Drugs in Pregnancy _ Lactation

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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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posted:5/15/2014
language:English
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