DRUG THERAPY IN

PREGNANCY & LACTATION

Department of Pharmacology & Therapy
Faculty of Medicine Diponegoro University
2018
• Pregnant women consumed approximately 4 drugs
during their pregnancy
• Common drugs that are used: antiemetic,
analgesic, antimicrobial, antacids, antihistamines
etc.

• Common question: “Is the drug safe for my baby?”

Focus
• Effect of pregnancy on drug
• Effect of drug on the fetus

Key points: placental drug transfer & drug effect to

the fetus
Physiological changes during pregnancy

• Increased fluid retention (7-9Lt).

• Increased extracellular volume (4-6Lt).
• Increased cardiac output.
• Decreased colloidal osmotic pressure.
• Increased renin level.
• Increased aldosterone.
• Decreased peripheral vascular resistant.
• Increased gastric acid secretion in 1st and 2nd Trimester.
• Delayed gastric emptying.
• Increased body fat.
 Physiological changes during pregnancy

– Decreased albumin serum concentration

– Induced activation of hepatic enzyme by
progesterone  Increase clearance and shorten half-
life.
– Increased fat and glycogen storage.
– Increased renal blood flow and GFR in early
pregnancy, and decreased in late pregnancy.
Factors affecting placental drug
transfer & drug effect
1. Physiochemical property of the drug
2. The rate at which the drug crosses the placenta &
the amount of drug reaching the fetus
3. The duration of drug exposure
4. Distribution characteristics in different tissue
5. The stage of placental and fetal development
6. The effect of drugs used in combination
Physiochemical properties of the drug

Lipid Solubility
Lipophilic drugs tend to cross the placenta easier.
 thiopental, nicotine, salicylate

Degree of ionization
Highly ionized drugs (obat polar) slowly crossed the placenta
i.e. succinylcholine and tubocurarine
Physiochemical properties of the drugs

Protein binding
- Decreased albumin serum concentration  more free
drugs
Be careful: sulfonamides, barbiturates, phenytoin and local
anesthetic agents.
Molecular Size
- Cross the placenta readily (250-500), with difficulty (500-
1000), or poorly (>1000).
- Majority of the drugs have MW 100 - 500.
- Eg: heparin is preferable compared to warfarin
Placental & Fetal drug metabolism

• Placenta: barrier and site of metabolism

• As the barrier:
• Passive diffusion
• Facilitated diffusion
• Active transport
Placental surface area
• As the site of metabolism: May lead to creation of
toxic metabolites. Eg. ethanol, benzyperenes 
augmented toxicity
The amount of drugs that enter the fetus
Decreased gastric motility
Decreased gastric acid secretion  higher gastric pH
Disturbed drugs absorption & plasma concentration

The rate of drug entering the placenta

Plasma concentration of the drug

The duration of exposure

Drug elimination in the fetus is through the kidney (urine)  enter
the amniotic fluid  re-absorbed by the fetus  longer
elimination
Tissue distribution

- Increased fat storage  more lipophilic drug is

stored  prolonged effect of the drug due to slow
release

Developmental Stage

- Before the 20th day after fertilization all-or-nothing effect

- During organogenesis (between 20 and 56 days after
fertilization): Teratogenesis is most likely at this stage
- After organogenesis (in the 2nd and 3rd trimesters):
Teratogenesis is unlikely, but drugs may alter growth and function
of normally formed fetal organs and tissues
Drug Affinity for Specific Tissues

Tetracycline Teeth
Warfarin
Aminoglycosides Middle ear
Quinine Retina
Chlorpromazine
Diethylstilbestrol Mullerian Duct
Vagina
Corticosteroids
Adrenal Gland
Phenytoin
Iodides
Propylthiouracil Thyroid Gland
Tissue distribution

