Drug Used in

Pregnancy and
Lactation

Prepared by
Dr.Most. Nazma Parvin
Assistant Professor
Department of Pharmacy
Stamford University Bangladesh

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 Drugs Used in Pregnancy

Q: What are the key points (guidelines) that should be

considered before using drugs in pregnancy?

The following key points should be considered before using

drugs in pregnancy-

1. Drugs should be avoided whenever possible and non-drug

treatment should be attempted first.

2. All drugs should be avoided in the first trimester whenever

possible.

3. Drugs should be given in the lowest effective dose for the

shortest time possible.

4. Drugs that have an established safety profile should be

selected and those that have not been used extensively in
pregnant women should be avoided.

 Indications for drugs used in pregnancy

Drug therapy during pregnancy should be avoided or

minimized. Nevertheless it has been estimated that over 90%
of women take three or four drugs at some stages of
pregnancy.

Usually, drugs are administered in the following conditions

1. Chronic illness:
I. Epilepsy
II. Depression
III. Rheumatoid arthritis
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 2. Diseases commonly associated with pregnancy:

I. Hypertension
II. UTI (Urinary Tract Infection)
III. GI complaints (nausea, vomiting)
IV. Diabetes

 Prenatal development
The human gestation period is 38 weeks and is conventionally
divided into

 First trimester
 Second trimester
 Third trimester

Each trimester lasts for 3 calendar months.

The stages of prenatal development are divided into

Stage Duration Development

1. Pre- 17 days post Fertilized ovum

embryonic conception consolidates (becomes
dense/ harden/ solid)
2.Embryonic 18 days to 8 weeks
The major organ systems
are formed.
3. Fetal 8 weeks to 38 weeks
Maturation, development
and growth of all organ
systems.

 Fetal exposure

Drug exposure at any one of the above three stages is known

as fetal exposure.
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  Teratogenicity and Dysmorphogenesis

 Teratogen

A teratogen is an agent (drugs or chemicals) that

interferes with the normal growth and development of the
fetus which leads to major or gross birth defects.

 Dysmorphogenesis
All structural and functional defects of the body are called
dysmorphogenesis. Literally, it means development of ill-
shaped or malformed body structure.

 Congenital Anomaly

Congenital anomaly is an irreversible birth defect which occurs

due to-

1. Genetic predisposition
2. Drug exposure, that adversely affect the development of
fetus.

Classification and examples of congenital anomaly:

Congenital Anomaly

A) Immediate B) Delayed
e.g- i) Spina bifida e.g-i) Behavioural and
ii) Hydrocephalus intellectual disorder
ii) Uterine cancer
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 A. Immediate

These type of anomaly was observed by birth. Examples are-

i) Spina Bifida: Detective closure of spinal column.

ii) Hydrocephalus: Characteristic enlarged skull due to

blockage of Cerebrospinal fluid (CSF) pathway and
accumulation of CSF in the ventricle of brain.

B. Delayed

It may take many years to develop or be identified. Examples

are-

i) Behavioural and intellectual disorder due to alcohol

exposure in pregnancy.

ii) Vaginal cancer

It occurs when the baby becomes young women, if her mother

takes diethylstilboestrol for the prevention of miscarriage.

 Examples of human teratogen

Approximately 2% of all live births are associated with a

congenital anomaly and it has been estimated that about 5%
(0.1% of all live births) of these are caused by drugs. Examples
of drugs that are known to be human teratogens are-

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 Human teratogens
i) Androgens vii) Penicillamine
ii) Cytotoxic drugs (some) viii) Phenytoin
iii) Carbimazole (methimazole) ix) Tetracycline’s
iv) Diethylstilbestrol x) Thalidomide
v) Ethanol xi) Vitamin A
vi) Lithium xii) Warfarin

 Drugs effects on the fetus

 Placental drug transfer

Most drugs diffuse easily across the placenta and thus enter
the fetal circulation to some extent.

 Drugs with large molecular weight such as heparin,

transfer is negligible.

 Lipophilic, nonionized drugs cross the placenta more easily

than the polar drugs.

 Weakly basic drugs may become trapped in the fetal

circulation due to slightly lower pH compared with
maternal plasma.

Advantage of placental drug transfer:

Drugs are administered to pregnant woman to treat fetal

disorders. For example, Flecainide is given to treat fetal
tachycardia.

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 Idiosyncratic effects

The effects of some drugs on the fetus are less predictable

and not related to the dose. These idiosyncratic effects are
caused by-

a) Fetal genetic predisposition

b) Unknown threshold dose of drug, above which drug

induce dysmorphogenicity may occur.

This theory justifies the use of lowest effective dose during

pregnancy.

Idiosyncratic effect usually lead to major irreversible

congenital anomalies.

 Timing of drug exposure

The stage of pregnancy at which a drug is administered

can determined the probability, severity or nature of any
adverse effect on the fetus. Some drugs may exhibit
different adverse effect on fetus if given in different
trimester. As for example- Phenobarbitone can cause
congenital anomalies if given in first trimester but bleeding
if given in third trimester.

 First trimester

All drugs should be avoided or minimized whenever possible

in the first trimester.

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 Drugs exposure during the pre-embryonic stage may
lead to either death of the embryo or complete recovery and
normal development (all are known law). Thus
dysmorphogenesis may not occur unless the half life of the
drug is sufficient to extent exposure into the embryonic
stage.

