Drugs and medications in

pregnancy
1. Basic principles of teratology
• The study of birth defects and their etiology is termed as teratology, derived
from the Greek teratos, meaning monster.

• A teratogen may be broadly defined as any agent that acts during embryonic or
fetal development to produce a permanent alteration of form or function.

• Thus, a teratogen may be a medication or other chemical substance, a physical

or environmental factor such as heat or radiation, a maternal metabolite as in
diabetes or phenylketonuria, or an infection such as cytomegalovirus.

• A teratogen causes structural abnormalities.

Criteria for Determining Teratogenicity
The abnormality has been completely characterized.

 Exposure must occur during a critical developmental period

The preimplantation period is the 2 weeks between fertilization and

implantation and is known as the “all or none” period. As the zygote
undergoes cleavage, an insult damaging a large number of cells typically
causes embryonic death. However, if only a few cells are injured,
compensation may be possible and allow normal development.
 The embryonic period extends from the second through the eighth week
postconception. It encompasses organogenesis and is thus the most crucial
period with regard to structural malformations.

The fetal period, which is beyond 8 weeks postconception, is characterized by

continued maturation and functional development. During this time, certain
organs remain vulnerable

 A biologically plausible association is supportive. Because birth defects and

medication exposures are both common, they may be temporally but not
causally related.
Epidemiological findings must be consistent. Because initial evaluation of
teratogen exposure is often retrospective, it may be hampered by recall bias,
inadequate reporting, and incomplete assessment of the exposed population.

The suspected teratogen causes a defect in animal studies. This criterion is not
obligatory.animal studies are necessary but insufficient. For example,
thalidomide was considered harmless in several animal species but resulted in
phocomelia in thousands of children born across Europe in the late 1950s and
early 1960s.
• Wilson’s six general principles of teratogenesis provide a framework for
understanding how structural or functional teratogens may act are as the
followings

1. Genotype and Interaction with environmental Factors

• The first principle is that susceptibility to a teratogen depends on the
genotype of the conceptus and on the manner in which the genotype interacts
with environmental factors.
• Certain genotypes show more vulnerability to the effects of teratogens than
others.
2. Timing of Exposure
• The second principle is that susceptibility of the conceptus to teratogenic
agents varies with the developmental stage at the time of exposure.

• It is during the second to the eighth weeks of development after

conception—the embryonic period—that most structural defects occur.

• For example, neural tube closure occurs between the 22nd and 28th days, so
exposure must occur during that time for the teratogen to result in defects.
• The classic teratogenic period is from day 31 after the last menstrual period in
a 28-day cycle to 71 days from the last period.

• Before day 31, exposure to a teratogen produces an all-or-none effect,

resulting in either death of the conceptus or survival with no anomalies.
3. Mechanisms of Teratogenesis

• The third principle is that teratogenic agents act in specific ways

(mechanisms) on developing cells and tissues in initiating abnormal
embryogenesis (pathogenesis).
 Folate antagonism
 Neural crest cell disruption
 Endocrine disruption
 Oxidative stress
 Vascular disruption
 Specific Receptor- or Enzyme-mediated

4. Manifestation
• The fourth principle is that irrespective of the specific deleterious agent, the final
manifestations of abnormal development are malformation, functional disorder,
growth restriction, and death.
• Embryonic exposure is likely to lead to structural abnormalities or embryonic
death; fetal exposure is likely to lead to functional deficits or growth
restriction.
5.Agent

• The fifth principle is that access of adverse environmental influences to

developing tissues depends on the nature of the influence (agent).
• The agents could be chemicals or drugs, as well as physical agents such as
radiation or heat.

• They are either transmitted indirectly through maternal tissues or directly

traversing the maternal body.

6. Dose Effect

• The final principle is that manifestations of abnormal development increase in

degree from the no-effect level to the lethal level as dosage increases.
2. Drugs of abuse
A. Alcohol
• Ethanol is a potent and prevalent teratogen.alcohol-related fetal defects
known as fetal alcohol syndrome.