- Increased fat storage  more lipophilic drug is

stored  prolonged effect of the drug due to slow
release

Developmental Stage

- Before the 20th day after fertilization all-or-nothing effect

- During organogenesis (between 20 and 56 days after
fertilization): Teratogenesis is most likely at this stage
- After organogenesis (in the 2nd and 3rd trimesters):
Teratogenesis is unlikely, but drugs may alter growth and function
of normally formed fetal organs and tissues
Drug Affinity for Specific Tissues

Tetracycline Teeth
Warfarin
Aminoglycosides Middle ear
Quinine Retina
Chlorpromazine
Diethylstilbestrol Mullerian Duct
Vagina
Corticosteroids
Adrenal Gland
Phenytoin
Iodides
Propylthiouracil Thyroid Gland
 Teratogenicity
Teratogenic agents
• 1) Drugs and chemicals
• 2) Infectious agents
• 3) Radiation
• 4) Other

alcohol (FAS), Thalidomide (phocomelia),

DES (uterine cancer), valproic acid (spina
bifida).
Teratogens
• A substance, organism, physical agents or
deficiency state capable of inducing
abnormal structure or function such as:
• Gross structural abnormalities
• Functional deficiencies
• Intrauterine growth restriction
• Behavioral aberrations
• Demise
Teratogenic Factors
• Timing of exposure
• Developmental stage during exposure
• Maternal dose and duration
• Maternal pharmacokinetics
• Genetic factors/phenotypes
• Interactions between agents
Teratogenic Risk
• It is recommended that all pregnant women
be counseled with regard to taking
medications during pregnancy.
• In reality, the risk of a neonatal abnormality
in the absence of any known teratogen is
less than 3%.
• Up till know about 30 compounds have
been identified to be teratogenic.
FDA teratogenic risk categories
• Category A : controlled studies in women fail to
demonstrate risk
• Category B : Either animal-reproduction studies have not
demonstrated a fetal risk but there are no controlled studies
in pregnant women or animal-reproduction studies have
shown an adverse effect
• Category C: Either studies in animals have revealed adverse
effects on the fetus (teratogenic or embryocidal, or other)
and there are no controlled studies in women or studies in
women and animals are not available.
• Category D: There is positive evidence of human fetal risk,
but the benefits from use in pregnant women may be
acceptable despite the risk.
• Category X: Studies in animals or human beings have
demonstrated fetal abnormalities, or there is evidence of
fetal risk based on human experience, or both.
Current FDA rules on teratogenic
risks

The labeling include relevant information about pregnancy testing,

contraception, and infertility for health care providers prescribing for females
and males of reproductive potential, described in narrative statements.
Current FDA rules
The information required by the FDA has 3 subsections:
• Pregnancy: Information relevant to the use of the drug
in pregnant women (eg, dosing, fetal risks) and
information about whether there is a registry that
collects and maintains data on how pregnant women
are affected
• Lactation: Information about using the drug while
breastfeeding (eg, the amount of drug in breast milk,
potential effects on the breastfed child)
• Females and males of reproductive
potential: Information about pregnancy testing,
contraception, and infertility as it relates to the drug
Drug Toxicity
- Beberapa penyalahgunaan obat menembus
placenta.
- Opioids  dependence pada fetus dan
withdrawal pada neonatus.
 Drugs that cause severe adverse effects
ACE Inhibitors Diazepam
Misoprostol
Aminopterin DES
Penicillamine
Amphetamines Ethanol
Androgens Phencyclidine
Etretinate
TCAs Phenytoin
Heroin
BARBs Propylthiouracil
Iodide
Busulfan Streptoycin
Isotretinoin
Carbamazepine Lithium Tamoxifen
Chlorpropamide Methadone Tetracycline
Clomipramine Methotrexate Thalidomide
Cocaine Methylthiouracil Trimethadione
Cyclofosfamide Metronidazole Valproic acid
Cytarabine Organic solvents Warfarin
Notes
Not all maternal drugs cross the placenta to the
fetus. Drugs that do not cross the placenta may still
harm the fetus by:
• Constricting placental vessels and thus impairing
gas and nutrient exchange
• Producing severe uterine hypertonia that results in
anoxic injury
• Altering maternal physiology (eg, causing
hypotension)
Fetal Therapy

Therapy directed to the fetus.

