA © BF © caution

HYDROXY CH

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A. Concept + F

There are limited reports of preg outcome in W taking G for Tt of RA. G doesn’t seem to impair fertility use adeq cc.

One approach for patients undergoing long term IMG is to time each monthly inject on the 1st day of period. Such regimen assure that G can be withdrawn as soon as preg is recognized.

GOLD

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B. Preg (F)

G cross the placenta and have been found in the fetal liver and kid. There is no evidence of in neon malformation in the small number of pregnancy reported.

GOLD

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C. Lact

There are small number of reports of rash, nephritis, hepatitis and immunological problems and it is difficult to ascribe a cause effect relationship.

AAP considers G compatible with Breast feeding but because of prolonged retention of G in the mother body and the potential for toxic effect in the infant, it may most prudent to avoid nursing.

GOLD

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D. RECOMMENDBecause preg freq improved during

preg, the potential risks of the drug seem to outweigh the benefit. However, in apt who is stable on G many rheumatologist are reluctant to risk a flare either during or after preg and may wish to have these patients continue taking the drug in that case a careful discussion with the patient and monitoring of the preg are essential.

GOLD FDA © BF © caution

GOLD

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Teratogenic and skin laxity, have been observed in animal studies and exposure of the human fetus to PCA has resulted in serious disorders including growth retard, hip dislocate, hernia.

In general, other drugs (NSAID or low dose CST) are effective and safer for pregnant or lactating patient with RA.

PCA its role in pregnant for W with sclerod is unknown and Tt should be D/C before conception or as soon as preg is confirmed.

P C A

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Experience in the Tt of RA is limited although it is approved by FDA for this use. Most of preg outcome data are from preg transpl recipient.

C S P

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A. Preg (M)

51 preg in 48 W treated have been reported and 11 patients have been conceived from men on CSP.

BP, G, Pyelon, uterine dyst, SZ, encephalopathy and Cr. Complicated almost 50% of these high risk preg.

C S P

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B. Preg (F)

In the study of 51 preg, 2 spontaneous and 6 elec abortions occurred, 1 for fetal an encephal of 43 deliveries, 15 prem, 17 required forceps and CS, 7 had others: -

jaundice, WBC, G, IC Hgg, Mild DIC

C S P

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C. Lact

Excreted and AAP considers drug C/E because of pot long term effect of immunosup WBC, + pot associated with carcino genesis.

D. Recommend

In general C/E during preg and pt should use (cc) breast feeding C/E.

CSP FDA © BF C/E

C S P