DRUGS IN PREGNANCY

Epidemiology
In pregnancy, it is
estimated that each
woman takes 1-3 drugs
beside vitamin
supplements or iron
About 1/3 of women in the
UK take drugs at least once
during pregnancy.
Only 6% take a drug during
the first trimester.
There has been a
considerable reduction in
drugs used in pregnancy
since the mid-1960s
>>> Self-administered drugs
from 64% to 9%

Maternal
Pharmacokinetics
Changes in body
fluid volume.
Changes in CVS
parameters.
Changes in
pulmonary
functions.
Alteration in gastric
activity.
Changes in serum
binding protein
concentrations.
Alteration in kidney
function

Drug transfer
Most drugs have a molecular weight
below 1000 Daltons.
Drugs less than 100o Daltons cross
the placenta(less than 600 Daltons
cross easily)
Main determinant of the drug
concentration in the Embryo/Fetus is

Fetal pharmacokinetics

Placental pharmacokinetics

Plasma binding proteins

differ from maternal so
free fractions of basic
drugs are elevated.
Liver expresses
metabolizing enzymes,
but capacity less than the
mother.
Drugs transferred across
the placenta undergo 1st
pass hepatic effect
through the fetal liver.
Fetal kidneys are still
immature.
Fetal urine enters
amniotic fluid which may
be swallowed by the fetus.

Blood flow through the placenta

(maternal side) increases
during gestation (50 ml/min at
10 weeks of pregnancy to 600
ml/min at 38 weeks)
Compounds that alter blood
flow alter maternal drug
disposition and placental
transfer.
Placental metabolism
(dealkylation, hydroxylation,
demethylation) affects drugs
transfer across the placenta.
At term, the surface area of the
placenta is at its maximum and
nearly all substances can reach
the fetus.

the mothers blood concentration.

Other factors:
>Lipid solubility and protein binding.
> Degree of ionization at physiologic
pH.
>placental blood flow and surface
area available for transfer.

The processes that govern the passage

of a drug into milk are similar to
placental condition:
Maternal serum concentration is
the main determinant.
The milk pH is slightly acidic
in comparison to serum pH;
so weak bases could become
trapped in milk ( ion trapping ).

Type of effects on the fetus:

Teratogenecity- readily detected at,
or shortly after, birth (thalidomide).
Long term latency- ( DES- increased
risk of vaginal adenocarcinoma after
puberty, or abnormalities in
testicular function and semen
production).
Impaired intellectual or social
development (exposure to
phenobarbitone alters programming
of brain)
Predisposition to metabolic diseases

Barker hypothesis:
The thrifty phenotype hypothesis
says that reduced fetal growth is
strongly associated with a number of
chronic conditions later in life. This
increased susceptibility results from
adaptations made by the fetus in an
environment limited in its supply of
nutrients. These chronic conditions
include coronary heart disease,
stroke, diabetes, and hypertension

Teratogenesis
It is defined as structural or
functional (e.g. renal failure)
dysgenesis of the fetal organs.
Typical manifestations include:
>congenital malformations with
varying severity.
>IUGR.
>Carcinogenesis.
>fetal demise.
In human, the critical time for druginduced congenital malformations is
in the first trimester.
Drug-induced toxicity can occur at
any time during gestation.

(Barker hypothesis: low birth weight

is associated with increased risk of
diabetes, hypertension and heart
disease in adulthood).
Malformations
The overall incidence of:
> Major congenital malformations is
around (2-3)%
>minor malformations is 9%
It has been estimated that:
>25% are due to genetic or
chromosomal abnormalities
>10% due to environmental causes
including drugs.
>65% of unknown etiology.
The part played by drugs is probably
small.

Organogenesis
The critical time for drug-induced
congenital malformations is usually
the period of organogenesis
>>about 20 to 55 days after
conception.
>>about 34 to 69 days (5-10 weeks)
after the first day of the last
menstrual period.
Interference in this process causes a
teratogenic effect.
If a drug is given after this time it will
not produce a major anatomical
defect, but more of a functional one.

