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Drugs in Pregnancy & Lactation Dr Fahmi.I.El-Uri,F.R.C.O.G. Plan of discussion. • Introduction • Drugs affecting the embryo • A- In the early days of conception • B-After the implantation • Drugs which may affect the fetus • Drugs acting on the neonate(lactation) • Conclusion Introduction • The great majority of drugs cross the placenta by “Simple diffusion” from high to low concentration • Rate of transfer depends on the following: • A- concentration gradient • B-thickness &surface area of the membrane • C-diffusion constant=K Diffusion constant=K • Molecular Weight of the drug i.e.M.W.<1500 pass ‘placental barrier” by simple diffusion,e.g.Warfarin. • M.W.>1500 doesn’t pass “placental barrier e.g.Heparin. Diffusion Constant =K • K will depend on the configuration of the molecule e.g. Immunoglobulin will pass its M.W. 100,000 or more. Continue • Molecules not bound to protein are available for transfer. • Molecules highly soluble in fat & in unionized state ll quickly pass to the fetus. • Molecules low solubility in fat & in an ionized state ll slowly pass to the fetus. The Effect of a drug on ‘offspring : • A-The dose absorbed by the mother. • B-The period of gestation . The period of gestation: • In the early days of conception; before implantation-NO TERATOGENICITY- Gregg 1940.The harmful drug ll kill the embryo or leave it unharmful. • After the implantation; drugs like THALIDOMIDE may act as Teratogens. • Congenital Malformation of ‘ embryo,occurs 20 - 50 days of gestation ,but from the 4th month no teratogenic effect , but injury to fetal organs& placenta may occur. Drugs which may affect the embryo: • 1)Cytotoxic drugs can lead to teratogenic effects & death. • a-Anti-metabolites e.g.Allopurinol,6mercaptopurine,methotrexate. • B-Alkylating agents e.g.Chlorambucil,Cyclophosphamide, • Explanation: These drugs owe their therapeutic action due to their ability to kill rapidly dividing cells.These drugs shouldn’t be use unless the pregnant woman is suffering from malignant leukaemia or some form reticulosis( termination of pregnancy is advised). Continue • Methotrexate : has been used in therapeutic abortion & in ectopic pregnancy.The incidence of fetal abnormality is around 10%. Continue • 2) Thalidomide: was used to prevent vomiting in 1968 but it caused fetal anomalies ( phocomelia + amelia ). • 3) Cortisone:large dose in pregnant rabbits,mice,monkeys caused cleft palate,hare lip.In human pregnant woman trials showed no abnormalities. Continue • 4)Tolbutamide,Chlorpropamide:were regarded with considerable suspicion in the management of the pregnant diabetic woman.No confirmation that these drugs are teratogenic . • 5)Nicotine:no teratognicity,but it causes small for dates,increase in abortion rate &incease in perinatal mortality(P.N.M.). Continue • 6)Salicylate:large dose in mice is teratogenic or can lead to resorption of the embryo.Na salicylate (acute rheumatic fever),the dose used, wt for wt approaches that which is teratogenic in pregnant mice.A study from CANADA reported premature closure of the ductus arteriosis, pulmonary hypertension leading to blue babies. Continue • 7)Phenothiazide,Ancoloxin,Metronidazole, Cannabis,L.S.D. : • All these drugs have been suspected at one time & this was based on few individual case reports but further experience of these drugs didn’t suggest that they are harmful in normal dose. Summary of teratogenic effects: • Lithium (cardiac e.g.ebstein’scomplex)- <5%. • Warfarin(chondrodysplasia punctate)10- 25%. • Phenytoin(cranio facial/limb)2-26%. • Valproate(CNS) 1-2%. • Carbamazepine(CNS/LIMB/CARDIAC)0.6- 36%. Continue • Primidone&Phenobarbitone(facial cleft/cardiac) –unknown. • Sex hormones(cardiac/limbs)-unknown. • Danazol(Masculination)-unknnown incidence • Isotretinoin ie Roaccutane(CNS)high incidence &the same for other retinoids. Drugs which may affect the fetus: • A number of drugs may cause ill-effects in ‘ developing fetus although they aren’t teratogenic. 