Drugs in pregnancy and Lactation

1. Drugs in pregnancy and Lactation By RADWAN A. M.B. B.Ch., M.Sc

2. How to manage a disease during pregnancy? Disease management in pregnancy starts by: • Conception timing (remission, well controlled). • Drug toxicity. • Risk-benefit ratio. • Least effective dose.

3. FDA classification of drug toxicity in pregnancy: A: controlled studies show no risk. B: no evidence of risk in humans (either animal findings show no risk or no adequate human studies and animal studies are lacking). C: risk cannot be ruled out (i.e human studies are lacking and animal studies are either positive or lacking), however, potential benefit can justify potential risk. D: positive evidence of risk, yet still potential benefits outweighs potential risk. X: contraindicated in pregnancy, potential risk outweighs potential benefit.

4. What about use of drugs in pregnant mothers with rheumatic disorders? Drugs for rheumatic diseases can be classified: • Drugs that should be stopped prior to conception. • Drugs stopped prior to conception and better avoided during pregnancy (FDA class D, unless potential benefit outweighs risk). • Drugs that might be used (FDA class C, potential benefit outweighs risk). • Drugs those are relatively safe during pregnancy (FDA class B).

5. Drugs that should be stopped prior to conception: FDA Class X • Methotrexate→ 3month before conception(reversible azospermia, potentially teratogenic). • Leflunomide → 3 month before conception as the drug is : • strongly protein bound • long half-life, • potentially teratogenic (assess blood levels after chelation with cholestyramine) Both drugs are FDA class X (contraindicated in pregnancy and lactation). • warfarin → FDA class X(contraindicated being potentially teratogenic),stop at least a month before conception planning .

6. FDA Class D • Cyclophosphamide → stop 3 months before fertility ( teratogenecity, reversible azospermia). FDA Class B • Sulfasalazine in malepatients causes significant azospermia and decreased sperm motility, hence, should be stopped 3 months before conception. Others • MMF, biologic agents (no enough data available) stop 3 months before conception planning.

7. Drugs better to be stopped prior to conception: Aspirin & NSAIDs: • Possible effect on fertility: • In females inhibit the rupture of the luteinized follicle as well as interfere with implantation → transient infertility (indomethacin, diclofenac, piroxicam and naproxen). • In men a decrease in sperm count and quality.

8. Azathioprine stop 3 months before conception • In females possible teratogenic effect. • In males, case reports of: • large myelomeningocele in the upper lumbar region, • bilateral dislocated hips, and • bilateral talipes equinovarus while father was on long-term ttt. • Gold , D-penicillamine (data are lacking as regards their effect on fertility, stop 1 month before conception). • Chlorambucil (chromosomal damage stop 3 months before conception) • Cyclosporin , better stop (3 months) unless a safer drug couldn’t be used.

9. Antimalarials are an exception: • Discontinuation of antimalarials might precipitate a flare, and any flare of disease may delay conception. • Current researches support continuation of antimalarials.

10. Drugs that can be used while planning to concieve: • Low dose aspirin: • Less than 325mg/day. • Corticosteroids: • Prednisone (less than 20mg/day). • Sulfasalazine: • In female patients with arthritis.

11. What about drugs during pregnancy?

12. Drugs used safely in 1st trimester:FDA class B Non Steroidal anti-inflammatory drugs: • Most commonly used anti-inflammatory drug. • No evidence of possible maternal toxicity with their use in 1st trimester. • No evidence of increase in congenital anomalies (case reports of congenital anomalies in GIT). • Rather safe during pregnancy, FDA class B (no evidence of risk in humans).

13. Corticosteroids: • FDA class B (no evidence of risk in humans). • No evidence of major maternal toxicites (exacerbation of pregnancy induced diabetes, osteonecrosis, osteoporosis and hypertension). • Weak evidence of possible fetal complications (small increase in oral clefts, low-birth weight babies, adrenal hypoplasia). • The safest preparation is prednisone(inactivated by placental hydroxylase), doesn't more than 20mg/day. • Avoid flourinated steroids esp dexamethazone as they are inefficiently inactivated by placental enzymes (fetal suprarenal suppression), unless for ttt of fetal problems in utero.

14. Sulfasalazine: • FDA class B (no evidence of risk in humans). • For pregnant women with arthritis, sulfasalazine may be a viable option with low risk. Etanrecept: Currently FDA class B.

15. Drugs that might be used in 1st trimester: FDA Class C • Risk can’t be ruled out. • Accordingly, if a drug can’t be stopped or replaced by a safer drug because of a potential risk of disease flare that might threaten the pregnant mother, the drug can be used. • However, still use the least effective dose.

16. Drugs that might be used in 1st trimester: FDA Class C Antimalarials: • Current recommendation for lupus patients who become pregnant unexpectedly is that it is safer to continue antimalarial medication throughout pregnancy than to discontinue it. • Hydroxychloroquine is the preferred one (2.5 times less toxic than chloroquine), HQ in least effective dose. • No data on possible maternal toxicity. • Fetal toxicities (case reports of retinal pigment deposition, cochleovestibular pareisis, mental retardation).