Pregnancy Risk Categories

The drugs are classified according to their risk factor category, and the definitions for each category are used by the Food
and Drug Administration (FDA)
Category A
Category B
Category C
Category D
Category X

Controlled
Animal reproduction Animal
There is positive
Studies in animals
studies in women
studies have failed
reproduction
evidence of human
or humans have
fail to demonstrate
to demonstrate a
studies have
fetal risk based on
demonstrated fetal
a risk to the fetus in
risk to the fetus and
shown an
adverse reaction data
abnormalities or

1)

2)
3)
4)

the first trimester,

there is no
evidence of a risk in
later trimesters,
and a remote
possibility of fetal
harm
The only few
medications
classified as
category A are:
Each of the
vitamins when used
in the
recommended
doses (RDA)
Levothyroxine
Antiemetic
doxylamine
Electrolytes
potassium citrate,
potassium chloride,
and potassium
gluconate

there are no
adequate and wellcontrolled studies in
pregnant women
OR Animal studies
have shown an
adverse effect, but
adequate and wellcontrolled studies in
pregnant women
have failed to
demonstrate a risk
to the fetus in any
trimester
The classical
example is
paracetamol

adverse effect on
the fetus and
there are no
adequate and
well-controlled
studies in
humans, but
potential benefits
may warrant use
of the drug in
pregnant women
despite potential
risks
These drugs
should only be
given if the
potential benefit
justifies the
potential risk to
the fetus

from investigational or
marketing experience
or studies in humans,
but potential benefits
may warrant use of
the drug in pregnant
women despite
potential risks
The benefits from use
in pregnant women
may be acceptable, as
if the drug is needed
in a life-threatening
situation or for serious
diseases for which
safer drugs are
ineffective or cannot
be used
Examples include ACE
inhibitors and
diazepam

there is evidence of
fetal risk based on
human experience,
and the risk of the
use of the drug in
pregnant women
clearly outweighs
any possible benefit
These drugs are
contraindicated in
women who are or
may become
pregnant!
NEVER EVER
PRESCRIBE THEM!!
Examples include
statins and
misoprostol

Diethylstilbesterol (DES)
Vitamin A analogues
Synthetic nonsteroidal estrogen that
The most common is isotretinoin,

was first synthesized in 1938, and

used for the treatment of acne
currently it is classified as Category X Classified as category X

drug
The teratogenic effects of retinoids on
It was prescribed during 1940-1970
animals were known for years before

to prevent miscarriages in high risk

their clinical use
pregnancies by increasing the level of The critical exposure time is between
estrogen and progesterone synthesis
3-5 weeks of pregnancy
by the placenta
Contraceptive measures are of at
In 1971, it was discovered that
least one month before, during
women between 16-20 years old
treatment, and no pregnancy for

developed vaginal adenocarcinoma,

2 years after a course of the drug
that was linked to their intrauterine
Fetal abnormalities have not been
fetal exposure
associated with topical retinoids but it
Approximately 1 in 1000 pregnancies
is advised to avoid their use in
were exposed, and 75% of which
pregnancy
resulted in girls with vaginal and
cervical carcinomas as well as uterine
anomalies
Male offspring had abnormal genitalia
and sperm defects
Thalidomide
It is no longer used as an antiemetic
It was used in the past by pregnant women in the 1 st trimester when they start having
The mechanism of action is thought to be partly due to antiangiogenesis
Fetal exposure caused high rates of abnormalities (20-30%) that include:
o Severe limb shortening defects (phocomelia)
o Loss of hearing, facial paralysis, anotia, microtia
o Renal malformations

Teratogenic effects are seen in

up to 25% of babies
50% of affected children have
an IQ below 85
It was approximately recorded
that between 1982 and 1987:
o 900-1300 malformed children
o 700-1000 spontaneous
abortions
o 5000-7000 elective abortions
The embryopathy includes:
o CNS defects
o Craniofacial defects
o Cardiovascular defects
o Thymic defects
o Miscellaneous defects

nausea and vomiting

o Congenital heart disease

It is now used for other diseases, such as drug-resistant multiple myeloma, cutaneous lupus erythematosis, erythema
nodosum leprosum, Behcets disease, and Kaposi sarcoma (care must be needed if the patient is a woman in reproductive
age or likes to become pregnant)

