Download Drug in Pregnancy

Drugs in Pregnancy
‫ جامعة دمشق‬/ ‫كلية الطب‬
‫الدكتور محمد طباع‬
Mohammed Tabbaa, M.D., FACOG
• Placental barrier
• Placenta allows the transfer of many drugs and dietary
substances.
• Lipid soluble compounds rapidly crosses the placenta,
water soluble substances pass less.
• The greater the molecular weight the less it passes
through placenta.
• The degree to which a substance is bound to plasma
protein.
Congenital malformations
• The incidence of major malformation in general
population is 2-3 %
• Major Malformation : incompatible with survival such
as Anencephaly or requiring major surgery for
correction such as cleft palate or congenital hear
disease, or producing major dysfunction in life
(cerebral palsy).
• Minor Malformation : if is included such as ear tag,
extra finger … the rate is as high as 7-10%
Marked Species Specificity in Drug
Teratogenicity
Thalidomide was not found to be teratogenic in rats and
mice but a potent human teratogen.
Corticosteroids cause cleft palate in mice while cause no
harm in humans.
Congenital malformations
Genetic 25%
Environmental
Unknown 65%
Drug exposure accounts for 2-3 % of all birth defects
The Food & Drug Administration (FDA) list 5 categories of
labeling drugs in pregnancy
A
Controlled studies in women fail to demonstrate a risk
to the fetus in the first trimester.
B
Animal studies do not indicate a risk t the fetus, there
are no controlled human study.
Studies have shown the drug to have animal
teratogenic or embryocidal effects, but no controlled
studies are available in women.
The Food & Drug Administration (FDA) list 5 categories of
labeling drugs in pregnancy
D
X
Positive evidence of human fetal risk exists, but benefits
in certain situations may make use of the drug
acceptable inspite its risk.
Studies in animals or humans have demonstrated fetal
abnormalities or evidence demonstrated fetal risk
based on human experience, or both, and the risk
clearly outweigh any possible benefits
•
•
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Drugs should ONLY used when necessary.
The risk - benefit ratio should justify the use of certain drug.
The minimum effective dose should be employed.
As long term effects of drug exposure in utero may not be
revealed for many years caution with regards to the use of
any drug in pregnancy is warranted ( DES ).
•
•
Until about day 3 after conception any cell is thought to
be totipotential able to develop to any organ system.
Separation of the cells during this period can give the
rise to monozygotic twins.
• The blastocyst is located in the uterus where
implantation occurs 6-9 days after conception.
• One group of cells forms the inner cell mass that will
develop into the fetus.
• The inner cell mass will differentiate into three cell
layers
Ectoderm
Brain – Nerves – Skin
Endoderm
Lining of digestive tract – Respiratory
tract – Part of the bladder – Liver Pancreas
Mesoderm
Connective tissue – cartilage –
muscle- blood vessels – heart –
kidneys - Gonads.
• The group of cells forming the periphery of the blastocyst
is termed the trophoblast. The placenta and fetal
membranes will develop from this outer cell layer.
•
From 3 – 8 weeks the embryonic disk undergoes major
development and will lay the foundation for all organ
systems and the blueprints for this human are set
5 weeks
• After conception embryo assume features of human
•
•
•
•
•
appearance.
Face is recognizable formation of eyes ears and nose.
Limbs emerges, digits cartilage and muscles develop.
Liver producing blood cells and bile.
Cerebral hemisphere begins to fill the brain area
The heart is beating at 5 weeks and completely
developed by 8th week.
Effects of Specific Drugs
Estrogen & Progesterone
X
• Oral contraceptives and other hormones blamed in the
past for a variety of birth defects but recent studies
have NOT confirmed any teratogenic risk for these
drugs.
• Data from the Collaborative Perinatal Project (studied
50.000 pregnancies) found NO association between
exposure and fetal congenital malformation.
Androgenic Steroids
X
• Progestational agents-testosterone derivatives (Danazol)
causes clitoromegaly and labial fusion if given before 13
weeks.
• Can be corrected surgically
Anticonvulsants
Valproic Acid (Depakene)
D
• Carries 1-5 % risk of neuro
•
tubal defect and other
abnormalities
Spina bifida occurs in
Depakene more than
anencephaly with a ratio of
5:1
Fetal Valproate Syndrome
Phenytoin (Dilantin)
D
• Decreases folate absorption and lowers the serum folate
which has been implicated in birth defects so it is
recommended to give folic acid supplement to women
taking Dilantin (4 mg /day).
• Fewer than 10% of offspring show the fetal hydantoin
syndrome :
Microcephaly - Growth deficiency – Developmental
delay – Mental retardation – Dysmorphic craniofacial
features-Cleft lip\palate – Hypoplasia of nails and distal
phalanges.
