PRINCIBLES OF DRUG
USE IN PREGNANCY
Prof.Dr. Zeliha Yazıcı
 Congenital defects are found in approximately 5% of
all live births, but only 10% of these events are due
to external factors (e.g., chemical, physical, or
biologic). Of this 10%, only 1% is estimated to be
due to medication use.
 Despite this low risk (0.005%), many women
unnecessarily terminate pregnancies due to fear of
drug-induced malformations.
 Teratogenic risk is determined largely by timing of
drug exposure. Establishment of full implantation of
the fertilized egg takes 1 to 2 weeks. Thus, negative
effects of drug exposure during this time typically
result in spontaneous abortion.
 The critical time for organogenesis is during the first
8 weeks of pregnancy; thus, the risk for birth defects
is highest during the first trimester. After 8 weeks,
most teratogenic effects are related to fetal growth
restriction or functional deficits such as mental
retardation.
Multiple physical and hormonal changes take
place during pregnancy that may cause related
problems.
 Anemia is common due to a 30% to 50% increase
in plasma volume with a disproportionate increase
in red blood cell mass.
 Increased levels of progesterone slow
gastrointestinal motility, relax esophageal sphincter
pressure, and increase mucosal edema.This leads
to constipation, heartburn, and rhinitis.
 Increased venous pressure and constipation
often result in hemorrhoids.
 Human chorionic gonadotropin produced by the
placenta is thought to induce nausea and vomiting
of pregnancy (commonly termed morning sickness).
 Increasing abdominal girth and posture changes
commonly cause back pain.
 Preterm labor and fetal growth restriction often
are caused by infection during pregnancy (e.g.,
chlamydia, bacterial vaginosis, and bacteriuria) or
untreated maternal chronic disease (e.g., diabetes
mellitus).
 After birth, a rapid drop in progesterone level
initially triggers lactation through reversal of
inhibitory effects on prolactin.
 Nipple stimulation then enables lactation to continue
once established. During lactation, ineffective
removal of milk from the breast, trauma, and skin
breaks may lead to problems such as milk stasis,
nipple pain, and mastitis.
 Some women have difficultly initiating lactation due
to improper technique and/or activity of inhibitors
such as dopamine.
The primary goal for drug use during pregnancy and
lactation is to treat maternal or fetal conditions as
necessary while minimizing risk to the developing fetus
or neonate. Numerous situations may necessitate drug
therapy:
 Maternal chronic disease
 Symptomatic conditions associated with pregnancy
or lactation
 Conditions associated with adverse fetal or neonatal
outcomes
General Approach to Treatment
The Food and Drug Administration (FDA) pregnancy
labeling system is the most commonly used source for
information regarding safety of drug use during
pregnancy.
 Category A: Adequate, well-controlled studies in
pregnant women have not shown an increased risk
of fetal abnormalities.
 Category B: 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.
 Category C: Animal studies have shown an
adverse effect and there are no adequate and wellcontrolled 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: 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.
 Category X: Studies, adequate well-controlled or
observational, in animals or pregnant women have
demonstrated positive evidence of fetal
abnormalities. The use of the product is
contraindicated in women who are or may become
pregnant.
General Principles of Drug Use in Pregnancy
and Lactation
 Avoid unnecessary medications during pregnancy
or lactation
 Avoid drugs with known teratogenic effects and
infant complications
 Choose single-drug, short-acting therapy with
agents having the longest safety record in
pregnancy or lactation.
 Choose drugs with characteristics such as high
molecular weights, strong ionization, high protein
binding, and high water solubility to limit entry into
the placental circulation or breast milk through
passive diffusion.
 Counsel women to take agents immediately after
breast-feeding to allow milk concentrations to fall
prior to the next feeding.