Antibiotics

Class of
Medication

Category B

Antibiotics

Azithromycin
Aztreonam
Cephalospo
rins
Clavulanate
Clindamycin
Ethambutol
Meropenem
Metronidazole
Nitrofurant
oin
Penicillins
Polymyxin B
Sulbactam
Tazobactam
Vancomycin

Category C

Category D

Gentamycin
Bacitracin
Chloramphenicol
Clarithromycin
Dapsone
Erythromycin
Imipenemciliastatin
Isoniazid
Linezolid
Pyrazinamide
Quinolones**
Rifampin
Spectinomycin
Sulfonamides
Trimethoprim

Quinine
Streptomy
cin
Tetracyclin
es

** Although in category C, give concern for fluoroquinoloneinduced fetal cartilage damage, as most obstetricians avoid
their use in pregnancy

They are the most commonly prescribed

drugs in pregnancy
The safest being Penicillins (B) and
Cephalosporins (B)
Trimethoprim (C) is a theoretical teratogen
as it is a folic acid antagonist
Aminoglycosides can cause ototoxicity
(e.g., gentamyicn (C) and streptomycin (D))
Erythromycin (C) is probably safe, but not
used from the start
Tetracyclines (D):
Safe during the first 18 weeks of
pregnancy
Minimal effect on bone but after 24
weeks of gestation, discoloration of the
teeth and enamel hypoplasia occur
Maternal hepatotoxicity in the form of
acute fatty liver, leading to death in
some cases where pregnant women
were treated with large doses
Pregnancy is not terminated if the
women was found to take them

Trimethoprim (C/D) is a theoretical teratogen as it is a

folic acid antagonist
The aminoglycosides(D) can cause ototoxicity
Erythromycin (C) is probably safe
Metronidazole (B)
o Is a teratogen in animals but there is no evidence
of teratogenicity in humans and its benefit in
serious anaerobic sepsis probably outweighs any
risks
Ciprofloxacin (C)
o Results indicate that may affect joints, so caution
and suggest the need for more studies

Antifungals
Griseofulvin (C)
o Is a known teratogen in laboratory animals
o Has ben demonstrated to cross the human placenta
o Is contraindicated during pregnancy
o Pregnancy should be avoided for 1 month after
treatment
o Men should not attempt to father children within 6
months of treatment
Ketoconazole (C)
o Inhibits placental microsomal aromatase and
cytochrome P450
o Should be avoided during pregnancy as there is not
enough information to confirm its safety

Chloramphenicol (C)
o Should be avoided in late pregnancy and during
labour because of the potential for the grey
syndrome in the newborn infant
Nitrofurantoin (B)
o May be administered in pregnancy, but should be
avoided near term; may predispose fetal hemolytic
anemia
Vancomycin (B)
o Possible fetal ototoxic effect and should be avoided
unless benefit outweighs potential risk

Triazoles-fluconazole and itraconazole (C)

o If treatment of these conditions is clinically
indicated, other safer antifungal agents should be
used
Terbinafine (B)
o Approved for the treatment of onchomycosis and it
is estimated that 4 million patients worldwide have
been treated with oral terbinafine
o Avoid as the adverse-effects profile of oral
terbinafine in pregnancy is limited

There is no obstacle in giving topical

antifungal agents, but systemic oral
medications are avoided

Class of
Medication

Category B

Category C

Antifungals

Amphotericin B
Clotrimazole

Caspofun Ketoconazole
gin
Nystatin
Fluconaz Terconazole
ole
Griseoful
vin

Antimalarial agents
Atovaquone/Proguanil (C)
o No fetal harm in pregnant rats and rabbits
o Proguanil is considered to be the least toxic
o Women taking the drug either alone or in
combination should be supplemented with FA
o Should be used with caution in the first trimester

