Principles of drug use in pregnancy

Maulana A. Empitu
Department of Pharmacology
Airlangga University – School of Medicine
m.a.empitu@gmail.com

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 History

 Thalidomide: probably the most notorious

human teratogen
 Marketed as a sedative in late 1950’s

Associated with up to 12,000 birth defects,
primarily phocomelias

Other effects included:
 facial hemangiomata, oesophageal & duodenal
atresia, teratology of Fallot, renal agenesis &
anomalies of the external ear
 Thalidomide
 No malformations if taken before the 34th day
after last menstruation & usually no
malformations if taken after the 50th day
 Sensitive time period: day 35 to day 49

Day 35 – 37: absence of ears & deafness

Day 39 – 41: absence of arms

Day 43 – 44: phocomelia with three fingers

Day 46 – 48: thumbs with three joints
 If taken throughout the sensitive period: severe
defects of the ears, arms & legs & internal
malformations often leading to early death (40%
died before their 1st birthday)
 Thalidomide

 20% of pregnancies exposed during this

period resulted in anomalies
 Administration to female rabbits did not
show any adverse effects on fertility

There was an increase in early pregnancy
loss (equivalent to miscarriage)

There were no thalidomide-associated
malformations in surviving foetuses
 Overview
 All drugs should be avoided in pregnancy unless they
are ‘essential’
 In practice, it may not be easy to know what treatment
is really necessary or whether a particular medicine is
an appropriate choice
 Requires a balanced approach:

Being over-cautious may deny a beneficial therapy

Lack of due caution might harm babies as a consequence of drug
exposure
 Benefits of treatment need to be weighed against the
risks of giving no medication

Note: while the benefits of Tx may be clear, the risks may be largely
unknown or unquantifiable

For minor conditions, the risks almost always outweigh the (often trivial)
benefits
 The problem
 80% of women use prescribed or OTC
drugs during pregnancy

3 – 8 different drugs (partly prescribed and
partly self-medication)
 The risks of drug use in pregnancy has
lagged far behind advances in other areas
of pharmacotherapy
 Main reasons: epidemiological difficulties
in establishing causality and ethical
barriers to prospective RCTs
 Treatment Goals

Utilize appropriate resources to determine
teratogenic risk and excretion in breast milk

Assess the risk: benefit ratio of
pharmacotherapy

Utilize drug regimen that is safe, effective
and minimizes risk to fetus or infant

Minimize drug exposure to neonate/infant
during lactation
 Teratogenicity and drugs
 In the UK, the spontaneous malformation rate at
birth is 2-3% i.e. approximately 1 in 40 babies will
be born with a malformation
 The incidence of malformations increases to
approximately 5% by 4-5 years of age
 Drugs are thought to cause less than 1% of
malformations
 Therapeutic drugs do not appear to be a
significant cause of birth defects
 However, most birth defects have no known
cause and exposure to drugs may play a part in
some of these
 Causes of developmental
disorders
• Unknown:- Spontaneous development disorders; multigenetic
conditions; combination and interactions of exogenic and endogenic
factors (65%)
• Genetic diseases:- (20%)
• Chromosomal disorders:- (5%)
• Anatomical factors:- Uterus anomalies; twin pregnancy;
oligohydramy (2%)
• Maternal conditions:- Diabetes mellitus; hypothyroidism;
phenylketonuria; cytomegaly; listeriosis; lues; rubella;
toxoplasmosis; Varicella (4%)
• Chemical and physical agents:- Medicinal products; drugs of
abuse (especially alcohol); ionizing radiation; hyperthermia;
environmental chemicals (4%)
 Some teratogenic drugs
ACE inhibitors Renal dysfunction and hypotension in the newborn, decreased skull
ossification, hypocalvaria and renal tubular dysgenesis
Alcohol Fetal alcohol syndrome
Aminoglycosides Deafness, vestibular damage
Androgens (e.g. danazol) Masculinisation of female fetus

Anti-cancer drugs Multiple defects, abortion

Anti-thyroid drugs Fetal goitre
Carbamazepine Neural tube defects
Cocaine Cardiovascular, central nervous system defects
Diethylstilboestrol Vaginal carcinoma after in utero exposure
Lithium Cardiovascular defects (Ebstein’s anomaly)
Phenytoin Fetal hydantoin syndrome
Retinoids Craniofacial, cardiac, central nervous system defects
Sodium valproate Neural tube defects
Thalidomide Limb-shortening defects, renal malformations, congenital heart
disease
Warfarin Fetal warfarin syndrome
 Embryo/fetotoxic risk
assessment
 Generally accepted that the predictive
value of animal studies for predicting
safety in humans is less than adequate
 With the exception of androgens, several
antimitotic drugs, sodium valproate and
vitamin A derivatives, all human
teratogens were discovered earlier in man
than in animals