Drugs with Known Teratogenic Effects
Drug or Class
Teratogenic Effect
ACE inhibitors
Barbiturates
Benzodiazepines
Carbamazepine
Chemotherapeutic
agents
Renal damage, growth restriction
Isotretinoin
Lithium
Misoprostol
Non-steroidal antiinflammatory agents
Opioids
Phenytoin
Tetracyclines
Thalidomide
Valproic acid
Neonatal withdrawal syndrome
Neonatal withdrawal syndrome
Neural tube defects
Multiple malformations (including
central nervous system, facial, and
limb)
Central nervous system, ear, and
heart malformations
Cardiovascular malformations
Limb and central nervous system
malformations
Premature closing of the patent
ductus arteriosus (late second and
third trimesters), hemorrhage,
necrotizing enterocolitis
Neonatal withdrawal syndrome
Central nervous system
malformations, fetal growth
restriction
Tooth and bone malformations
Limb and internal organ
malformations
Neural tube defects
Warfarin
Growth restriction, fetal
hemorrhage, skeletal and
central nervous system
malformations
Contraindicated Drugs and Drugs of Concern
During Lactation
Contraindicated Drugs and Drug Classes
Neonatal hypothyroidism and
Amiodarone
Bromocriptine
Chemotherapeutics
Ergotamine
Isotretinoin
Lithium
pulmonary toxicity
Lactation suppression
Neonatal immune suppression and
neutropenia
Neonatal diarrhea, vomiting,
convulsions; lactation suppression
Possible neonatal tumors
Neonatal central nervous system
and cardiovascular disturbances
Drugs and Drug Classes of Concern
Neonatal hypotension,
Acebutolol
Al-containing
antacids
Antidepressants
Antipsychotics
Atenolol
Benzodiazepines
Clemastine
Metronidazole
Phenobarbital
bradycardia, tachypnea
Developmental retardation
Unknown, but possibly of concern
Unknown, but possibly of concern
Neonatal bradycardia, cyanosis
Unknown, but possibly of concern
Neonatal drowsiness, irritability
In vitro mutagen
Infantile spasms, neonatal
Primodone
Radioactive drugs
sedation
Neonatal sedation
Transfer of radioactivity
MATERNAL PHARMACOKINETIC CHANGES IN
PREGNANCY
 Reduce in gastrointestinal motility
 Increase in gastric pH
 Increase in pulmonary alveolar drug uptake
 Increase in maternal plasma volume (50%)
 8 L increase in total body water. 40% is distributed
to maternal compartment, 60% to amnionic fluid,
placenta and fetus.
 Decrease in serum albumine binding capacity
 Increase in hepatic and renal elimination of drugs
 Progestrone and estradiol enhance the hepatic
methabolism of some drugs (eg phenytoin), inhibit
of others (eg theophylline)
 The clearence of drugs excreted into biliary system
may slow (estrogen-cholestasis)
 Increase in renal blood flow and glomerular filtration
 These changes usually do not result in a need for
altered drug dosing
TRANSPLACENTAL DRUG TRANSFER
 Most drugs move across the membranes by passive
diffusion, borh to the fetus from mother and from the
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fetus to the mother, as maternal serum levels
decline.
Maternal dose, administration route, maternal
pharmacokinetic handling of the ingested
substance, and maternal plasma protein binding
may influence the actual amount of drug that
reaches the fetus.
High lipophilicity, low ionization, low protein binding,
and low molecular weight enhance the decree of
transfer.
Drug exposure during the embriyonic period has the
greatest potential influence on organ development.
Teratonergic effects may include loss of pregnancy,
structural abnormalities, growth impairment, and
functional loss.
More subtle changes in function or behavior may be
associated with drug exposure at the other times.
In the first 2 weeks, exposure to the teratogen may
result in an “all or nothing” effect which could either
destroy the embryo or cause no problems.
Teratonergic exposure (e.g., chemotherapeutics,
sex hormones, Li, retinoids, thalidomide,
antiepileptics, coumarine) may result in structural
anomalies from 18 to 60 days (organogenesis);
retardation of growth, CNS abnormalities, or death.
ACE inhibitors, NSAIDs and tetracycline exhibite
effects in the second and third trimester.
PHARMACOLOGIC THERAPY
Preconception Planning
 Planning prior to pregnancy is an important strategy
for reducing the risks of birth defects and fetal or
neonatal complications.
 Clinicians should consider childbearing potential
when selecting therapy for chronic medical
conditions and follow the same general principles of
drug selection described earlier.
