Drugs use in

Pregnancy

I Made Jawi
 Drugs in Pregnancy-The issues

Only half of all pregnancies are planned

Many women need medications for pregnancy
induced conditions (e.g. Morning Sickness),
chronic conditions (e.g. Epilepsy), intercurrent
conditions (Allergies)
Women work with chemicals, exposed to
radiation and use illicit drugs
During embryogenesis-drugs &chemicals may
adversely affect development
 Situational Analysis

A) Anxiety of birth defects:

Leads women not to take medications during
pregnancy& lactation.
Leads pharmaceutical companies not to develop
drugs for pregnant &lactating women.
B) Women are not treated appropriately even
after first trimester, or for life threatening
conditions
 Aims
• How pregnancy alters
pharmacokinetics
• Placental transfer
• Teratology
• Drugs utilised in pregnancy
 Pharmacokinetics and
Pharmacodynamics in Pregnancy
 Physiological changes of Pregnancy

•  in plasma volume
•  in cardiac output
•  in renal blood flow and GFR
• Induction of liver enzyme pathways
•  in plasma protein content
• Delayed gastric emptying
 Resulting changes in pharmacokinetics

•  volume of distribution

•  plasma concentration

•  renal excretion

•  hepatic metabolism
 Placental Transfer

• Golden rule is that every drug crosses the placenta and under
normal circumstances most drugs equilibrate between maternal and
fetal compartments. The only exception is heparin, which because
of its large molecular weight and polarity, does not cross
 Teratology

Teratogens : An agent that causes physical and/or

developmental abnormalities by preventing the
developing embryo or fetus reaching its full
genetic potential
 Potential of drug teratogenicity
. Bioavailability
• Critical periods of development
• Dosage of the drug or chemical
. degradation products
• drug interactions
• Genotype (genetic constitution) of the
embryo and mother
Early development Main embryonic period (weeks) Fetal period (weeks)

1 2 3 4 5 6 7 8 9 16 32 38

Neural tube defects Mental retardation CNS

TA, ASD, and VSD HEART

Amelia/Meromelia LIMBS

Cleft lip UPPER LIP

Low-set malformed ears and deafness EARS

Microphthalmia, cataracts,glaucoma EYES

Enamel hypoplasia TEETH

Cleft palate PALATE

Masculinsation GENITALIA

Embryo Death Major congenital anomalies Functional & minor anomalies

Common site(s) of action Highly sensitive period Less sensitive period

 FDA Classification of Drugs Risk to
Fetus
• Cat A
– Controlled studies in women fail to demonstrate a risk to the fetus in the
1st trimester (and there is no evidence of risk in later pregnancy) and the
possibility of fetal harm is remote
• Cat B
– Either animal studies have not demonstrated a fetal risk but there are no
controlled studies in women, or animal studies have shown an adverse
effect but this has not been confirmed in controlled studies in women
• Cat C
– Either studies in animal have shown an adverse fetal effect and there
are no contolled studies in women or studies in women and animals are
not available
 FDA Classification of Drugs Risk to
Fetus
• Cat D
– There is positive evidence of an adverse risk in the human fetus but the
benefits from use in pregnant women may outweigh the risk
• Cat X
– Studies in animals or humans have demonstrated significant fetal
abnormalities and the risk of the use of the drug in pregnant women
clearly outweighs any potential benefit
 Evidence of teratogenicity
of a drug
• double blind randomised control trials in humans
• isolated case reports
• epidemiological studies
• laboratory experiments
 Laboratory experimental work

• testing on cell lines

• testing on tissue culture models
• in vitro embryo culture models
– e.g. whole rat embryo culture
• pregnant mammalian studies
Thalidomide
 History of Thalidomide

• Synthesised by Ciba in 1953

• Taken over by Chemie Gruenthal in 1954
• Trials indicated it had mild sedative properties
• Marketed in 1957 for nausea and morning sickness
• “drug of choice to help pregnant women”
• Known as Contergan but also incorporated into many over the
counter preparations
• Licensed in Europe and Australia and Japan
 History of Thalidomide

• First affected child born in \West Germany in 1956

• Dr McBride in Sydney Australia published a letter in Lancet in
December 1961
• Rare limb and ear defects noticed in unprecedented numbers
• 60% of mothers gave a history of taking Contergan
• Drug was withdrawn between 1962-1963
• 10,000 affected children were born world-wide
• 40% of victims died before their first birthday
 Abnormal limb development secondary to
thalidomide ingested by pregnant mother
• Thalidomide is a tranquiliser,
• sedative & immunosuppressant
• Critical exposure window
• 24 to 36 days post fertilisation
• Defects :
– amelia - no limbs
– micromelia - short limbs
– cardiac defects
– haemangiomas
– defects of urinary tract
– defects of digestive tract
 Major Medicinal Teratogens
 Antiepileptics
 Carbamazepine-NTD(1%)
 Valproate-NTD(2%);other malformations (Holmes 2003)
 Phenytoin: Fetal Hydantoin Syndrome(10-15%?)