Most were case studies from alert clinicians
rather than epidemiological studies
 Drugs and the fetus
 Nearly all drugs, except those with a very high
molecular weight e.g. insulin and heparin, cross
the placenta to the fetus
 Lipid-soluble un-ionised drugs cross the placenta
more rapidly than polar drugs
 In practice, all drugs should be regarded as
having the potential to affect the unborn child
 The effect of drug exposure will depend upon:

Timing of exposure

Dosage

Concomitant maternal disease

Genetic susceptibility
 Drugs and the fetus

 However, it should be remembered that:


Teratogens do not cause defects in all fetuses
exposed at the critical period of gestation

A drug that harms a baby in one pregnancy
may have no effect in a subsequent
pregnancy in the same woman
 Timing of drug exposure
 Exposure during the pre-embryonic period (until
14 days post-conception)  the ‘all or nothing
effect’
 Damage to all or most cells  death
 If only a few cells are injured  normal development

Women with a history of drug use in the month
following their last menstrual period can often be
reassured

Limitations
 Drug must be completely eliminated before this time (not
useful for drugs with long half-life)
 Dates of conception uncertain
 Timing of drug exposure
 Fetus most vulnerable to teratogens from week
3 to week 8 after conception (embryonic phase)
when major organ systems formed
 For some drugs there is a period of greatest risk

Exposure to sodium valproate at the time the neural
tube closes (between day 17 & 30 post-conception)
may result in spina bifida
 Cleft palate develops at about 36 days post-
conception & so a drug exposure outside this
period is unlikely to be implicated in any a/e
 Timing of drug exposure
 During the fetal period (week 9  birth)
the fetus is less susceptible to toxic
insults, although some organs (cerebellum
& urogenital structures) continue to be
formed

Exposure is more likely to cause growth
retardation or interfere with functional
development within specific organ systems
 Danazol can cause virilisation of a female fetus
after 8 weeks gestation
 Warfarin may cause intracranial haemorrhage in
the second & third trimesters
 Timing of drug exposure
 Drugs taken close to term cause
predictable pharmacological effects

Beta-blockers can cause neonatal
hypoglycaemia

SSRIs can cause withdrawal effects after
regular in utero exposure
 Rarely, exposure can have delayed effects

Diethylstilboestrol – synthetic oestrogen used
for threatened spontaneous abortion
 Many female fetuses exposed before the 9th week
developed vaginal or cervical cancer later in life
 Dose & polypharmacy
 In general teratogenicity is dose
dependent

Neural tube defects & sodium valproate have
shown a correlation with:
 Total daily dose
 Dose per administration
 Peak level achieved

Dose is only a relative risk factor

Normal babies have been born to women who
have received high doses of valproate & vice
versa
 Dose & polypharmacy
 Risk of malformations increases with
exposure to multiple drugs

e.g. anti-epileptics
 4% incidence of defects for 1 drug
 23% incidence for 4+ drugs
 Potential for confounding with disease
severity can be discounted as epilepsy is
not thought to be associated with an
increase in malformation rate
 Avoid polypharmacy whenever possible
 Where to look up?

FDA Category of drug in

pregnancy
 FDA Categories

 Category A: Safest
Adequate, well-controlled studies in pregnant women have
not shown an increased risk of fetal abnormalities

 Category B: Use as necessary

Animal studies have revealed no evidence of harm to the

fetus, however, there are no adequate and well-controlled
studies in pregnant women.
or
Animal studies have shown an adverse effect, but adequate
and well-controlled studies in pregnant women have failed to
demonstrate a risk to the fetus.
 FDA Categories
 Category C: Avoid

Animal studies have shown an adverse effect and there

are no adequate and well-controlled studies in pregnant
women.
or
No animal studies have been conducted and there are
no adequate and well-controlled studies in pregnant
women

 Category D: Never use, unless extremely

needed
Studies, adequate well-controlled or observational, in
pregnant women have demonstrated a risk to the fetus.
However, the benefits of therapy may outweigh the
potential risk.
 FDA Categories

 Category X: Contraindicated

Studies, adequate well-controlled or

observational, in animals or pregnant
women have demonstrated positive
evidence of fetal abnormalities.