• Fetal alcohol spectrum disorder (FASD) is an umbrella term that includes five
conditions attributed to prenatal alcohol damage:
(1) fetal alcohol syndrome
(2) partial fetal alcohol syndrome
(3) alcohol-related birth defects
 (4) Alcohol-related
neurodevelopmental disorder, and
(5) Neurobehavioral disorder
associated with prenatal alcohol
exposure.
Criteria for prenatal alcoholexposure
Criteria for Fetal Alcohol Syndrome
• The prevalence of FASD exceeds 1 percent in 76 countries

• Alcohol-related birth defects include cardiac and renal anomalies, orthopedic

problems, and abnormalities of the eyes and ears. An association has further
been reported between periconceptional alcohol use and omphalocele and
gastroschisis . There are no established sonographic criteria for prenatal
diagnosis of fetal alcohol syndrome

• Binge drinking, however, is believed to pose particularly high risk for alcohol-
related birth defects and has also been linked to a greater risk for stillbirth
 B. cocain
• With this CNS stimulant, most adverse outcomes result from its vasoconstrictive
and hypertensive effects.

• Serious potential maternal complications are cerebrovascular hemorrhage,

myocardial damage, and placental abruption.

• Studies of congenital abnormalities and cocaine exposure have yielded

conflicting results, but associations with
 cleft palate,
 cardiovascular abnormalities, and
 urinary tract anomalies have been reported
 fetal-growth restriction and preterm delivery. Children exposed as
fetuses have risks for behavioral abnormalities and cognitive
impairments in children exposed as fetuses
 C. Marijuana
• This is the recreational drug most commonly used in pregnancy.

• Based on data from the National Survey on Drug Use and Health, nearly 4
percent of pregnant women reported using marijuana in 2014.

• Among women diagnosed with nausea and vomiting of pregnancy, the

prevalence of marijuana use increased from 7 to 11 percent from 2009 to
2016. Of concern is that the increase in prevalence is related to perceived
safety and efficacy.
• Cannabinoids are not considered to be major teratogens, but they cross the
placenta, and endogenous cannabinoids play key roles in brain development.
In animals, cannabinoids are involved in neuronal proliferation, migration,
and differentiation.

• Adverse developmental outcomes reported in exposed children include

decreased attention span
 lower scores on tests of visual problem solving and visual-motor
coordination
 neurodevelopmental concerns as the effects of marijuana may be as
serious as those of cigarette smoking or alcohol consumption.
• Because of reasons mantioned above women who are pregnant or contemplating
pregnancy should avoid marijuana use.
D. Methamphetamine
• This sympathomimetic amine is derived from dextroamphetamine.

• It enhances dopamine release and blocks its reuptake.

• Methamphetamine is prescribed to treat attention deficit hyperactivity disorder and

narcolepsy.

• Methamphetamine is not considered teratogenic.

• However, use in pregnancy is consistently associated with small-for-gestational
age newborns, and children are at risk for developmental delays and behavioral
abnormalities.

• Adverese outcome associated with amphetamine use during pregnancy include

Behavioral abnormalities have been described in both infants and
school-aged children
 Hypertensive complications
placental abruption
preterm birth
stillbirth are other associated adverse outcomes
E. Opioids
• The dramatic rise in narcotic use among nonpregnant and pregnant individuals
has been aptly termed an epidemic.

• Opioids are not major teratogens. Howeveit is identified a slightly greater risk
for
 spina bifida,
 gastroschisis, and
 cardiac abnormalities with periconceptional opioid exposure.

• It is stressed that this potential, small increase in birth defects with

maintenance therapy should be weighed against the risks associated with
uncontrolled opioid abuse.
• Heroin addiction is associated with adverse pregnancy outcomes from the effects
of repeated narcotic withdrawal on the fetus and placenta. These include
 preterm birth
 placental abruption
 fetal-growth restriction
 fetal death

• Neonatal narcotic withdrawal, called the neonatal abstinence syndrome, may

manifest in 40 to 90 percent of exposed newborns, CNS irritability may progress to
seizures if untreated and may be accompanied by tachypnea, apneic episodes,
poor feeding, and failure to thrive.
• At-risk neonates are closely monitored using a scoring system, and those
severely affected are treated with opioids.