Antiviral drugs

Chloroquine (C)
o At high doses, it is embryo toxic and teratogenic in
rats
o Chloroquine should not be withheld during
pregnancy because the risk of comlications from
malarial infection in pregnancy is increased
o Safe to be breastfeed
(C) Hydroxychloroquine, Mefloquine, Primaquine,
Pyrimethamine, Dapsone, D.Halofantrine

Acyclovir (B)
Anti-retroviral agents
o Not fond to be teratogenic in pregnant mice, rats
o Amprenavir (C), Indinavir (C), Nelfinavir (B/C),
and rabbits
Ritonavir (B/C) and Saquinavir (B/C) are protease
o Probably safe in pregnancy and breastfeeding
inhibitors used for the treatment of HIV infection
Amantidine (C)
o No evidence of teratogenicity has been observed
o Dose-related teratogenicity in rats at doses
in animals (exceptions of Indinavir)
o Benefit outweigh risks
equivalent to the human dose
o No fetal harm was observed in pregnant rabbits
Zidovudine (for HIV positive) category C, must be given
o Birth defects have been observed in humans but the
for the pregnant woman if she is HIV+ve
data are very limited
o Avoid during lactation
Anticoagulants
Warfarin (D)
It is contraindicated in pregnancy, as it Fetal Warfarin Syndrome (FWS)
Associated with nasal hypoplasia and
crosses the placenta and may cause
Aka dysmorphism due to warfarin,
chondrodysplasia in the first
bleeding in the fetus
warfarin embryopathy, or DiSala
trimester
syndrome
Its use in pregnancy is commonly
CNS abnormalities in later pregnancy
associated in with spontaneous
It occurs when warfarin (or another High incicence of hemorrhagic
abortions, stillbirth, neonatal death,
4-hydroxycoumarin derivative) is
complications toward the end of
and preterm birth
given during the first trimester
pregnancy
Neonatal hemorrhage is difficult to
particularly between the sixth and
Coumarins (such as warfarin) are
ninth weeks of pregnancy
also teratogens; the incidence of birth
prevent because of the immature
defects in infants exposed to
Associated conditions include:
enzymes in fetal liver and low stores
warfarin in utero appears to be around
o Hypoplasia of nasal bridge
of vitamin K
5%, although higher figures (up to
Recent study doses >5mg had
o laryngomalacia
30%) have been reported in some
significantly more fetal complications
o Pectus carinatum
studies
independent of the maternal INR
o Congenital heart defects
Warfarin administration in the second
o Ventriculomegaly
and third trimesters is much less
o Agenesis of the corpus
commonly associated with birth
callosum
defects, and when they do occur, are
o Stippled epiphyses

different from fetal warfarin syndrome.

The most common congenital
abnormalities associated with warfarin
use in late pregnancy are central
nervous system disorders,
including spasticity, seizures, and eye
defects

o
o

Telebrachydactyly
Growth retardation

Anticoagulants
Heparin (UFH & LMWH) (B)
Fast-acting anticoagulant with a high binding affinity for antithrombin III
Used in the prophylaxis and treatment of VTE and PE associated with pregnancy, which brings very high mortality to the
women if left untreated
Safe during pregnancy as it doesnt cross the placenta
The most significant side effect is heparin-induced thrombocytopenia, in addition to elevation of aminotransferase,
hyperkalemia, and osteoporosis in chronic use
Does not cross the placenta but may cause maternal osteoporosis and HIT
Cytotoxic drugs
Anticonvulsants
Cyclophosphamide (D) and
Class of
Category Category C
Category D
chlorambucil (D), are
Medication
B
teratogenic and
Anticonvulsants
Magnesiu
Ethosuxamide
Carbamazepine
contraindicated in
m
sulfate
Gabapentin
Clonazepam
pregnancy
Lamotrigine
Diazepam
Methotrexate (X) should be
Levetiracetam
Phenytoin
discontinued at least 3
Oxcarbazepine
Primidone
months prior to conception
Topiramate
Valproic acid
and FA (5mg) given preZonisamide
conceptually