The use of the drug is contraindicated in
women who are or may become pregnant.
 Pregnancy alters the Pharmacokinetics

 Increase in total body water (~8L)

 Increase in total body fat
 Increase in GFR
 Decrease in gastrointestinal motility
and changes in absorption and
gastric acidity
 Increase in CO, blood volume and
plasma proteins
 Decrease in plasma albumin
concentration

Changes in serum albumin effect the
bioavailability of protein-binding
 Pregnancy and
Pharmacokinetics
 Pregnancy often accompanied by nausea
and vomiting, which may prevent
absorption of the medication, but…

 Increased plasma volume, fetal growth,

and increased interstitial tissue result in a
wider distribution of medications
 Bottom Line

 Every woman requires thorough history of

pregnancy complaints prior to
pharmacologic treatment
 Dosages may need to be considered
based on the stage of pregnancy
 Prescribing in pregnant patient requires
more than just attention to FDA drug
categories
 In Translation…
 Absorption affected by decreased GI tone

Drug remains in stomach longer leading to increase in
absorption through stomach and delayed in
absorption of drugs
 Distribution affected by increased plasma
volume causing prolonged half lives

Fat soluble drugs stay longer in the body

Drugs with high protein binding and lower lipid
solubility (such as anticonvulsants) have longer half
lives

Hormones (strongly protein bound) compete for
available binding sites-resulting in wide distribution of
free, unbound drug in the body
 Pregnancy and
Pharmacokinetics
 Metabolism of drugs in liver relatively
unchanged

Drugs cleared through liver eliminated similar
to non pregnant women
 Excretion-increased rates of clearance

Renal blood flow increases by 25-50%

GFR increases by 50%

Serum level of drug must fall to allow diffusion
of drug from the fetus’s circulation
 Placental Transfer
 Simple diffusion: molecular size may/not permit
transfer
 Active transport: where concentration of substances
are higher in fetus and transported back to the
mother
 Pinocytosis: where soluble molecules (such as
viruses) cross membrane in small vesicles and are
released
 Facilitated diffusion: glucose is rapidly transferred
to fetus
 Leakage: fetal cells enter mother’s circulation
through small membrane breaks
 Properties of Medications that easily
cross the placenta

 Small molecular size and weight (250-

500d)

Most drugs have weights < 600d
 Non-protein bound
 Non-ionized
 Lipophilic
 Selecting a Drug for a Pregnant
or Nursing Mother
 Principles of teratology:

Timing of exposure in fetal development
 Based on fetal developmental stage when insult is applied can help
predict the possible defect
 Exposure at time of conception and implantation may kill the fetus
(all or nothing effect)
 If exposure occurs in first 14 days after conception when the cells can
assume another cell’s function (totipotential), the fetus may not be
damaged
 Most sensitive period: time from implantation to the end of
organogenesis (days 18- 60)
 Damage to developing organs
 heart is most sensitive during the 3rd and 4th weeks of gestation,
external genitalia are most sensitive during the 8th and 9th weeks
 brain and skeleton are sensitive from the beginning of the 3rd week to
the end of pregnancy and into the neonatal period.
 Factors that Influence
Teratogenicity of a drug
 Genotypes of the mother and fetus
 Embryonic stage at exposure
 Drug dose
 Duration of exposure
 Nature of the agent and
mechanism by which it causes a
defect
 Simultaneous exposure to other
drugs and environmental agents
that potentiate a drug
 Maternal and fetal metabolism of
the drug
 Extent to which the drug crosses
the placenta
 The safest pregnancy-related pharmacy is as
little pharmacy as possible

 However, women with a history of psychiatric,

seizure-related, or hematologic illnesses
frequently require medication throughout
pregnancy.
 In such patients, care must to be taken to
select the safest drug from the necessary class
of medication.
 Misri and Kendrick noted that prescribing
drugs for women during the antenatal and
postnatal period is a balancing act and that
no risk-free alternatives exist
 Misri S, Kendrick K. Treatment of perinatal mood and
anxiety disorders: a review. Can J Psychiatry. Aug 2007
 Overview of
Frequently Used
Drug
 Drug Exposure Options for Pregnant and
Lactating women

1. Withhold the drug (e.g., headache medications)

 E.g., Ergotamine: Pregnancy category - X
 Trimesters of risk - all
 Associated defects and complications: LBW, and
preterm birth, ergotamine-induced vasoconstriction
in the placenta of pregnant women.
 The effect of ergotamine most obvious in male
newborn infants, particularly after treatment in the
third trimester.

2. Delay drug therapy (if woman is close to end of lactation)

 Options
 Choose drugs that pass poorly into placenta or
breast milk- (e.g., some variations even within
same class of drug)
 e.g., Benzodiazepines-Pregnancy category - D
or X
 Trimesters of risk: The first, second, and third
trimesters are times or risk for flurazepam
(dalmane), temazepam (restoril), and triazolam
(Halcion) (category X).
 Avoid alprazolam (Xanax-cat D) during
pregnancy
 Chlordiazepoxide(Librium) appears to be safest
choice during pregnancy.
 Options
 Choose alternate routes of administration when
possible
 Avoid long acting/medications with long half lives
 Advise lactating women to time their
medications before the infant’s longest sleep
period
 Temporarily withhold breast feeding

Can safely resume after 1-2 half lives (50%-75%
elimination)
 For drugs with high toxicity, must delay 4-5 half lives
 Discontinue nursing if medication is for life
threatening condition (e.g., chemotherapy)
Treatment for common condition:

