Principles of drug use in pregnancy
Maulana A. Empitu
Department of Pharmacology
Airlangga University – School of Medicine
[email protected]
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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
Any questions?
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