• The proportion of exposed newborns developing neonatal abstinence

syndrome has risen significantly in recent years

• Treatment includes either buprenorphine, which may be given in an office-

based setting by a licensed buprenorphine prescriber, or methadone, usually
through a licensed outpatient opioid treatment program.
• A multidisciplinary treatment program is recommended to reduce the
likelihood of additional opioid abuse while on maintenance therapy.

• Withdrawal from methadone during pregnancy is discouraged because of

high relapse rates.

• pregnant opioid users who decline maintenance therapy are offered inpatient
hospitalization for controlled methadone taper. The goal is to reduce the
likelihood of neonatal abstinence syndrome
F. Tobacco
•Cigarette smoking is the leading preventable cause of perinatal mortality.

•Cigarette smoke contains a complex mixture of nicotine, cotinine, cyanide,

thiocyanate, carbon monoxide, cadmium, lead, and various hydrocarbons.

•In addition to being fetotoxic, many of these substances have vasoactive effects
or reduce oxygen levels.
• Tobacco is not considered a major teratogen, although selected birth defects
have been reported to occur with greater frequency among newborns of
women who smoke.

• It is plausible that the vasoactive properties of tobacco smoke could produce

congenital defects related to vascular disturbances.

• The prevalence of Poland sequence, which is caused by an interruption in the

vascular supply to one side of the fetal chest and ipsilateral arm, is two-fold
greater in smokers.
•The best-documented adverse reproductive outcome from smoking is a dose-
dependent reduction in fetal growth.

•Newborns of mothers who smoke weigh on average 200 g less than newborns
of nonsmokers.

•Women who stop smoking early in pregnancy may have neonates with normal
birthweights.
• Other adverse outcomes associated with cigarette smoking include

 preterm birth,
 placenta previa,
 placenta abruption,
 spontaneous abortion, and
 sudden infant death syndrome

• All forms of nicotine cross the placenta. None is considered safe in pregnancy.
■ Anticonvulsants

• Newer drugs have better side effect profile than the olds .
• The most frequently reported anomalies is due to valproate exposure.
orofacial clefts
cardiac malformations, and
neural-tube defects with first-trimester exposure.
Cont.
• School-aged children with prior in utero exposure to valproic acid have poorer
cognitive development including quotient (IQ) scores than children exposed to
other antiepileptic drugs. older anticonvulsants may produce a constellation of
findings similar to the fetal hydantoin syndrome.
Cont.
• The syndrome is characterized by distinctive features such as
hypertelorism
low nasal bridge, and
midface hypoplasia
intellectual disability
• Importantly, these risks do not appear to hold for the newer agents
levetiracetam and lamotrigine
Antihypertensives

• For treatment of chronic hypertension in pregnancy, α-methyldopa has been

widely used. Although postural hypotension may occur, no unusual fetal effects
have been noted.

• Hydralazine is used frequently in pregnancy, and no teratogenic effect has been

observed
Cont.
Angiotensin converting enzyme inhibitors and Angiotensin receptor blocker
• Fetal exposure in the first trimester doesn’t increased risk of birth defects.
• ACE inhibitors such as enalapril and captopril and ATII receptor antagonists such
as valsartan can cause fetal renal tubular dysplasias and related complications .
• These medications may result in angiotensin-converting enzyme (ACE)- inhibitor
fetopathy
fetal renal tubular dysplasia leading to
oligohydramnios,
fetal limb contractures,
craniofacial deformities, and
hypoplastic lung development.
Fetal skull ossification defects have also been described.
■ Antifungal Medications

• From this class of drugs, fluconazole is associated with a pattern of

congenital malformations resembling the autosomal recessive Antley-
Bixler syndrome.
Abnormalities include
oral clefts,
abnormal facies, and
cardiac, skull, long-bone, and
joint abnormalities.
• The findings reported only with chronic, first-trimester, high-dose
treatment at doses of 400 to 800 mg daily.
Cont.
• Regarding low-dose treatment of vulvovaginal candidiasis, the Motherisk
Program conducted a systematic review of pregnancies with first-trimester oral
fluconazole exposure of 150 or 300 mg.
• A population-based cohort study from Denmark identified a threefold greater risk
for tetralogy of Fallot following exposure to low-dose fluconazole Nielsen.
Antiinflammatory Agents

