Prescribing in Pregnancy
Prof Louise Kenny PhD MRCOG
Professor of Obstetrics and
Consultant Obstetrician and Gynaecologist
Cork University Maternity Hospital
UCC
Aims
• Awareness of physiology of pregnancy
• How pregnancy alters pharmacokinetics
• Placental transfer
• Teratology
• Drugs utilised in pregnancy
Terms and definitions
• Pharmacokinetics
– Study of the time course of drug absorption, distribution, metabolism
and excretion
• Pharmacodynamics
– Study of the biochemical and physiological effects of drugs and their
mechanisms of action
Terms and definitions
• Plasma half-life
– The time taken for drug concentration to fall by 50%
• Steady state
– Occurs when the amount of the drug administered during the dosage
interval equals the amount of drug eliminated during the dosage
interval. This is dependent on the half-life. The actual steady state
concentration is directly proportional to the size of the dose and
indirectly proportional to the volume of distribution and the eliminator
constant
Terms and definitions
• Clearance
– The volume of plasma cleared of drug in unit time (ml/min)
• First pass effect
– Metabolic breakdown of drugs before entering the systemic circulation
on iniial passage through the liver (e.g. lidocaine, pethidine and
oestrogen), the intestinal mucosa (e.g. L-dopa, chlorpromazine and
ethanol) or lungs (e.g. isoprenaline).
Terms and definitions
• Bioavailability
– Extent to which a drug is absorbed systemically. It is dependent upon
tablet formulation, gut motility, disease states and first pass effect.
• Volume of distribution
– The theoretical fluid volume which would contain the total body content
of a drug at a concentration equal to the plasma concentration. Drugs
that are highly lipophilic and extensively tissue bound have a large
volume of distribution (e.g. nortriptyline)
Terms and definitions
• Drug elimination
– First order (linear) elimination.
• Most common type for drug absorption and elimination.
• The rate of reaction is directly proportional to the amount of drug
available (i.e. constant fraction of drug absorbed or eliminated in
unit time)
– Zero order elimination
• Proceeds at a constant rate independent of the amount of drug
available.
Drug concentration
Terms and definitions
first order kinetics
zero order kinetics
Dose
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
• excretion 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
(the study of monsters)
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
• dose
• exposure time
• bioavailability
• degradation products
• drug interactions
Drugs in Pregnancy
• Most pregnancies are unexpected
• Even ‘planned’ pregnancies are not detected until 8-10 weeks
gestation
• Many women take vitamin supplements and over the counter
medications
The Lesson of Thalidomide
Thalidomide
History
• 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 II
• 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
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
Limitations of laboratory experimental
work
• what dose to study?
• what exposure window?
• which experimental model to use?
• does evidence of toxicity provide evidence of teratogenicity?
• different species sensitivity and bioavailability
• Classic example - thalidomide!
Early development
1
2
Main embryonic period (weeks)
3
4
5
6
7
Neural tube defects
8
9
Cleft lip
16
CNS
LIMBS
UPPER LIP
Microphthalmia, cataracts,glaucoma
Enamel hypoplasia
Cleft palate
Masculinsation
Common site(s) of action
38
HEART
Low-set malformed ears and deafness
Embryo Death
32
Mental retardation
TA, ASD, and VSD
Amelia/Meromelia
Fetal period (weeks)
Major congenital anomalies
Highly sensitive period
EARS
EYES
TEETH
PALATE
GENITALIA
Functional & minor anomalies
Less sensitive period
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
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
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
Amniotic
cavity
paraxial
mesoderm
ectoderm
notochord
Intermediate
mesoderm
Dorsal
aorta
amnion
Neural groove
somite
mesoderm
mesoderm
endoderm
mesoderm
Developing embryo day 17 to 21
Showing closure of neural tube
endoderm
Various degrees of Spina Bifida
Spina bifida occulta
Spina bifida with
meningomyelocele
Spina bifida
meningocele
Spina bifida
with myeloschisis
Normal
lower
limbs
Affected
lower limbs
Neural tube Defects of the Brain
Hydranencephaly
Anencephaly
(Closed cranium)
(Open cranium)
Formation of the upper lip and palate
Later nasal prominence
Maxillary prominence
Medial nasal prominence
Inferior view of palate
showing fusion of
palatal plates of
maxillary prominences
Fusion of facial
bones
Scanning electron micrograph
of facial bones before fusion
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
(enlarged clitoris and labia majora)
AF
Fetal Alcohol Syndrome
•
thin upper lip
• short palpebral fissures
• flat nasal bridge
• short nose
• elongated philtrum
• microcephaly
• mental retardation
• cardiac abnormalities
• joint abnormalities
Spectrum of signs, the
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
• ↑ strength and
Tocolytic agents
• ↓ strength and
frequency of uterine
frequency of uterine
contractions
contractions
Uses
Uses
– termination of
pregnancy
– induction of labour
– augmentation of
labour
– prevention of PPH
– premature labour
– uterine
hyperstimulation
Drugs affecting uterine contractility
• Toco agents
• Tocolytic agents
•
oxytocin
•
ergometrine
•
prostaglandin
– analgesics
•
mifepristone
– calcium antagonists
•
misoprostol
– indamethacin
•
carboprost
– Atosiban (oxytocin receptor
– Ritodrine
(β2adrenoceptor agonist)
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
Cytotoxic Drugs
Vinca alkaloids
Vincristine
Joint pain
Paralytic ileus
Alkylating agents
Peripheral neuropathy
Cyclophosphamide
Vinblastine
Haemmorhagic cystitis
Infertility
Antimetabolites
M
Methotrexate
Skin pigmentation
G0
Busulphan
G2
Heptatotxicity
Aplastic anaemia
Pneumonitis
Skin pigmentation
Encephalopathy
cell
cycle
Azothiaprine
Hepatitis
Lymphoma
Pulmonary fibrosis
G1
Daunorubicin
Myocardial toxicity (also Adriamycin and
S
Doxorubicin)
6-Mercaptopurine
Adriamycin
5-fluoruracil
Chlorambucil
Actinomycin-D
Steroids
G0= latent phase; G1= resting pase; G2 premitotic phase; S= synthesis of DNA; M= mitosis and division
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
Drugs and the endocrine system
• Galactorrhoea
– Methyldopa, L-dopa, phenothiazines, metoclopramide, cimetidine,
benzodiazepines, oestrogens, tricyclic antidepressants
• Gynaecomastia
– Spironolactone, cimetidine, methyldopa, phenothiazines, tricyclic
antidepressants, cytotoxic drugs, digoxin, oestrogens
• Hypothyroidism
– Iodides, lithium, amiodarone
• Vaginal carcinoma
– Diethystilboestrol