Corticosteroids  Rangsang maturasi paru
pada prematur
Phenobarbital pada TM3  Rangsang
enzymes hepar fetus  mengurangi
incidence of jaundice.
Antiarrhythmic drugs. For the treatment of
fetal arrythmias.
Nutritional issues in pregnancy

• 300 calorie / a day increase during second and third

trimester
• No increase needs in first trimester
• 25-35 # weight gain
• 60 gms protein/ a day
Food and Nutrient alterations
Interference with nutrient delivery may cause
anemia and poor growth.
Alterations of certain factors such as vitamins or
minerals may be teratogenic.
e.g. Vitamin A (Retinol) has important differentiation-directing
actions in normal tissues. Excessive amounts may cause
birth defects, bone abnormalities and liver damage.
Excess niacin may cause ocular abnormalities.

Deficiencies
Alterations of certain factors such as vitamins or minerals
may be teratogenic.
e.g. Folic acid deficiency causes neural tube defects,
supplementation reduces the incidence of spina bifida.
Nutritional supplementation

• Routine supplementation (other than folic acid) is

not recommended for women reporting adequate
dietary intake
• There are high risk conditions requiring
supplementation
 Pregnancies requiring nutritional supplementation

• Multiple gestation
• Frequent pregnancies (<3 month intervals)
• Illicit drug use
• Hyperemesis
• Adolescence
• Vegetarians
• Chronic illness
• Previous history of obstetrical
• complications/ low birth weight or preterm labor
 Calcium
• Nonpregnant women consume only 75% of
recommended calcium
• Adolescent diet poor in calcium
• Bone mass increases up to age 25
• Pregnancy can cause bone loss
• Daily requirement of 1200mg/day
Fe
• Maternal volume increases by 50%
• Iron needed for increase production of RBCs for
mom and fetus
• Fetal needs increase in third trimester
• Supplement in second and third trimester : 27 mg
elemental iron/ day
• For women who are anemic (Hct<33%) : 60 - 120
mg/day
 Folic acid ?
• Shown to decrease risk of NTDs recurrence and
occurrence
• Begin 3 months prior to conception and 4 weeks into
pregnancy
• Occurrence: 400 microgram (prenatal vitamins have
800 micrograms)
• Recurrence: 4 mg/day
 Issues for patients
• Avoid all meds except those prescribed or approved
by you
• Abstain from alcohol
• Check rubella status prior to pregnancy
• Take prenatal folic acid
Drug Transfer into breast milk
• Depends on:
• Molecular weight
• Lipid solubility
• Ionization
• Protein binding
• Drug concentration
• Drug equilibrium
Drug Transfer into breast milk

• Into Breast Milk

• Size < 200 daltons
• Drug pKa
• Equilibration speed
• High blood concentration
Examples of drug-related abnormality
Dilantin- phenytoin syndrome

• Microcephaly
• Nail dysplasia
• Developmental delay
• Characteristic facies

Risk for syndrome 10%

Risk for some adverse effect (low IQ)- 30%
Dilantin- phenytoin syndrome
 Valproic acid (Depakote)
• 1-2% risk of NTD
• Nail and bone hypoplasia
• Valproic acid syndrome?
 Recommendations for women
with seizure disorders ?
• Preferably a preconceptual consultation
• Folate 4mg/day
• Work with a neurologist to find the least teratogenic
agent (monotherapy)
• Do not instruct a patient to d/c medication. A seizure is
worse than effects of meds.
• Status epi.-30% maternal mortality
• 50% fetal mortality
 Vitamin A derivative / Retinoic acid
• Timing is key- beyond 15 days postconception
• Dose specific