Nonsteroidal Antiinflammatory Drugs

• indomethacin may cause constriction of the fetal ductus arteriosus and
subsequent pulmonary hypertension. Fetal ductal constriction is more likely with
third trimester use that exceeds 72 hours.
• The drug also may decrease fetal urine production and amnionic fluid volume .
• In one systematic review, indomethacin tocolysis was associated with a 1.5-fold
risk for
bronchopulmonary dysplasia,
intraventricular hemorrhage, and
necrotizing enterocolitis.
• the FDA recommends that pregnant women ≥20 weeks’ gestation avoid NSAID
use for more than 48 hours.
• Oligohydramnios usually resolves within 6 days of discontinuing.
■ Antimicrobial and Antiviral Drugs

• Medications used to treat infections are among those most frequently

administered during pregnancy.
Cont.
Nitrofurantoin
• From NBDPS results, first-trimester nitrofurantoin exposure is linked to a twofold
risk for cleft lip.

• In the absence of G6PD deficiency, the There are no concerns with second or
third-trimester nitrofurantoin use, and

• first-trimester use is appropriate if no suitable alternatives are available.

Cont .
• Nitrofurantoin is contraindicated in pregnant women with known or suspected
(G6PD) deficiency because of risk for hemolytic anemia and other hematologic
abnormalities
Cont.
Sulfonamides
• These drugs are often combined with trimethoprim and used to treat infections
during pregnancy. One indication is treatment of methicillinresistant
Staphylococcus aureus (MRSA) infection.
• a fivefold greater risk to have offspring with esophageal atresia or diaphragmatic
hernia
Cont.

• Sulfonamides are contraindicated in pregnant women with known or suspected

G6PD deficiency because of risk for hemolytic anemia and other hematologic
abnormalities.

• Additionally, sulfonamides displace bilirubin from protein-binding sites.

Cont .

Tetracyclines
• These drugs are not commonly used in pregnant women.
• They have been associated with yellowish-brown discoloration of the deciduous
teeth when used after 25 weeks’ gestation.
• Doxycycline has a reduced ability to chelate calcium orthophosphate compared
with other tetracyclines and is preferred if needed.
Antiretroviral Agents

Zidovudine (ZDV)

• should be included as a component in the antiretroviral regimen

whenever possible because of its record of safety
• first-trimester exposures to ZDV and lamivudine, and no increase in
teratogenicity was reported.
Cont.
Efavirenz
• is not recommended during pregnancy because of reports of significant
malformations in monkeys who received during the first trimester and also three
case reports of fetal NTDs in women who received the drug.
Cont .
Ribavirin
• This antiviral nucleoside analogue is a component of therapy for hepatitis C
infection.
• Reported malformations include skull, palate, eye, skeleton, and gastrointestinal
abnormalities.
• Ribavirin use is also contraindicated in men whose partners are pregnant
Antineoplastic Drugs and Immunosuppressants

Mycophenolate mofetil

• Used to prevent rejection in organ-transplant recipients and to treat

autoimmune disease.
• is a potent teratogen.
• causes mycophenolate embryopathy
Cont.
• mycophenolate embryopathy include
microtia,
auditory canal atresia,
clefts,
coloboma and other eye other eye anomalies,
short fingers with hypoplastic nails, and cardiac defects.
Cont.
Methotrexate
• A folic acid antagonist,
• appears to be a human teratogen.
• Infants of the women known to have received methotrexate in the first trimester
of pregnancy had multiple congenital anomalies including cranial defects and
malformed extremities.
Psychiatric Medications
Antipsychotic Medications
• No antipsychotic medications are considered teratogenic.
• Exposed neonates can manifest abnormal extrapyramidal muscle movements and
withdrawal symptoms
agitation
abnormally enhanced or diminished muscletone,
tremor
respiratory abnormalities, and
feeding difficulty.
Cont .

• An FDA alert cited all medications in this class. Included are older medications like
haloperidol and chlorpromazine and

• newer medications such as aripiprazole, olanzapine, quetiapine, and risperidone.

