Transcript Drugs in pregnancy

‫بنام خدا‬
‫‪Drugs in pregnancy‬‬
‫دارو ها و حاملگی‬
Teratogens
• Teratogens are agents used during pregnancy that
interfere with development and increase
the incidence of congenital malformation:
– neural tube defect
– cleft lip/palate
– cardiac defects and . . . . . . . .
• Teratos =
‫غول‬
Teratogenic risk
• Baseline risk for major malformations
–
3%
‫نقص خلقت مادر زادي‬
‫حدود ‪ 3‬در صد هنگام تولد و‬
‫حدود ‪ 5‬در صد پس از ‪ 5‬سال‬
‫اما و اما ‪. . .‬‬
‫چرا رويان و جنين‬
‫‪ - 1‬بسرعت در حال رشد است‬
‫‪ - 2‬عبور داروها از جفت‬
‫‪ - 3‬جنين با دارو چه ميكند‬
‫‪ - 4‬دارو با رويان و جنين چه ميكند‬
‫‪ – 5‬اين يك تومور دارد كه تومور نيست‬
‫كليات‬
‫خواص فيزيكوشيميايي داروها (وزن ملكولي – حل در چربي ‪)...‬‬
‫سرعت عبور از جفت و در صدي كه به جنين ميرسد‬
‫مدت مجاورت دارو با جنين‬
‫نحوه پخش دارو در بدن جنين‬
‫وضع و درجه رشد رويان و جنين‬
‫نقص خلقت مادر زادي‬
:‫لطفا به اين موضوعات توجه بفرماييد‬
– Exact identity and dose of the teratogen
– Stage of embryogenesis
– Genetic sensitivity of the mother and fetus
EMBRYOS ‫رويان‬
FETUS
‫جنين‬
Embryonic period
• Period of organogenesis: 2-8 weeks
• Time of greatest susceptibility to teratogens
• Critical stages for malformations of
different organ systems during this period:
– Neural tube closes by day 30
– Limb buds develop
– Heart
Fetal period
• Fetus less susceptible to teratogens but
still susceptible to toxicity and behavioral
teratogenicity
• Some agents paradoxically cause more
problems in 2nd trimester than in 1st:
Varicella
Fetal period
Birth defects:
Oligohydramnios:
NSAIDS
ACE inhibitors
Hypotension/ Cardiac arrhythmia/
Ischemia:
Cocaine,
phenytoin, anti-arrhythmics
‫مطالعه و بر رسي تراتوژنيك بودن داروها‬
‫غالبا مطالعات حيواني است‪ .‬هميشه نميتوان به آن تكيه‬
‫كرد‬
‫مطالعات انساني غالبا گزارش تك مورد است‬
‫اثبات رابطه علت و معلولي آسان نيست‬
Factors determining teratogenic
action
Dose-response relationship:
Every teratogen has a “no-effect” level. Agents
are true teratogens only when they disrupt
development at doses that are not toxic to the mother.
Susceptibility depends on stage of development:
Pre-implantation period = “all-or-none” period
Organogenesis = 2-8 weeks post conception
Fetal period = 9 weeks- delivery
Genetic susceptibility
‫علل نقص خلقت مادر زادي‬
‫فقط در حدود ‪ 50‬در صد علت معلوم است‬
‫عواملي كه شناخته اند (نا شناخته هم داريم) ‪:‬‬
‫محيطي ‪ -‬فيزيكي ‪ -‬اشعه ‪ -‬اكسيژن و‬
‫عفونت ها ( تب ‪ -‬سرخجه )‬
‫مادر (ديابت – فشار خون – صرع – اعتياد و سن)‬
‫پدر (پر فشاري خون ‪ -‬سن و ‪ ...‬كوچكترين اثري ندارد)‬
‫ژنتيك‬
‫دارو ها‬
‫اشعه ايكس‬
– Max dose: 10 rads
– CXR:
– Upper GI:
– IVP:
– BE:
8 rads
558 rads
407 rads
805 rads
– With large doses, if not lethal, get microcephaly
and mental retardation
‫عفونت ها‬
• Cytomegalovirus (CMV)
– Most common congenital infection
No effective therapy
– Hydrocephaly, Microcephaly, chorioretinitis,
cerebral calcification, symetrical IUGR,
microphtalmos, brain damage, hearing loss
• Rubella (SOR KHEH JEH)
– Microcephaly, mental retardation, cataracts,
congenital heart disease,
– Cytolytic virus, all organs may be affected
‫عفونت ها‬
• Syphilis
– If severe: fetal demise with hydrops
– If mild: detectable anomalies of skin, teeth and bones
– Penicillin is effective
• Toxoplasmosis
– All organs mainly CNS, hydrocphaly, microcephaly, cerebral
calcifications
• Varicella (ABELEH MORGHAN)
– Skin scarring, chorioretinitis, cataracts, microcephaly,
hypoplasia of the hands and feet, muscle atrophy
Genetic Conditions:
Chromosomal Abnormalities
• Trisomy 21 (Down’s Syndrome)
• Trisomy of other chromosomes
Critical Period Defect:
Cleft Palate
• Irreversible congenital
abnormality affecting a
critical period (palate
development) during the
embryonic and early fetal
stages
• May affect pituitary
growth as the palate and
anterior pituitary are
derived from the same
embryonic tissue.