17. Gold: • No data available on proven maternal toxicity. • Fetal toxicity (a case report of cleft palate and severe CNS abnormalities). Cyclosporin: • No data on definite maternal toxicity in 1st trimester. • As regards fetal toxicity, human studies are lacking.

18. Drugs better avoided in 1st trimester: (FDA Class D) • Positive evidence of risk. D-penicillamine: • Fetal toxicities (cutis laxa connective tissue disorders). Chlorambucil: • Fetal toxicities (renal angiogenesis). Azathioprine: • Fetal toxicity: IUGR (40%), prematurity. Cyclophosphamide: • A Case report of thyroid papillary cancer and neuroblastoma of a male twin at 11 & 14 ys.

19. Drugs in 2nd trimester • Most of the drugs that are safe/ can be used in the 1st trimester. • Remember, use the least effective dose. • Special concern about possible maternal and fetal complications of some of these drugs in 2nd trimester: • Corticosteroids (PROM, hypertension, glucose intolerance, osteoporosis, osteonecrosis). • Cyclosporine ( renal insufficiency, spontaneous abortions).

20. Drugs in the 3rd trimester • Drugs that can be used in 1st and 2nd trimester can also be used. • Some of these drugs that were being classified as FDA class B i.e ( no evidence of risk in humans) in 1st and 2nd trimester, shifted to FDA classification class D in 3rd trimester (evidence of risk in humans, but potential benefit outweighs potential risk). These drugs are: • Aspirin and NSAIDs: • Maternal complications: peripartum hge, anemia, prolonged labour. • Fetal complications: premature closure of ductus arteriosus, pulmonary hypertension, IChge.

21. Sulfasalazine: • Kernicterus if given near term. I.V. immunoglobulins • For ttt of pregnant patients with: • Complications of APLS. • ITTP, RH immunization. • Protect against in utero infection in PROM. • No evidences of fetotoxicity. • but case reports of hemolytic anemia in newborn. • The drug is competible with pregnancy.

22. Other Drugs in common use in a pregnant rheumatic patient Antiplatelet: • Low dose aspirin less than 325 mg/day, safe and beneficial (APLS, vasculitis). Anticoagulants: • Drug of choice is low molecular weight heparin : Clexane 40 mg every 24 hrs S.C. fraxiparine 0.3 ml t.d.s S.C. • Subcutaneous unfractionated heparin (cal-heparin, calciparin, heparin) 7,500 to 12,500 IU can also be used; its use has declined. • Both low molecular weight heparin and subcutaneous heparin treatment have to be stopped for the time of labour, 12 hours before induction of labour.

23. Warfarin is contraindicated (fetal hge, embryotoxic). Antiresorptives: • With Corticosteroids or with heparin, prevention of osteoporosis is important. • Bisphosphonates accumulate in bone for long periods. • Because of insufficient data, pregnancy should be postponed for 6 months after withdrawal of bisphosphonates (transient fetal hypocalcemia). • Oral calcium and vitamin D supplements is recommended in pregnancy and lactation.

24. Antihypertensives: Drugs safe to use: • Adrenergic beta-receptor blocking agents, labetalol is the most used and is the drug of choice. Atenolol can cause fetal growth retardation. • Selective alpha2 agonist methyl-dopa (Aldomet, Farcodopa 250mg 1x3). • Nifedipine is useful (Epilat 10mg 1x3) Don’t use: • ACE-blocking agents are forbidden during pregnancy (increase the risk of fetal malformations, inhibit normal gestational development of the vascular system). • Diuretic drugs are also not recommended ( decreased plasma volume is associated with chronic hypertension and especially with pre-eclampsia).

25. Oral hypoglycemics and insulin therapy: • Insulin therapy is the best choice because of potential teratogenecity of oral hypoglycemics. Antiepileptics: • Good preconceptional control of the antiepileptic medication is important. • Drugs used before conception are usually continued during pregnancy. • Daily administration of folic acid in the 1st trimester is essential.

26. Breast feeding

27. Drugs compatible with breast feeding:- NSAIDs and aspirin less than 325 mg/day (more than 325mg/day feeding preferable before a dose).- Corticosteroids less than 20 mg/day (more than 20 mg/day consider breastfeeding timing 4 hours after the dose).- Sulfasalazine allowed in the healthy full term babies.- Gold compatible with breast feeding.

28. Drugs incompatible with breast feeding : • Methotrexate • Leflunomide • Cyclophosphamide (bone marrow suppress) • Antimalarials (increased risk of retinal toxicity). • Azathioprine (immunosuppression, growth retardation, carcinogenesis). • D-penicillamine (no data). • Cyclosporine, chlorambucil, I.V Igs, etanrecept, MMF and 6-mercaptopurine are contraindicated with breast feeding.

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