Risk of syndrome-
10-30%
Microcephaly/hydroce
phaly
CHD
Microtia
Cleft lip/palate
Drug Trimester Effect
ACE inhibitors All, especially Renal damage
second and third
Aminopterin First Multiple gross anomalies
Amphetamines All Suspected abnormal
developmental patterns,
decreased school
performance
Androgens Second and third Masculinization of female
fetus
Antidepressants, Third Neonatal withdrawal
tricyclic symptoms have been
reported in a few cases
with clomipramine,
desipramine, and
imipramine
 Anticoagulants
• Warfarin: D
• Fetal warfarin syndrome: 10%
• Exposure- 4-7 weeks
• MR Stippled epiphysis
• Hemorrhage Depressed nasal bridge
• Normal: 65%
• Spontaneous AB/ stillbirth- 25%

• Heparin
• Not teratogenic
 Angiotensin-converting enzyme inhibitor
D?

• Reduced fetal renal blood flow

• Fetal anuria
• IUGR
• Oligohydramnios
Alcohol  D ?
• 1-2% women of child-bearing age have an alcohol abuse
problem
• Fetal alcohol syndrome- most common cause of mental
retardation in the US
Drugs Contraindicated during Lactation

• Antineoplastics
• Immune suppressants
• Ergot Alkaloids
• Gold
• Iodine
• Lithium carbonate
• Radiopharmaceuticals
• Social drugs & drugs of abuse
• Certain antibiotics
General Recommendations