All the anticonvulsants cross the placenta, and the four principal anti-epileptic drugs
Azathioprine (D)
o Current evidence
are of category D, and so, most of them are teratogenic

indicates that
maternal use is not
associated wth an
increased risk of
impaired fetal
immunity, IUGR,
prematurity and
congenital
abnormalities
o Conflicting
information regarding
breast-feeding
Cyclosporin (D)
o Benefits outweighs
risk, so use with
caution

o
o
o
o
o

Background risk = 3%
Untreated epileptic = 4%
1 drug = 7%
2 or more drugs = 15%
Val + Carb + Phenytoin = 50%
It is allowable to prescribe one drug, as an optimal treatment needed to stop the fits
rather than the required drug levels, as having a fit is more dangerous to the mother
and baby than the teratogenic effect.
So, this is a classical example of outweighing the benefits over the risks of
teratoegenesis , which the mother must be aware of
Folate has to be given to prevent neural tube defects (5mg/day)

Anti-inflammatory drugs
Aspirin and NSAIDS do not produce structural defects but
may increase the risk of neonatal hemorrhage (they are
considered in category C, but when used in large doses or
for prolonged duration, they will be in category D)
NSAIDS may also lead to oligohydraminos via effects on
the fetal kidney
Some are prescribed in early pregnancy in patients with
history of antiphospholipid syndrome, recurrent
miscarriages, or babies with IUGR
They are usually avoided in the last trimester as they may
cause premature closure of the ductus arteriosus, with
consequent neonatal primary hypertension

COX-2 inhibitors
o Fetal COX-2 inhibitors can be resposible for
neonatal chronic renal failure
o Mternal uage should be avoided untl further
studies confirm the safety of this group of drugs
Colchicine (D)
o Given around conception may result in an
increased frequency of trisomy 21 by causing
chromosomal non-dysjnction
o Fetal karyotyping is recommended
o It is recommended that colchicine ingestion by
either parent be discontinued 3 months before

conception

Cardiovascular drugs

Class of
Medication

Category B

Category C

Cardiovascular
drugs

Methyldopa
Hydrochlorothia
zide

Acetazolamide
Calcium-channel
blockers
Clonidine
Digoxin
Esmolol
Flecainide
Hydralazine
Isosorbides

Category D
Labetalol
Metoprolol
Minoxidil
Nitroglycerin
Nitroprusside
Prazosin
Propanolol
Terazosin

ACE inhibitors
Amiodarone
ARBs
Spironolactone
Atenolol

Cardiovascular drugs
If the treatment of hypertension
is required before 28 weeks,
Methyldopa (B) should be the
first drug of choice
There is concern for use of betablockers in the 2nd and 3rd
trimesters given reports of
intrauterine growth restrictions,
although labetalol has the most
safety data of the class
Calcium channel blockers mainly
used for severe pre-eclamptic
toxemia (PET)
Spironolactone , amiodarone,
and ACE inhibitors never
prescribed!

Endocrine drugs

Beta-adrenergic antagonists (C)

o Safety in pregnancy is not so well
established
o Guidelines of the ISSHP do not
recommend the use of oral betaadrenergic antagonists for mild
hypertension in pregnancy
Angiotension converting enzyme inhibitors
(D)
o Have been associated with
a. Prolonged renal failure and
hypotension in the newborn
b. Decreased skull ossification ,
hypocalvaria, and renal
tubular dysgenesis
c. IUGR, oligohydromnios, PDA
o Is not thought to produce structural
malformations, so it is acceptable to
cease treatment early in pregnancy
and not necessarily preconception

Calcium channel blocker (C)

o Safe to use, caution with
MgSO2
Spironolactone (D)
o Anti-androgenic effects
were observed in exposed
male animal fetuses in one
study
o Is contraindicated in
pregnancy
Amiodarone (D)
o Can reach the fetus by
transplacental passage and
induce fetal hypothyroidism
o Non-verbal Learning
Disability Syndrome
o Should be avoided during
the 1st trimester of
pregnancy