1) Anti-thyroid drugs;(carbimazole,neomercazole,thioura- cil);these drugs cross ‘ placenta,interfere with ‘ synthesis of ‘ thyroid hormone in ‘ fetal thyroid gland causing compensatory overaction of ‘ pitiutary leading to fetal goitre which may cause neonatal respiratory obstruction. Continue Lack of thyroid hormone ll cause fetal cretinism& mental retardation. If anti-thyroid drugs are used, they should be combined with L-Thyroxine. In the past Iodides were used in expectorant mixtures & asthma powders , large doses ll impair the inorganic binding of iodine in the thyroid gland causing fetal goitre. Continue: Radio –Active Iodine ;shouldn’t be used in pregnancy, because the fetal thyroid gland ll be destroyed if Iodine 131 is ingested by the mother. 2) Hypotensive Drugs : • Beta-Blockers;(eg propanol=inderal, atenalol=hypoten,tenormin). These drugs may cause hypotonia,hypoglycaemia& intrauterine growth retardation of the fetus ,in addition increase in P.N.M.due to placental insufficiency. Continue • Reserpine=Adelphan, the fetus ll sufer of marked lethergy,nasal blockage & discharge leading to respiratory difficulty & inspiratory costal retraction of the fetus. • Methyldopa=Aldomet,is relatively harmless,may cause +ve Coombs test in the fetus. Emergency Hypotensive: • Hydralazine=Apresoline:causes decrease of syst.BP without decrease renal flow,but S.L.E. like picture in the treating mother. • Dioxide=Hyperstat:causes mother hyperglycaemia due to decrease insuline + fetal alopcia. • Nowadays we are treating PET by : • Methyldopa,NIFEDIPINE(adalat),LABETA TOL(trendate),& HYDRALLAZINE. 3)Drugs causing kernicterus& jaundice. The causitive drugs ll cause dissociation of the bilirubin from its protective binding to serum albumin in the fetus.The free bilirubin diffuse readily into the CNS producing Kernicterus:eg the following; Sulphonamide(sulphafurazole),Long acting Sulpha(sulphamethoxazole+trimethoprim=septri n) Salicylates,Phenylbutazone(butazolidin) Phenothiazides + water soluble vit K(not used now Vit K1 is ok- NO KERNICTERUS. 4)Antibiotic drugs: • Tetracycline;after 4th month of pregnancy it enters ‘ fetal circulation ,chelates with Ca & deposites in teeth,bones,nails.When ‘teeth erupt in ‘ infant ,they are at 1st light yellow & fluoresce in ultraviolat light & later the colour fades gradually to a non florescent brown, in addition to hypoplasia of ‘ enemal leading to dental caries Large doses may cause Acute Fatty Liver of pregnancy. Ampicillin& penicillin :safe • Cephalosporins :safe • Chloramphenicol :B.M. depression in ‘ mother & very dangerous to premature neonate “Grey Syndrome. • Metronidazole:not teratogenic in man ,but is teratogenic in rats its not used in pregnancy in USA,but it is used in routine dose in 2nd & 3rd trimester in UK. Anti-TB drugs: Isoniazid,PAS,Streptomycin,Rifampicin,& Ethambutol. The risk of fetal ototoxicity with strept,is 3- 11%. Rifamp, causes 3% malformation rate (toxic labyrinthine damage). Aminoglycoside: Streptomycin, risk of ototoxicity in the fetus as it affects the auditory components of ‘ 8th cranial nerve , this is rare in normal dose, but consider this risk before prescribing . Nitrofuratin: This drug may be used to treat UTI. It may produce neonatal haemolysis because it acts on neonatal RBCs which is deficient in Glutathione & Glucose 6 phosphatase dehydrogenase. 5) Drugs causing fetal or neonatal haemorrhage: Warfarin, Phenindione( small M.W.) may cause retroplacental He or cerebral He in ‘ fetus if ‘ level of prothrombin in ‘blood is brought too low.In 5% of cases facial & CNS anomalies may occur. Heparin (large M.W.) doesn’t pass to the fetus. Thiazides diuretics used in PET to produce fluid loss may cause thrombocytopenic purpura in the neonate ( the risk is small). 