• Drugs considered safe for pregnancy are usually

safe during lactation
• Decrease the drug dose to the infant by feeding just
prior to a dose
• Infant blood levels can be monitored and should be
less than therapeutic
TYPE EXAMPLES PROBLEM
Antibiotics Chloramphenicol •Gray baby syndrome
•In G6PD deficiency breakdown of red
blood cells
Ciprofloxacin Possibility of joint abnormalities
Kanamycin Damage to the fetus's ear, resulting in
deafness
Nitrofurantoin In G6PD deficiency breakdown of red
blood cells
Streptomycin Damage to the fetus's ear, resulting in
deafness
Sulfonamides •Jaundice and possibly brain damage in
the newborn
•In G6PD deficiency breakdown of red
blood cells
Tetracycline •Slowed bone growth, permanent
yellowing of the teeth, and increased
susceptibility to cavities in the baby
•Occasionally, liver failure in the
pregnant woman
TYPE EXAMPLES PROBLEM
Antianxiety Diazepam late in pregnancy  depression,
irritability, shaking, and exaggerated
reflexes in the newborn
Anticoagul Heparin a long time  osteoporosis & a
ants decrease in the number of platelets in
the pregnant woman
Warfarin •Birth defects
•Bleeding problems in the fetus and the
pregnant woman
Anticonvul •Carbamazepine •Some risk of birth defects
sants •Phenobarbital •Bleeding problems in the newborn
•Phenytoin (need vitamin K)
•Some risk of birth defects
•Trimethadione •Increased risk of miscarriage
•Valproate •Increased risk of birth defects (cleft
palate and abnormalities of the heart,
face, skull, hands, or abdominal organ)
70% with trimethadione and 1% with
valproate)
TYPE EXAMPLES PROBLEM
Antihyperten ACE inhibitors late in pregnancy kidney damage,
sives reduction in amniotic fluid, deformities
of the face, limbs, and lungs
Thiazide decrease in the levels of oxygen and
potassium and the number of platelets
in the fetus's blood
Chemoterapy •Busulfan Birth defects such as less-than-
•Chlorambucil expected growth before birth,
•Cyclophospham underdevelopment of the lower jaw,
ide cleft palate, abnormal development of
•Mercaptopurine the skull bones, spinal defects, ear
•Methotrexate defects, and clubfoot
Mood- Lithium Birth defects (mainly of the heart),
stabilizing lethargy, reduced muscle tone, poor
drug feeding, underactivity of the thyroid
gland, and nephrogenic diabetes
insipidus in the newborn
TYPE EXAMPLES PROBLEM
NSAIDs •Aspirin •large doses delay in the start of labor,
•Other premature closing of ductus arteriosus,
salicylates jaundice, and (occasionally) brain damage in
the fetus and bleeding problems in the woman
during and after delivery and in the newborn
•late in pregnancy reduction in the amount of
amnionic fluid
Oral •Chlorpropam •A very low level of sugar in the blood of the
hypogly ide newborn
cemic •Tolbutamide •Inadequate control of diabetes in the pregnant
woman
Vaccines Live-virus •rubella vaccine potential infection of the
vaccines placenta and developing fetus;
•other vaccines (measles, mumps, polio,
chickenpox, and yellow fever) potential but
unknown risks
TYPE EXAMPLES PROBLEM
Sex hormones •Danazol •Masculinization of a female
•Synthetic progestins fetus's genitals, sometimes
(but not the low doses requiring surgery to correct
used in oral
contraceptives)
•Diethylstilbestrol •Abnormalities of the uterus,
(DES) menstrual problems, and an
increased risk of vaginal cancer
and complications during
pregnancy in daughters
•Abnormalities of the penis in
sons
Skin •Etretinate Birth defects, such as heart
treatments •Isotretinoin defects, small ears, and
hydrocephalus
Thyroid drugs •Methimazole •An overactive and enlarged
•Propylthiouracil thyroid gland in the fetus
•Radioactive iodine •An underactive thyroid gland in
the fetus
Drug Trimester Effect
Barbiturates All Chronic use can lead
to neonatal
dependence.
Cognitive loss has
been described.
Busulfan All Various congenital
malformations; low
birth weight
Carbamazepine First Neural tube defects
Chlorpropamide All Prolonged
symptomatic
neonatal
hypoglycemia
Clomipramine Third Neonatal lethargy,
hypotonia, cyanosis,
hypothermia
Drug Trimester Effect
Cocaine All Increased risk of spontaneous
abortion, abruptio placentae,
and premature labor;
neonatal cerebral infarction,
abnormal development, and
decreased school performance
Cyclophosphamide First Various congenital
malformations
Cytarabine First, second Various congenital
malformations
Diazepam All Chronic use may lead to
neonatal dependence and
increase risk for oral cleft
Diethylstilbestrol All Vaginal adenosis, clear cell
vaginal adenocarcinoma
Drug Trimester Effect
Ethanol All Risk of fetal alcohol syndrome
and alcohol-related
neurodevelopmental defects
Etretinate All High risk of multiple congenital
malformations
Heroin All Chronic use leads to neonatal
dependence
Iodide All Congenital goiter,
hypothyroidism
Isotretinoin All Extremely high risk of CNS,
face, ear, and other
malformations
Lithium First Ebstein's anomaly
Drug Trimester Effect
Methadone All Chronic use leads to neonatal
dependence
Methotrexate First Multiple congenital
malformations
Methylthiouracil All Hypothyroidism
Metronidazole First May be mutagenic (from animal
studies; there is no evidence for
mutagenic or teratogenic effects
in humans)
Organic solvents First Multiple malformations and
effects on brain development
Misoprostol First Möbius sequence
Penicillamine First Cutis laxa, other congenital
malformations
Drug Trimester Effect
Phencyclidine All Abnormal neurologic
examination, poor suck reflex and
feeding

Phenytoin All Fetal hydantoin syndrome

Propylthiouracil All Congenital goiter
Streptomycin All Eighth nerve toxicity described in
a few cases
Smoking All Intrauterine growth retardation;
(constituents of prematurity; sudden infant death
tobacco smoke) syndrome; perinatal
complications

Tamoxifen All Increased risk of spontaneous

abortion or fetal damage
Drug Trimester Effect
Tetracycline All Discoloration and defects of teeth
Thalidomide First Phocomelia (shortened or absent
long bones of the limbs) and
many internal malformations

Trimethadione All Multiple congenital anomalies

Valproic acid All Neural tube defects
Warfarin First Hypoplastic nasal bridge,
chondrodysplasia

Second CNS malformations

Third Risk of bleeding. Discontinue use
1 month before delivery.