Critical Period Defect:
Anencephaly (absence of brain)
•
Autism
A neurodegenerative
disorder characterized by
impairment in social
interaction and
communication.
‫فرياد‬
‫ساير عوامل‬
• Hyperthermia
Increased neural tube defects (X 2.8)
• Lead
Increased abortion rate, stillbirth
• Organic mercury
Cerebral atrophy, microcephaly, mental
retardation, spasticity, seizures, blindness
Examples of critical timing
• Warfarin
– critical period 6-9 weeks gestation
• Tetracyclines
– safe until 16 weeks
• ACE inhibitors
– probably safe until 14-16 weeks
• NSAIDs
– avoid from 30-32/40 until term
‫سد جفت‬
‫مواد قابل حل در چربي براحتي عبور ميكنند‬
‫مواد قابل حل در آب راحت عبور نميكنند‬
‫موضوع اتصال به پروتيين هاي پالسما‬
Factors determining teratogenic
action of drugs
Access to the embryo depends on :
• lipid solubility
• degree of ionisation
• protein binding
• surface available for diffusion
• pH
• molecular weight
– MW >1000 do not readily cross placenta
– MW less than 600 usually cross the placenta
FDA classification of drugs
used in pregnancy
• Category A
– Drugs which have been taken by a large number of
pregnant women of childbearing age without any
proven increase frequency of malformations
• Category B
– Drugs that have been taken by only a limited
number of pregnant women without an increase in
frequency of malformation
FDA classification of drugs
used in pregnancy
• B1- studies in animals have not shown evidence of an
increased occurrence of fetal damage
• B2- Studies in animals are inadequate or may be
lacking, but available data show no evidence of an
increased occurrence of fetal damage
• B3- studies in animals have shown evidence of an
increased occurrence of fetal damage, the significance
of which is considered uncertain in humans
FDA classification of drugs
used in pregnancy
• Category C
– Drugs, which owing to their pharmacological effects, have
caused or may be suspected of causing , harmful effects on
the human fetus or neonate without causing malformations.
These effects may be reversible.
• Category D
– Drugs which have caused, are suspected to have caused or
may be expected to cause, an increased incidence of human
fetal malformations or irreversible damage. These drugs
may also have adverse pharmacological effects
FDA classification of drugs
used in pregnancy
• Category X
– Drugs that have such a high risk of causing
permanent damage to the fetus that they
should not be used in pregnancy
– Examples:
• Retinoic acid
• Misoprostol
• Ribavirin
Management
• COUNSELLING
• INVESTIGATION
• APPROPRIATE REFERRAL
‫پيشگيری‬
Investigation
• Age ‫ايشاال موباراك بادا‬
• Family history, AFP
• Ultrasound
• Invasive testing : CVS
• Follow-up
Teratogens and cardiac defects
•
•
•
•
Valproic acid , Carbamazepine
Thalidomide , Lithium , Phenytoin
Maternal diabetes
Amphetamines
Teratogens and skeletal defects
• Valproic acid , Thalidomide
• Cyclophosphamide
• Fluconazole
• Maternal diabetes
Teratogens and neural tube
defects
•
•
•
•
Valproic acid , Carbamazepine
Maternal diabetes
Hyperthermia
Folate antagonists
Preconceptional counselling
• Consider drug discontinuation
• Try best single agent
• Lifestyle modifications :
– Sleep , diet
– alcohol/cigarettes
• Folate supplementation
“Drugs of choice”
in pregnancy
• Some drugs may be safe to take at one
stage of pregnancy but not at other times
– ACE inhibitors: safe in 1st trimester
– Tetracyclines: safe until 17 weeks
‫آنتي بيوتيك ها‬
• Penicillins, Erythromycin, Cyclosporines
– no proven teratogenicity
• Tetracycline
– yellow discoloration decidous teeth
• Steptomycin, kanamycin
– Hearing loss, eight nerve damage
– Gentamycin and vancomycin appear safe
Hypertension
• Preferable drugs :
– methyldopa
– beta blockers
– hydralazine
• Drugs to be avoided if possible :
– ACE inhibitors
– Calcium channel blockers
Coughs, colds, allergies and
fevers
• Antihistamines are regarded as being safe
for use during pregnancy
• Ephedrine at usual doses is safe
• Paracetamol is safe.