Organogenesis occurs predominantly during the

embryonic stage (except CNS, teeth, external genitalia and
ear) and the formation is completed by the end of the 10th
week of pregnancy. Exposure to drugs during this period
represents the greatest risk of major birth defects by
interfering with the formation.

 Second and Third trimester

During this period, organ system continues to develop and

mature and there is continued susceptibility to drug effects.

a) CNS

CNS can be damaged by exposure to some drugs (e.g

ethanol) if given at any stage of pregnancy.

b) External genitalia

The external genitalia continue to form from the seventh

week until term. Danazol which has week androgenic
properties can cause virilization of the female fetus if given in
any trimester. Conversely spironolactone and cyproterone
acetate because of their anti- androgenic properties, have the
potential to cause feminization of the male fetus.

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c) Kidney
ACE inhibitors if given in the second or third trimester can
cause

 Fetal renal dysfunction.

 Oligohydramnios (small amount or absence of amniotic

fluid).

d) Blood

Sulphonamide and thiazides can cause neonatal hemolysis

and thrombocytopenia respectively, when given in the third
trimester.

 NSAIDs in third trimester

These drugs are inhibit prostaglandin synthesis in a dose

related fashion and when given late in pregnancy may cause-

 Closure of fetal ductus arteriosus

 Fetal renal impairment

 Bleeding disorders
 Delay labour and birth.

Therefore, regular use of NSAIDs in pregnancy should be

avoided during the third trimester.

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 Drug dosing in pregnancy

General principle:

 The dose of a drug given at any stage during should be

kept as low as possible to minimize toxic effect to the
fetus.

 Essential drug therapy during pregnancy can be tapered

to the lowest effective dose either prior to conception or
during the first trimester.
[

 The dose of drug that have the potential to cause

neonatal withdrawal effects such as antidepressants and
antipsychotics can be reduced as term approaches.

 Pharmacokinetic changes

Pharmacokinetic parameters in which there may arise some

changes due to pregnancy are-

1. Volume of distribution
2. Protein binding
3. Clearance

1. Volume of distribution

The weight gain of pregnancy is significant as a result of the

fetus and an increase in total body water and fat. These
factors increase the volume of distribution of drugs such that
increased loading doses may be required. This may be
important if a rapid drug effect is required or if the
magnitude of the effect is proportional to peak plasma
concentration.
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2. Protein binding

Albumin is the main plasma protein responsible for binding

acidic drugs such as phenytoin and salicylates, and α1-acid
glycoprotein predominantly binds basic drugs, including β-
blockers and opioids analgesics. Plasma albumin
concentrations fall significantly in pregnancy and this leads to
an increase in the fraction of unbound drug.

3. Clearance

Clearance of drugs may increase during pregnancy due to

 Rise in GFR
 Increased drug metabolism due to enzyme induction

GFR increases by approximately 50% within first few

weeks of pregnancy and remain raised until after delivery.
Consequently, the clearance of drugs that are excreted
unchanged mainly by kidney (e. g Lithium, Some beta lactam
antibiotics) are increased and higher maintenance dose are
required.

The hepatic metabolism of many drugs is increased during

pregnancy.

 Drug safety and selection

In general, drugs which have been used extensively in

pregnant woman without apparent problems should be
selected in preference to new drugs for which there is less
experience of use.

For example, Methyldopa has a long history of safe

use for the treatment of hypertension in pregnancy. New
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 drugs can be used if sufficient experience is gained for
them. The use of Atenolol and Labetalol is gradually
replacing Methyldopa as more experience is gained with
these newer antihypertensive agents.

Drugs and Lactation

All drugs distribute into human milk. It should always

be remembered that the infant is an “innocent bystander”.
The possible risks to the infant must therefore be considered
carefully when a mother takes a drug while breast feeding.

When drugs is given as a one off e.g. Sumatriptan for

migraine, it is usually not too inconvenient for the mother to
avoid breast feeding for a short time after the dose,
assuming no safe data available.
When the drugs is used to treat a chronic condition
such as epilepsy, thus the risk of infant exposure to drug
must be considered. Where possible, the infant should be
fed immediately before the dose. Fortunately, drug
exposure from lactation is less risky then fetal exposure.

Examples of drugs that given high infant exposure and

which must be avoided during lactation-

 Amiodarone
 Carbimazole
 Ethosuxamide
 Isoniazid
 Lithium
 Metronidazole
 Phenoberbitone
 Theophylline
 Propylthiouracil

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  Effects of drugs on the neonate

The neonate can be adversely affected by maternal drugs

therapy. Neonates are affected because the capacity of the
neonate to eliminate drugs is minimal as enzyme responsible
for metabolism of drugs example-CYP450 dependent mixed
function oxidase conjugating enzyme is very low. As a result,
some drugs accumulate significantly in neonates leading to
toxicity.

 Remedy

The dose of the drug should be slowly reduced close to

parturition (delivery). For example, the dose of antidepressants
and neuroleptics are slowly reduced to minimize-

 Neurological disturbance due to direct toxicity in

neonate.

 To minimize drug withdrawal effects.

 Neonatal drug withdrawal effects

After maternal drug therapy, drugs cross through placenta, thus

fetus receives drug from mother. After birth, this drug transfer is
closed abruptly. Then the neonate may react with some adverse
manifestation in the drug previously exposed continuously.

Neonate withdrawal effect can be very distressing and

symptoms often require treatment-

 Treatment with sedative.

 Drug replacement (Morphine oral solution is used to

wean babies off methadone).

Assignment: List the drugs that are strictly prohibited

during pregnancy and lactation
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