Trimethadione (Tridione) & Carbamazepine (Tegretol)
C
• Also associated with dysmorphic syndrome, but children
exposed to Dilantin scored 10 points less in the IQ score
than those exposed to Tegretol.
• It is recommended to adjust the dose of medications and
obtain monthly blood levels to give the least possible dose.
Isotretinoin (Accutane)
X
• Used mainly in the treatment of cystic acne.
• 154 exposed human pregnancies reported to date 21 reported birth
•
•
•
•
defects, 12 spontaneous abortions, 95 elective abortions and 26
normal infants.
Structural defects and mental retardation
Microtia \ anotia (small \ absent ears) micrognathia, cleft palate,
heart defects (great vessels transposition and VSD), thymic defects,
CNS malformations including hydrocephalus and optic nerve and
retinal anomalies.
It is not detected after 5 days from ingestion in serum.
Topical tretinoin has not been associated with any teratogenic risk.
Vitamin A
A
• There is NO evidence that vitamin A itself in normal
doses is teratogenic.
• The levels in prenatal vitamins are 5.000 IU\day orally.
• 18 cases of birth defects reported after exposure to
levels of 25.000 IU\day.
• Vitamin A in doses greater than 10.000 IU\day increases
the risk of malformations.
Lithium
D
• In the International Register of Lithium Babies 217 are exposed at
least during the first trimester of pregnancy 25 (11.5 %) were
malformed, 18 had cardiovascular anomalies including six cases of
the rare Ebstein anomaly .(anomaly of tricuspid valve)
• of the 60 unaffected infants were followed to age 5 years were
normal.
• 2 cases of polyhydramnios reported because of nephrogenic
diabetes insipidus in adults taking Lithium the presumed mechanism
of polyhydramnios if fetal diabetes insipidus and polyhydramnios
may indicate fetal Lithium toxicity.
• It is recommended to change medication during pregnancy although
replaces are as high as 70% in one year as opposed to 20% to
those who remain on Lithium
Antidepressants
Imipramine (Tofranil)
D
• The original tricyclic antidepressant claimed to be associated
with cardiovascular defects but the number of cases studied
are small (75 newborn 6 had CVS anomalies)
Fluoxetine (Prozac)
B
• Widely used 2 major studies showed NO increased risk of
major malformations in so far 237 infants exposed in utero.
Warfarin (Coumadin)
• The drug has been associated
with Warfarin embryopathy seen in
5% of exposed pregnancies
includes : Nasal hypoplasia –
Bone stippling – ophthalmalgics
anomalies including bilateral optic
atrophy and mental retardation
(seen even when exposed later
than 1st ).
• Heparin is an alternative drug
does NOT cross the placenta
because of high molecular weight.
D
Thyroid & Antithyroid Drugs
D
• Propylthiouracil (PTU) and Methimazole (Tapazole) both cross
the placenta and may cause a degree of fetal goiter while the
thyroid hormones T3 & T4 cross the placenta poorly so that
fetal hypothyroid can not be corrected by giving the mother
thyroid hormone.
• It is suggested to keep the mother slightly hyperthyroid.
• Methimazole (Tapazole) has been associated with scalp
defects in infants, so Propylthiouracil (PTU) is the drug of
choice
Radioactive Iodine
• Radio active Iodine for thyroid
ablation 131I & 125I or for
diagnostic studies is not
concentrated by the fetal
thyroid till 12 weeks.
• Early inadvertent exposure
carries NO specific risk.
• Topical Iodine preparation are
absorbed through vagina.
Digoxin
C
• In 52 exposures reported NO teratogenicity of digoxin
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•
•
was noted
It is used in fetal therapy.
Maternal blood levels should be monitored during
pregnancy.
In hydropic fetuses digoxin may not easily cross the
placenta.
Antihypertensive Drugs
• Alpha Methyl Dopa (Aldomet) has been widely used for
•
the treatment of chronic hypertension in pregnancy.
Hydralazine (Apresoline) has also been widely used in
pregnancy.
B
No Unusual Fetal Effects
Sympathetic Blocking Agents
C
• Propranolol (Inderal) b - adrenergic blocking agent,
theoretically might increase uterine contractility but this has
not been reported. As the drug is not specific for b2 receptors
in the uterus.
NO evidence of teratogenicity.
Fetal bradycardia is seen.
•
•
• New studies associated Inderal with increased risk of IUGR.