Insulin is preferred over oral

hypoglycemic agents
Many women are taking
progesterons in the 2nd
trimester
Corticosteroids are relatively
safe, but they are not
prescribed, even if the woman
is breast-feeding

Class of
Medication

Category
B

Category C

Category D

Category X

Hormones

Acarbose
Desmopres
sin
Insulin
Metformi
n
Somatosta
tin
Troglitazon
e
Vasopressi
n
Micronize
d
Progester
one

Adrenal
hormones
Calcitonin
Glipizide
Glyburide
Melatonin
Repaglinide
Rosiglitazone
Tolbutamide

Methimazole
Propylthioura
cil
Tamoxifen
Hydroxyproge
st-erone

Danazol
Estrogens
Iodide131
Leuprolide
Mifepristone
Testosterone

Endocrine drugs
Oral hypoglycemic drugs
o Suphonylureas (D) have been reported as direct
cause of neonatal hypoglycemia
o There is no firm evidence that these drugs are
teratogenic
Progestogens (D)
o Can masculinize the female fetus
o No evidence this occurs with the small amount in
the COCP

Corticosteroids (C)
o Do not appear to give rise to any serious problems
o Transient suppression of the fetal HPAA has been
reported
o May affect growth later in life
Danazol (X)
o Reports suggest virilization of the external genitalia of
female fetuses
o Should be avoided in pregnancy

Tranquilizers & antidepressants

In the United States, the FDA has categorized
benzodiazepines into categories D or X due to
potential harm to the fetus, SSRIs into category C,
and Lithium into D that is not commonly used
Their use by expectant mothers shortly before the
delivery may result in a floppy infant syndrome, with
the newborns suffering
from hypotonia, hypothermia, lethargy, and breathing
and feeding difficulties

Class of
medication

Category B

Category C

Antidepressants/
antipsychotics/
anxiolytics

Buproprion
Buspirone
Zolpidem

Aripiprazol
e
Chlorproma
zine
Clozapine
Haloperidol
Olanzapine
Quetiapine
Risperidon
e

Bronchial Asthma

Cases of neonatal withdrawal syndrome (usually selflimited) have been described in infants chronically exposed
to benzodiazepines in utero
If used in pregnancy, those benzodiazepines with a better
and longer safety record, such
as diazepam or chlordiazepoxide, are recommended over
potentially more harmful benzodiazepines, such
as alprazolam or triazolam
Using the lowest effective dose for the shortest period of
time minimizes the risks to the unborn child

SSRIs
TCAs
Thioridazine
Ziprasidone

Category D

Category X

Alprazolam
Chlordiazepoxid
e
Clonazepam
Diazepam
Lithium
Lorazepam
Midazolam
Oxazepam

Other
BDZ

Treat as non-pregnant,
despite of the side effects of
drugs, as an asthma attack
(status asthmaticus) can be
very serious to the mother
and baby
In general, respiratory drugs
are either into category B or
C, and so are relatively safe
during pregnancy

Class of
Medication

Category B

Category C

Respiratory
drugs

Acetylcystein
e
Budesonide
Cromolyn
sodium
Ipratropium
Montelukast
Zafirlukast

Albuterol
Corticosteroids (inhaled)
Dextromethorphan
Guaifenesin
Salmeterol
Theophylline

Summary
The decision to use any potentially harmful drug in pregnancy should be made on a case-by-case basis
There should be thorough counseling with the patient
Each case is an individualized case!
Before prescribing any drug, consideration must be given to any harmful effects on the fetus. However, no harm must
come to the mother or the baby because a disease is inadequately treated
To minimize the fetal risks, the lowest effective dose should be used
It is not a shame that you dont know exactly the possible side effects, search for them! To prevent any misinformation
about the teratogenicity of certain drugs
Keep always up-to-date with the drugs information, especially through the teratogen-information service