• Hyperthermia (>390) may cause fetal
damage,
encourage patients to take paracetamol if
they have a fever
Analgesia
• Paracetamol and narcotic analgesics are
safe for use during pregnancy
• High doses of narcotics near term may
result in neonatal withdrawal
• Avoid aspirin and NSAIDs in last
trimester (especially after 32 weeks)
– bleeding
– premature closure of ductus arteriosus
Epilepsy and pregnancy
• Over 90% of pregnant patients using anticonvulsants now can expect favorable maternal
and infant outcome
• Variable effect of pregnancy on seizure frequency,
but overall most women do not experience
significant changes in seizure frequency
• Some causes of increased seizure frequency
– sleep deprivation
– changes in free-drug levels
– poor compliance with drugs
• nausea/vomiting in first trimester
• fear of anomalies
Epilepsy drugs
• Preferable drugs
– Carbamazepine, benzodiazepines
• Drugs to be avoided if possible
– Phenytoin, valproic acid
• New drugs with little data
– Lamotrigine, topiramate, vigabatrin
Folic acid supplementation
•
•
•
•
•
Folic acid, methionine, RNA & DNA
Start 1 month prior to conception
Continue for first 12 weeks
0.4 mg for low-risk population
5 mg for high-risk population
Factors in anticonvulsant
teratogenesis
• Specific drug
– Dose, mono/ polytherapy
• Gestational timing of exposure
• Folic acid
• Genetic influences
– Maternal epilepsy
– Pharmacogenetics
‫موضوع مصرف مواد مخدر در حاملگي‬
• 5% to 15% of pregnant population USA
• Doctors detect <3%
• Use all opportunities for screening
•
•
•
•
Gynecologic visit-preconception
Prenatal visits
Obstetrical emergency
Postnatal
‫موضوع مصرف مواد مخدر و الكل در‬
‫حاملگي‬
• Always think « POLYTOXICOMANY »
• Remember : HIV testing
• َAsk multidisciplinary team help
• Social worker
• Psychologist
• Parents
‫الكل‬
‫شايع ترين ماده (داروي) تراتوژن است‬
Leading preventable cause of mental retardation in
children
10-20% of mental deficiency (IQ 50-80)
Dose-dependant relation
Alcool passes freely through the placenta
Increase rate of spontaneous abortion and stillbirth
Fetal Alcool Syndrome (FAS): Large spectrum of anomalies
(1/500 to 1/1000 births): Midfacial hypoplasia,,
microphtalmia,, thin upper lip, short maxilla, IUGR
etc...
Fetal Alcohol Syndrome
‫كوكايين‬
• Sympathic Hyperactivity  HR, BP, etc
– Heart: infarct
– Seizures
– Malnutrition
• Vasoconstriction:
–  Uterine and placenta blood flow
• Cocaine found in breast milk
‫كوكايين‬
: ‫اثرات روي جنين‬
–
–
–
–
–
–
–
Stillbirth
IUGR
Prematurity
Cerebral infarct
Limbs hypoplasia
Bowel atresia
Facial dysmorphism
‫ماري جوانا‬
‫تراتوژن نيست اما ‪:‬‬
‫اثر مصرف طوالني مدت هنوز روشن‬
‫نميباشد‬
‫باعث كاهش ”فرتي لي تي“ ميشود‬
‫دارو درماني جنين‬
‫كورتيكو استروييد ها براي ”رسيدن“ ريه‬
‫فنوباربيتال براي تحريك آنزيمهاي كبدي‬
‫آنتي آريتمي ها براي مقابله با آريتمي جنين‬
‫‪ HIV‬زيدو ويدين براي جلوگيري از انتقال‬
‫خالصه‬
‫روز هاي بين ‪ 20‬تا ‪ 60‬خطرناك است‬
‫اسيد فوليك يادمان باشد‬
‫هواي سن را داشته باشيم‬
‫مراقب باشيم‪ .‬مراقب باشيم‪ .‬مراقب باشيم‬