Angiotensin-Converting Enzyme Inhibitors (ACE)
D
• Enalapril (Vasotec), Captopril (Capoten) can cause fetal
renal failure in the 2nd and 3rd leading to
oligohydramnios, fetal limb contractures, craniofacial
deformities and hypoplastic lung development.
• Its use during the 1st
teratogenic.
has NOT been reported to be
Antineoplastic Drugs & Immunosuppressants
Methotrexate
D
• Folic acid antagonist appears to be human teratogen
although experience with it is limited.
Azathioprine (Imuran)
D
• Used in patients with renal transplants or SLE of 80
women treated in the 1st
anomalies was NOT
increased. 2 infants has leukopenia, one has IUGR
Cyclosporine
C
• 67 infants exposed in utero NO increased risk of
•
anomalies.
Increased risk of prematurity and IUGR.
Chloroquine
C
• NO risk of anomalies when given in prophylactic doses
•
for Malaria among 169 infants exposed to 300 mg
weekly.
Doses of 250-500 mg daily TWO cases reported of
cochleovestibular paresis.
Antiasthmatics
Theophylline & Aminophylline
C
• Both are SAFE for the treatment of asthma in pregnancy.
NO evidence of teratogenic risk in 76 exposures in the
Collaborative Perinatal Project.
Epinephrine
C
• Minor malformations have been reported with
sympathomimetic as a group in 3082 exposures in the 1st
Terbutaline
B
• Used in preterm labor NO Risk of birth defects has been
reported
Corticosteroids
• All steroids cross the placenta to some degree but Prednisone
and Prednisolone are inactivated by the placenta.
B
• Only 10% of the maternal dose reaches the fetus, the
drug of choice in treating asthma in pregnancy.
• Betamethasone & Dexamethasone they are minimally C
inactivated by placenta. Used for fetal lung maturity.
• Several hundred infants exposed to corticosteroids in the 1st
NO abnormalities was noted.
Iodide
D
• Saturated solution of potassium Iodide (SSKI) expectorant
crosses the placenta causes large fetal goiter to produce
respiratory obstruction.
Vitamin B6
A
• Vitamin B6 (Pyridoxine) reported in 2 randomized placebo
•
controlled studies to be effective for treating nausea and
vomiting in pregnancy.
In several other controlled trial NO evidence of
teratogenicity.
Diphenhydramine (Benadryl)
C
• In 595 patients treated in the Collaborative Perinatal Project
NO teratogenicity was noted. (Drowsiness can be a
problem)
Phenothiazine
Chlorpromazine (Thorazine)
C
• Very effective in the treatment of hyperemesis gravidarum.
• 976 patients treated in the Kaiser Health Plan.
• 1309 patients treated in the Collaborative Perinatal Project
NO Fetal Malformations Noted
Promethazine (Phenergan)
C
• 58 mothers treated NO risk of malformation
Antihistamines
• NO increased risk of anomalies has been associated with
•
•
most antihistaminics used.
An association between exposure during the last 2 weeks of
pregnancy to antihistaminics in general and retrolental
fibroplasia in premature infants has been reported.
One retrospective study showed increased risk of
gastroschisis was associated with 1st pseudoephedrine
(Sudafed) use.
Antibiotics
Penicillins
B
• Penicillin, ampicillin and amoxicillin are safe in
•
•
pregnancy
3546 patients in the Collaborative Perinatal Project
mothers took penicillin in the 1st with NO increased
risk of anomalies
Transplacental passage of penicillin is by simple
diffusion, high protein binding penicillins e.g. oxacillin,
cloxacillin and dicloxacillin cross the placenta less
than poorly bound penicillin e.g. penicillin and
ampicillin
Cephalosporins
B
• In a study of 5000 Michigan Medicaid Recipients there was a
suggestion of possible teratogenicity with Cefaclor,
Cephalexin and Cephradine
Sulfonamides
B
• 1455 human infants exposed to sulfonamides in the 1st
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NO teratogenic effects.
These drugs should be avoided in women deficient in G6PD.
There is a theoretical risk of hemolysis in the fetus if drug is
used near delivery as fetal red cells are deficient in
glutathione.
Sulfamethoxazole (Bactrim)
C
• Two published trials have failed to show any increased risk of
•
birth defects.
One Unpublished study of 2000 Michigan Medicaid Recipients
suggested increased risk of cardiovascular defects after
exposure in the 1st
Nitrofurantoin (Macrodantin)
B
• 590 infants were exposed in the Collaborative Perinatal
•
Project 80 in the 1st
NO increased risk of abnormality, more
recent studies confirmed these findings.
Macrodantin can cause anemia in patients deficient in G6PD
and theoretically in infants.
Tetracycline
D
• Readily crosses the placenta and firmly bound by chelation to
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calcium in the developing bone and tooth structures.