 This is especially important for the treatment of
conditions such as hypertension or epilepsy
because many medications used for these
conditions are known teratogens.
 Engage women in discussions regarding the
potential risks to an exposed fetus prior to starting
therapy.
Preconception Care
 Folic acid deficiency is a major cause of neural tube
defects because dietary intake alone is seldom
sufficient to prevent the occurrence. Advise most
women of childbearing potential to take a
multivitamin containing 400 mcg folic acid.
 Additional benefits of multivitamin intake include the
calcium and iron components.
Hypertansion
 Chronic hypertansion: present either before
pregnancy or before 20 weeks’ gestation.
 Gestational hypertansion: >140/>90 mmHg after 20
weeks’ gestation.
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Nausea and Vomiting
 The combination of pyridoxine (vitamin B6) and
doxylamine appears to offer the most favorable
benefit-to-risk ratio for the treatment of nausea and
vomiting in pregnancy.
 Ginger is safe and effective when used as an
antinausea agent in pregnancy.
 Second-line agents include first generation
antihistamines (diphenhydramine), dopamine
agonists (metoclopramide), and the serotonin
agent (ondansetron).
 Nonpharmacologic measures recommended include
lifestyle and dietary changes, acupuncture, and
acupressure.
 to avoid or minimize nausea triggers such as
objectionable odors and food textures, rapid
positional changes, and car rides.
 Administration of the prenatal vitamin at bedtime
because the iron content often triggers nausea.
 to eat small, frequent meals that are bland, high in
carbohydrates, and low in fat.
 to keep saltine crackers, water, or ginger ale (small
sips only) at the bedside so that they can ingest a
small snack immediately before getting out of bed.
 If nausea occurs, to lie down to relieve symptoms.
Constipation
 Bulk-forming laxatives such as psyllium and
calcium polycarbophil are safe for use in
pregnancy and lactation.
 Second-line agents are stimulant laxatives
(bisacodyl and sena) for short-term or intermittent
use, but side effects of diarrhea and abdominal pain
may limit use.
 Stool softeners (docusate) are recommended
commonly but have shown little efficacy for the
treatment of chronic constipation.
 Avoid magnesium-containing laxatives or
phosphosoda owing to the potential for electrolyte
disturbances and fluid retention.
 During lactation, bulk-forming laxatives and the
stimulant laxative senna are likely safe for use.
 Nonpharmacologic treatment include to eat a highfiber diet, drink plenty of fluids, and avoid foods
such as white rice and cheese that often exacerbate
constipation.
Hemorrhoids
 Recommend only topical anti-inflammatory
agents.
 Patients should avoid prolonged time on the toilet.
Soaking in warm sitz baths also may help
hemorrhoids by relaxing the anal sphincter. Icing the
area may decrease pain and inflammation. If
hemorrhoids are severe, surgical resection or
banding can be performed. However, it is generally
preferable to delay even minor surgery until after
delivery.
Heartburn
 Calcium- or magnesium containing antacids are
recommend as first-line therapies for heartburn in
pregnancy.
 Avoid antacids containing aluminum hydroxide
owing to associations with fetal neurotoxicity. If
antacids fail to improve symptoms, recommend
ranitidine.
 Although most H2 blockers are thought to be safe in
pregnancy, ranitidine is the only agent with doubleblind, randomized trials evaluating its use in this
population.
 Other agents that appear to be safe for use in
pregnancy include the proton pump inhibitors,
sucralfate, and metoclopromide. The proton pump
inhibitor with the largest body of human safety data
during pregnancy is omeprazole.
 During lactation, sucralfate may be the best choice
for treatment of heartburn because it is not
absorbed systemically. If symptoms are not
controlled, the H2 blockers are acceptable
alternatives.
 Avoid aluminum-containing antacids during lactation
owing to reports of aluminum toxicity in otherwise
healthy infants.
 Nonpharmacologic recommendations include eating
small, frequent meals, remaining upright after
eating, elevating the head of the bed, and avoiding
foods known to decrease lower esophageal
sphincter tone (such as chocolate, coffee, fatty
foods, and peppermint).