Asthma
 Asthma:

Asthma complicates approximately 4% of
pregnancies

In some cases, asthma improves during
pregnancy

Those with poorly controlled asthma are at
risk for:
 Hyperemesis, uterine hemorrhage, preeclampsia,
placenta previa, hypertension and premature labor
 IMPLICATIONS of Pregnancy on Asthma

 Pregnancy has a significant effect on the respiratory

physiology of a woman
 Respiratory rate and vital capacity do not change in
pregnancy, but there is an increase in tidal volume,
minute ventilation (40%), and minute oxygen uptake
(20%) with resultant decrease in functional residual
capacity and residual volume of air due to elevation of
the diaphragm 
 Airway conductance is increased and total pulmonary
resistance is reduced, possibly as a result of
progesterone 
 Asthma:

Asthma complicates approximately 4% of
pregnancies

In some cases, asthma improves during
pregnancy

Those with poorly controlled asthma are at
risk for:
 Hyperemesis, uterine hemorrhage, preeclampsia,
placenta previa, hypertension and premature labor
 Improved Outcomes associated
with controlled asthma

 Current EVIDENCE Supports Treatment

 Almost all anti-asthma drugs are safe to use in
pregnancy and during breastfeeding. 


Under-treating is a frequent occurrence for the pregnant
patient because patients are worried about the medication
effects on the fetus

With a few exceptions, the medications used to treat asthma
during pregnancy are similar to the medications used to treat
asthma at other times during a person's life.
 Common Asthma
medications
 Inhaled B2 Agonists

Albuterol-Category C
 Mild, infrequent episodic
 May cause maternal hyperglycemia, tachycardia,
hypotension or neonatal hypoglycemia
 Briggs, et al., 2002: study of 1090 infants
exposed to albuterol in 1st trimester-possible
association with polydactyly
 No congential defects link in 2nd, 3rd trimester
 No adverse effects during lactation

Possible B2Choice-Brethine (category B)
 Other Asthma Drugs
Theophylline (Cat C)
Crosses placenta in equal concentrations to mother
Not associated with congenital defects but can cause
jitteriness, cardiac arrythmias, hypoglycemia, feeding
difficulties in infants

Neonates more likely affected

Corticosteroids (Cat C)
Spontaneous abortion, prematurity, cardiac
abnormalities reported in one study
Prednisone <20mg/day safe in lactation

In larger doses, delay nursing 3-4hours after dose
 The Common Cold

 No value in treating with medications

 If using medication, avoid combination products
 Limit duration of treatment
 Antihistamine of choice: Loratidine (cat B)
 Avoid brompheniramine (Dimetapp-Bromfed)
 Antihistamines excreted in breast milk
 Nasal cromolyn, beclomethasone useful alternative
 Clubfoot and inguinal hernias associated with first
trimester use of decongestants (e.g., Sudafed)
 Anti-tussives and expectorants: bromhexine, n-
acetylcysteine
 If necessary: codeine and dextromethorphane short
term
 Nausea and Vomiting
 80% of women experience n/v during 1st trimester
 Hyperemesis gravidarum-intractable, causes lyte
imbalances, weight loss, possible end organ
damage
 Cause unknown-tx focused on sx

Non pharmacologic measures not supported by
evidence

OTC phosphorated carbohydrate (EMETROL) safe

Drug of choice: Doxylamine combined with vit.B6

Metocloperamide can be use in 1st and 2nd trimester.
Use in 3rd trimester associated with pre-term birth.

Domperidone: no sufficient data in human

Ondancentron: use if other fail
 Nausea (Cont.)

 Antacid: can be use in all stages of

pregnancy, but no longterm use.
magaldrate and sucralfate may be
considered the drugs of choice
 Ranitidine: use if antacid fails. Avoid use
of cimetidine.
 Proton-pump inhibitor: Omeprazole is a 3rd
line drug
 Bismuth salt: contraindicated
 Analgesic and antipiretic

 Paracetamol: the first choice, the safest

 Aspirin: 2nd choice but, avoid in 3rd
trimester
 Metamizole: do not use, cause PDO
 Analgesic combination: not recommended
 Hemorrhoids

 OTC external preparations preferred, not

supposituria.
 Avoid suppositories d/t potential for
systemic absorption across rectal mucosa
 Principles of prescribing in
pregnancy
 Consider non-drug treatments
 Avoid all drugs in 1st trimester if possible
 Avoid drugs known to have harmful effects
 Avoid new drugs where possible

More experience with ‘older drugs’ – greater evidence of
safety, but can’t assume they are necessarily safe
 Avoid polypharmacy
 Use the lowest effective dose for the shortest
duration possible & review regularly
 Consider the need for dosing changes & TDM due
to the effect of pregnancy on drug handling

Changes in serum albumin & total body water
Thank you

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