6) Oral Hypoglycaemic agents: Long acting agents “Chlorpropamid” pass to the fetus from ‘ mother causing severe & prolonged neonatal hypoglycaemia & neonatal death. 7) Anti-Convulsant drugs: Phenobarbitone,Phenytoin,Primidone ; Retrospective study suggested that cleft lip & palate may occur in the fetus, but prospective study of 16 neonates of mother on anti-convulsant drugs showed that 7neonates had severe coagulation defects similar to vitamin K deficiency. Prophylactic RX of ‘ mother with vit,K may prevent this risk. 8) Sex Hormones : • Androgens & progestogens; have been used in ‘ management of threatened abortion ,causing masculinization of female fetus with clitorial enlargement & labial fusion. • Oestrogens carry the risk of adenosis or adenocarcinoma of ‘ vagina of the female offspring 15-20 years later, in addition hypospadias in ‘ sons of pregnant women treated on Diethyl still-boestrol. • O.C.pills , risk of fetal limb reduction & cardiac abnormality. Vitamin A (retinoids): • CNS malformation (5-6000iu / day );in addition anomalies in the eye,palate & uro- genital tract occurred in experimental animals. Folic acid tablets: • Prospective studies showed a decrease in the incidence of CNS anomalies in women taking folic tablets. Adverse effects of drugs on fetal growth & development : • Drugs used to treat hyperthyroidism can cause fetal & neonatal hypothyroidism. • Tetracycline antibiotics may inhibit growth of fetal bones &teeth. • Aminoglycoside antibiotics can cause 8th nerve damage. • Drugs such as opiates,benzodiazepines,dextropropoxyphene ,can lead to fetal drug dependence & withdrawal symptoms if taken regularly during pregnancy. Continue : • An important structural defect that may occur in later pregnancy is premature closure of ‘ ductus arteriosus; this results from taking potent prostaglandin synthetase inhibitors, such as indomethacin. • ACE inhibitors (captopril) may reduce fetal & neonatal blood pressure & cause renal impairment. Drugs acting on the neonate: A number of drugs when taken by ‘ mother are by her milk & therefore pass to’ infant. Most of these drugs are secreted in such small amounts that is seldom necessary to discontinue breast feeding. a) iodide, sulphonamides,antihistamines. b) Bromides;lead to skin eruption in ‘neonate Continue; c)Diazepam, chlordiazepoxide, the level of these drugs in ‘ milk is 1/8 that in ‘ maternal blood,if given in large doses ,neonatal lethergy & hypotonia. d) Phenobarbitone ;secreted in sufficient amounts in ‘ milk & makes ‘ infant drawzy , The rate of elimination of ‘ drug by ‘neonate is slow,also it induces ‘ glycuronil transferase enzyme & so it is used to decrease ‘ free bilirubin.It is similar to ‘ withdrawal symptoms of ‘ Heroin addicted mother. Continue; e)Two groups of drugs; lead to discontinue Breast feeding. -Anti-thyroid drugs:carbamazole, thiouracil. -Anti-coagulants : warfarin, phenindone. N.B.Heparin ,is safe,doesn’t cross to ‘milk. f)Chloramphenicol ,( B.M. suppression). g)Tetracyclines:(discoloured teeth). h)Sulphonamides:(kernicterus ,haemolysis inG6PD deficiency ). Continue; i)Isoniazid;causes neurological complications(convulsions, neuropathy). j) Aspirin; possible risk of Reye’s syndrome. Maternal drug addiction & ‘neonate Heroin ,2/3 of ‘ infants will have withdrawal symptoms within 24 hours.Light B.W., low Apgar score ,irritability ,tremors, twitching,piercing cry,RDS,frequent yawning & sneezing. CONCLUSION: Our knowledge of the drugs on the human embryo is extremely small & at the present time it’s the duty of all doctors to avoid prescribing any drugs in the 1st trimester of pregnancy unless its absolutely indicated.
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