Pain
 Acetaminophen generally is considered the drug of
choice for the treatment of pain during pregnancy.
 If acetaminophen does not relieve pain, nonsteroidal antiinflammatory drugs (NSAIDs) may be
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used cautiously during the first trimester only in
women who do not have a history of gastrointestinal
bleed, peptic ulcer, or aspirin allergy.
Also avoid NSAID use in women who have had
difficulty conceiving or have experienced
miscarriage.
Use of NSAIDs in the late second or third trimester
has been associated with multiple fetal and neonatal
complications.
Avoid opioid use during pregnancy owing to reports
of fetal growth restriction, neonatal dependence,
and neonatal respiratory depression.
Brief treatment with small doses of codeine is
acceptable for severe pain unresponsive to
acetaminophen or NSAIDs.
For lactating women, acetaminophen, NSAIDs, and
most opioids are considered compatible with breastfeeding by the American Academy of Pediatrics.
Upper Respiratory Symptoms
 For common cold symptoms such as congestion
and cough, recommend nasal oxymetazoline, oral
guaifenesin, and dextromethorphan
 Counsel patients using oxymetazoline to limit use to
3 to 5 days in order to minimize the incidence of
rebound congestion.
 Oral pseudoephedrine is also acceptable for
treatment of congestion during the second and third
trimesters, but avoid use in the first trimester owing
to the risk of fetal gastroschisis (incidence 20 per
10,000 treated women).
 Codeine is not a preferred therapy for cough.
 Treat allergy symptoms with nasal corticosteroids
during pregnancy. Budesonide has extensive
safety data in pregnant women.
 If antihistamines are indicated, chlorpheniramine is
preferred. Fewer data are available regarding the
safety of second-generation antihistamines during
pregnancy. Animal and human studies seem to
suggest overall safety for cetirizine and loratadine.
However, guidelines recommend their use only in
women on topical corticosteroid therapy who are
unable to tolerate chlorpheniramine. Avoid
fexofenadine owing to reports of teratogenic effects
in animals.
 During lactation, oral or nasal decongestants, nasal
steroids, and loratadine are acceptable for treatment
of upper respiratory symptoms. However, one case
of adverse neonatal outcome has been reported
with the first-generation antihistamine clemastine.
Few data are available regarding the safety of other
first-generation antihistamines during lactation.
Therefore, avoid use of this drug class during
lactation.
Bacteriuria
 Bacteriuria during pregnancy, including
asymptomatic disease, is associated with
pyelonephritis, low birth weight, and preterm
delivery. Treatment improves these risks; thus, treat
all women testing positive for bacteriuria empirically
with antimicrobial therapy targeted at Escherichia
coli infection.
 Safe agents for empirical therapy include
amoxicillin, cephalexin, and nitrofurantoin.
Sulfonamides and ampicillin also have been used,
but increasing bacterial resistance to these agents
renders them second-line choices.
 Avoid quinolones owing to the possible risk of bone
and cartilage malformations.
 Recommend standard 3-day antimicrobial therapy
because there is insufficient evidence among
pregnant women to support 1-day regimens.
Bacterial Vaginosis
 Bacterial vaginosis is associated with preterm
delivery, but treating asymptomatic disease does
not appear to decrease this risk.
 Consequently, treat only symptomatic disease by
oral metronidazole for the treatment of bacterial
vaginosis in pregnant women. Metronidazole is
deemed safe for use during all stages of pregnancy
despite package labeling listing a contraindication in
the first trimester.
 Oral clindamycin is an option for women not
tolerating metronidazole. It is not a first-line agent
owing to lower efficacy compared with oral
metronidazole in non-pregnant populations. Avoid
clindamycin vaginal cream due to associations with
premature labor and neonatal infection.
 metronidazole causes nausea, vomiting, and
abdominal pain. to avoid alcohol or alcoholcontaining substances during therapy with
metronidazole owing to the risk of disulfuram-like
reactions.
 Clindamycin vaginal cream is the preferred therapy
for bacterial vaginosis during lactation.