This leads to brown discoloration hypoplasia of the enamel
and inhibition of bone growth. The staining of the teeth takes
place in the 2nd & 3rd
Hepatotoxicity has been reported in pregnant women using
large doses of tetracycline.
341 exposed infants in the 1st in the collaborative perinatal
Project and another 174 women in other study found NO
teratogenic effects.
Erythromycin
B
• 9 patients in Collaborative Perinatal project and 260 patients
•
in another study NO teratogenic risk or increased birth
defects.
Erythromycin estolate (Ilosone) has been associated with
subclinical reversible hepatotoxicity during pregnancy.
Metronidazole
B
• Several studies showed NO risk of congenital defects with the
•
use of Flagyl early and late in pregnancy.
Some controversy rose when Metronidazole showed to be
mutagenic in bacteria by the Ames test, which correlates with
carcinogenicity in animals. Its carcinogenicity in human has
not been confirmed
Quinolones (Cipro)
C
• The quinolones have a high affinity for bone tissue and
•
cartilage and may cause bone stippling and arthralgia if
given in utero or to young children.
38 infants exposed to quinolones in utero in the 1st NO
abnormalities noted.
Acyclovir (Zovirax)
C
• The Acyclovir Register has recorded 601 exposure during
•
pregnancy including 425 in the 1st
with NO increased risk
of abnormalities.
The CDC recommended its use in pregnant women with
disseminated infection (herpes encephalitis or hepatitis)
Antifungal
B
• Nystatin (Mycostatin) poorly absorbed from intact skin and
mucus membranes, topical use has NOT been associated
with teratogenesis.
• The Imidazoles are absorbed in small amounts from
vagina has NOT been associated with congenital
malformation
• One study showed a statistically significantly increased
risk of 1st
abortion.
Aspirin
C
• NO evidence of any teratogenic effect of aspirin taken in the
•
•
1st
Aspirin inhibits prostaglandin synthesis leads to decrease
uterine contractions and delay onset of labor.
Aspirin also decrease platelets aggregation increase risk of
bleeding. As well as in infants up to 5 days after exposure.
Acetaminophen (Tylenol-Panadol)
B
• NO evidence of teratogenicity.
• It inhibits prostaglandin synthesis but in reversible manner.
NSAD
B
• NO evidence of teratogenicity has been reported for
•
nonsteroidal anti-inflammatory drugs.
Chronic use may lead to oligohydramnios and constriction of
fetal ductus arteriosus or pulmonary hypertension has been
reported with Indomethacin use.
Codeine
C
• In the Collaborative perinatal Project NO increased risk of
•
malformations
Codeine can be addictive and may lead to infant withdrawal
symptoms.
Smoking
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Spontaneous abortion
PROM
PTL
Low birth weight
IUGR
Placenta Previa
Placenta Abruption
SID (Sudden infant death syndrome)
Smoking
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The physiologic mechanism responsible for adverse
effects of pregnancy and smoking are carbon
monoxide and nicotine
Carbon monoxide crosses the placenta and binds to
hemoglobin forming carboxyhemoglobin which
reduces the oxygen carrying capacity of the blood
Nicotine also crosses the placenta causes elevation
of catecholamine and vasoconstriction at the uterine
artery and fetal
Marijuana
•
NO teratogenic effect of marihuana. In a
prospective study of 35 pregnancies no birth
defects but more meconium staining.
Also increased incidence of precipitate labor (<3h).
Alcohol
Fetal Alcohol Syndrome (FAS)
• Growth retardation before and/or after birth
• Facial anomalies
• CNS dysfunction including microcephaly, varying degrees of mental
retardation as well attention deficit disorder (ADI) with hyperactivity.
Cocaine
• It is difficult to access the effects of cocaine on the infants because
those mothers usually abuse other drugs.
• Increased rate of spontaneous abortions abruptio placenta preterm
birth and SGA.
• three studies showed increased risk of congenital anomalies mainly
cardiac & CNS and microcephaly.
Caffeine
B
• 5773 women in the Collaborative Perinatal Project showed
•
•
NO evidence of teratogenic effects in human.
Some studies showed that taking more than 8 cups of coffee
a day (cup contains 100 mg caffeine) was associated with low
birth weight, spontaneous abortions, prematurity and stillbirth.
Maternal coffee decrease iron absorption may contribute to
maternal and fetal anemia.
Aspartame (Nutrasweet)
B
• The major metabolite of aspartame is phenylalanine.
Sustained high levels of phenylalanine in the fetus are
associated with mental retardation (PKU). High doses is
required to produce fetal toxicity.