 ACE inhibitors: renal insuffuciency, hypocalvaria

 Lithium-Ebstein’s anomaly(1/5000)

 Coumadin-Fetal Warfarin Sundrome

 Anticonvulsants

• Phenytoin
– craniofacial abnormalities
– hypoplasia of distal phalanges
– growth deficiency
– mental deficiency
• Valproic acid
– associated with neural tube defects
• Carbamazepine (Tegretol)
– similar to phenytoin but decreased risk and therefore drug of choice
 Neural tube closure
Posterior view Transverse section
notochord paraxial Intermediate
Amniotic mesoderm
ectoderm mesoderm
cavity

Dorsal
aorta

amnion Neural groove

somite
mesoderm
mesoderm
endoderm
mesoderm

Developing embryo day 17 to 21 endoderm

Showing closure of neural tube

Various degrees of Spina Bifida

Spina bifida occulta Spina bifida

meningocele

Spina bifida with

meningomyelocele
Spina bifida
with myeloschisis

Normal
lower
limbs

Affected
lower limbs
 Abnormal formation of upper lip and
palate
• phenolbarbitone (anticonvulsant)
• trimethadione
• ? isotretinoin (retinoid)
• ? methotrexate
• ? valproic acid

Cleft palate

Cleft lip & palate

Cleft lip
 “Tetracycline teeth”

• Discolouration of the
tooth enamel

• Exposure
• 14 weeks gestation to 10th postnatal month - primary teeth
• 14 weeks gestation to 16th postnatal year - permanent teeth
 Genital abnormality (8 -10 weeks)
FEMALE MALE
• Genital tubercle (GT) - Clitoris Penis
• Genital swelling (GS) - Labia majora Scrotum
• Urethral fold (UF) - Labia minora Dorsum of penis
• Anal fold (AF) - Anus Anus

GT
GS UF

Masculinisation of female genitalia

AF
(enlarged clitoris and labia majora)
 Fetal Alcohol Syndrome

• thin upper lip

• short palpebral fissures
• flat nasal bridge
• short nose
• elongated philtrum
• microcephaly
• mental retardation
• cardiac abnormalities
Spectrum of signs, the
• joint abnormalities greater the intake the more
severe the signs
 Congenital Goiter
(enlargement of the Thyroid gland)
• Excessive administration of
antithyroid drugs to the mother
during pregnancy
 Drugs affecting uterine contractility

Toco agents Tocolytic agents

• ↑ strength and • ↓ strength and

frequency of uterine frequency of uterine
contractions contractions

Uses Uses
– termination of – premature labour
pregnancy – uterine
– induction of labour hyperstimulation
– augmentation of
labour
– prevention of PPH
 Drugs affecting uterine contractility

• Toco agents • Tocolytic agents

• oxytocin – Ritodrine
• ergometrine (β2adrenoceptor agonist)
• prostaglandin – analgesics
• mifepristone – calcium antagonists
• misoprostol – indamethacin
• carboprost – Atosiban (oxytocin receptor
antagonist)
 Coagulation and pregnancy

• Pregnancy produces a thrombophilic state in the mother

• helps prevent post partum haemorrhage
• thrombophilia, decreased venous return due to the gravid uterus
and immobility during labour

Risk of DVT and Pulmonary embolus

• Warfarin is Teratogenic
– chondroplasia punctata
– optic atrophy
– mental retardation
Heparin and Low
molecular weight
heparins are safe
 Drugs and Lactation

• Drugs excreted in breast milk

– Antibiotics, e.g. aminoglycosides, sulphonamides, tetracycline,
metronidazole, chloramphenicol
– Anti-TB drugs, e.g. isoniazid
– CNS drugs, e.g. narcotic analgesics, benzidiazepines, chlorpromazine
– Anti-thyroid drugs, e.g. carbimazole, radioactive iodine
– Anti-convulsant drugs, e.g. phenytoin, phenobarbitone
– Anticoagulation, e.g. phenindiones (warfarin and heparin)
– Cytotoxic drugs and high dose corticosteroids
Conclusions
 Conclusions

 Pregnant and lactating women are commonly orphaned from the

benefits of drug therapy, even when solid data on
safety/effectiveness exist.
 Change labeling system
 Allow evidence-based counseling
 Always consider the risk of untreated maternal condition