Vulvovaginal Candidiasis
 Treat symptomatic vulvovaginal candidiasis in
pregnant women with topical azole therapy.
 Oral fluconazole is not recommended.
 Asymptomatic disease does not require treatment.
 Vulvovaginal candidiasis during pregnancy is
considered a “complicated” case; thus, 7-day
therapy (instead of 1- to 3-day therapy) is
recommended.
 During lactation, topical azoles remain the drug of
choice for vulvovaginal candidiasis. Oral fluconazole
is not recommended in order to minimize the
development of fluconazole resistant Candida
species in the general population.
Sexually Transmitted Infections
Chlamydia
 Treat chlamydia infections during pregnancy,
including those that are asymptomatic, with
erythromycin or amoxicillin in order to reduce risk
of preterm labor.
 Amoxicillin is better tolerated than erythromycin and
has fewer discontinuations owing to adverse drug
reactions than erythromycin.
 Azithromycin may be a safe alternative in women
unable to take, tolerate, or adhere to these first-line
recommendations. However, azithromycin is a thirdline therapy because there are longer safety records
for erythromycin and amoxicillin in pregnancy.
 Avoid doxycycline in pregnant women owing to
known teratogenic effects.
 During lactation, azithromycin and doxycycline are
firstline choices for chlamydia. Both are generally
are more effective and better tolerated than
erythromycin or amoxicillin.
Gonorrhea
 Treat gonorrheal infections during pregnancy,
including those that are asymptomatic, with
cefixime or ceftriaxone in order to reduce the risk
of preterm labor.
 Spectinomycin, second-line agent in pregnancy for
cephalosporin-allergic patients
 Avoid tetracyclines during pregnancy owing to
known teratogenic effects.
 Avoid quinolones owing to the possible risk of bone
or cartilage malformations.
 Ceftriaxone, first-line agent in pregnancy or
lactation
 Ciprofloxacin, ofloxacin and levofloxacin,
contraindicated in pregnancy; first-line agent in
lactation.
Herpes Simplex
 Herpes simplex virus may be transmitted to the
neonate if active vaginal lesions or the prodrome is
present at the time of birth. Consequently, cesarean
section often is recommended for these women.
 Oral acyclovir is preferred for treatment of genital
herpes simplex episodes during pregnancy in order
to help reduce the need for cesarean section and
during lactation.
Pelvic Inflammatory Disease
 Clindamycin plus gentamicin, in order to reduce
maternal morbidity, preterm delivery, and fetal
death.
 Avoid regimens using doxycycline owing to known
teratogenic effects.
 Avoid quinolones owing to the possible risk of bone
and cartilage malformations.
Syphilis
 Treat syphilis during pregnancy with benzathine
penicilin G in order to prevent transmission of
syphilis to the fetus and to cure the disease in the
fetus. It is also first-line agent during lactation.
 Doxycycline and Tetracycline are alternative
during lactation (but not pregnancy) for penicillinallergic patients
Trichomoniasis
 Treat symptomatic trichomoniasis with oral
metronidazole in order to alleviate maternal
symptoms. Do not treat asymptomatic disease.
 Safe during pregnancy. During lactation, temporarily
stop breast-feeding for 12–24 hours.
Preterm Labor
 Administration of antenatal corticosteroids
during preterm labor having an onset prior to 34
weeks’ gestation has been proven to decrease the
risk of neonatal respiratory distress, intraventricular
hemorrhage, necrotizing enterocolitis, and death.
 Agents commonly used as tocolytics include
magnesium sulfate, terbutaline, indomethacin,
and nifidepine.
 Systemic review concludes that tocolytic therapy
with the calcium channel blockers offers the best
benefit-to-risk ratio.
 Data proving that magnesium sulfate prolongs
pregnancy is lacking. It is contraindicated for use in
women with myasthenia gravis, and serious
complications such as maternal pulmonary edema
and cardiac arrest have been reported. Flushing,
headache, and nausea often cause discontinuation
of therapy.
 Terbutaline has been shown to prolong pregnancy
but has not been associated with decreased
neonatal morbidity. It is contraindicated for use in
women with preexisting cardiac arrhythmia.
Potentially serious adverse effects include
pulmonary edema, cardiac arrhythmia, or
myocardial ischemia in the mother. Reported fetal
and neonatal adverse effects include tachycardia,
hyperglycemia, and hyperinsulinemia.
 Indomethacin prolongs pregnancy but has not been
independently associated with decreased neonatal
morbidity. It may be of particular benefit in women
with hydramnios. Avoid use in women with a
history of severe renal or hepatic impairment,
aspirin allergy, or a history of peptic ulcer disease or
other bleeding disorders. Although typically well
tolerated by the mother, reports of increased risk of
postpartum hemorrhage and patent ductus
arteriosus is worrisome.
 The calcium channel blockers (nefedipine) have
been associated with both prolonged pregnancy and
decreased neonatal morbidity. Potential minor
maternal adverse effects include headache,
flushing, dizziness, and transient hypotension.
Group B Streptococcus
 Maternal transmission of group B Streptococcus
during the intrapartum period is a cause of
neonatal sepsis and death.
 Antibiotic therapy has been proven to reduce the
incidence of early-onset neonatal disease in highrisk groups of women
 The antibiotic of choice for group B streptococcal
disease is penicillin G, although ampicillin is an
alternative.
 Resistance has developed with the use of
alternative choices for penicillin-allergic patients
(Cefazolin, Clindamycin, Erythromycin,
Vancomycin).
Labor Induction
 Two drugs have proven efficacy for cervical
ripening: the prostaglandin E analog dinoprostone
(available as a gel or a vaginal insert) and
misoprostol.
 Pharmacologic agents used for cervical ripening
often induce contractions. However, if contractions
do not begin within 6 to 12 hours of dinoprostone
use or within 3 hours of misoprostol use, oxytocin
may be administered.
Breast Infections
Acute Mastitis
 Treat acute mastitis with antistaphylococcal
antibiotics such as dicloxacillin or cephalexin for
10 to 14 days in order to prevent recurrent disease
and breast abscess
 Penicillin-allergic women alternatively may be
treated with erythromycin.
Nipple Candidiasis
 Treat nipple candidiasis by applying topical
ketoconazole, nystatin, or miconazole to the
nipples after each feeding and by administering oral
nystatin drops to the breast-feeding infant
 In severe or recurrent cases, the mother may be
treated with oral fluconazole.
Enhancement of Lactation
 Metoclopramide is the drug of choice for
enhancement of lactation when improved feeding
technique fails to increase milk flow
 Metoclopramide exerts its effect through dopamine
antagonism. Increases in milk production should be
noted within 2 to 5 days of metoclopramide
initiation.
 Other agents used for lactation enhancement
include domperidone (dopamine antagonist) and
fenugreek.
 Risk of extrapyramidal effects is lower with
domperidone because it does not cross the bloodbrain barrier.
OUTCOME EVALUATION
 Report birth defects that are believed to be
teratogenic effects.
Preterm Labor
Many tocolytic drugs require special monitoring of both
mother and fetus.
 Monitor cardiac status by electrocardiogram and
pulmonary status by physical examination in
mothers receiving terbutaline or magnesium sulfate
owing to the risk of cardiac arrhythmia, cardiac
ischemia, and pulmonary edema.
 Monitor blood pressure and heart rate in mothers
receiving terbutaline, magnesium sulfate, or
nifedipine owing to the risk of hypotension.
 Monitor fetal heart rate during therapy and neonatal
heart rate, respiratory rate, and oxygen saturations
after delivery.
Labor Induction
Continuously monitor uterine activity and fetal heart rate
when giving drug therapy for cervical ripening or
oxytocin.
 Dinoprostone gel. Start monitoring 15 minutes prior
to gel insertion and continue for 30 to 120 minutes
after administration.
 Dinoprostone insert. Start monitoring 15 minutes
prior to insertion and continue for 15 minutes after
removal.
 Misoprostol. Start monitoring 15 minutes prior to
insertion and continue for 3 hours after
administration.
 Oxytocin. Monitor until delivery.