Cont .
Lithium
• associated with Ebstein anomaly, a rare cardiac abnormality with occurance only
1 per 20,000 births.
• Ebstein anomaly is characterized by
apical displacement of the tricuspid valve, often resulting in
severe tricuspid regurgitation and
marked right atrial enlargement.
Cont .
• Neonatal lithium toxicity stems from exposure near delivery. Findings may persist
for up to 2 weeks and may include
cardiac arrhythmias,
hypoglycemia,
nephrogenic diabetes insipidus, and a “floppy infant syndrome” The latter may
include hypotonia, respiratory distress or apnea, bradycardia, cyanosis, and
feeding difficulties
Cont.
Selective Serotonin- and Norepinephrine-reuptake Inhibitors
• As a class, they are not considered major teratogens .
• paroxetine is an exception ,which has been associated with a slightly higher risk
for cardiac anomalies, particularly atrial and ventricular septal defects.
• Another concern with late-pregnancy exposure is the possible association of SSRI
medications with persistent pulmonary hypertension of the newborn (PPHN)..
 Cont .
• jitteriness,
• irritability,
• hyper- or hypotonia,
• feeding abnormalities,
• vomiting,
• hypoglycemia,
• thermoregulatory instability, and
• respiratory abnormalities

• collectively termed the neonatal behavioral syndrome .these neonatal behaviors are typically
mild and self-limited and last approximately 2 days.
Sex Hormones

Androgen exposure may cause varying degrees of virilization in female fetuses

and may result in ambiguous genitalia.
Thalidomide and Analogues

• Possibly the most notorious human teratogen.

• The characteristic malformation is phocomelia—an absence or
underdevelopment of one or more long bones.
• As a result, hands or feet may attach to the trunk, occasionally by a small
rudimentary bone. Cardiac defects, gastrointestinal abnormalities, external ear
and eye malformations, and other limb-reduction defects also are common
following thalidomide exposure.
 Anticoagulant

• Anticoagulants Warfarin has been associated with chondrodysplasia punctata.

• Warfarin embryopathy occurs in about 5% of exposed pregnancies and includes
nasal hypoplasia,
bone stippling seen on radiologic examination, ophthalmologic abnormalities
including
bilateral optic atrophy, and
mental retardation.
Cont.
• the alternative drugs, heparin and enoxaparin, do not cross the placenta because
they are large molecules with a strong negative charge

• Because heparin does not have an adverse effect on the fetus when given in
pregnancy, it should be the drug of choice for patients who require
anticoagulation, except in women with artificial heart valves they require
warfarin anticoagulation
Cont.
• The risk of heparin-induced thrombocytopenia and clinical bleeding at delivery is
lower, but studies that suggest less risk of osteoporosis are preliminary.
 Antiasthmatics

Terbutaline
• Terbutaline has been widely used in the treatment of preterm labor. It is more
rapid in onset, has a longer duration of action than epinephrine.
• preferred for asthma in the pregnant patient.
• No risk of birth defects has been reported with terbutaline, although long-term
use has been associated with an increased risk of glucose intolerance.
Cont.
Corticosteroids
• All steroids cross the placenta to some degree, but prednisone and prednisolone
are inactivated by the placenta therefore
• these agents are the drugs of choice for treating asthma.
• Inhaled corticosteroids are also effective therapy, and very little drug is absorbed.
Cont.
• When steroid effects are desired in the fetus to accelerate lung maturity,
betamethasone and dexamethasone are preferred
 because these are minimally inactivated by the placenta.

• A meta-analysis of exposure to corticosteroids in the first trimester showed an

odds ratio of 3.0 for cleft lip and/or cleft palate.
Antiemetics
• None of the current medications used to treat nausea and vomiting have been
found to be teratogenic

 except possibly methylprednisolone used before 10 weeks of gestation because

of the potential risk of cleft lip and/or cleft palate.
 DRUGS IN BREAST MILK

The rate of transfer into milk depends on the lipid

solubility, molecular weight, degree of protein binding,
degree of ionization of the drug, and the presence or
absence of active secretion.
Nonionized molecules of low molecular weight, such as
ethanol, cross easily
Short-term effects of most maternal medications on
breastfed infants are mild and pose little risk to the
infants.
• The amount of drug in breast milk is a variable fraction of the
maternal blood level, Thus the dose to the infant is usually
subtherapeutic, approximately 1% to 2% of the maternal dose
on average. This amount is usually so trivial that no adverse
effects are noted.
• In the case of toxic drugs, however, any exposure may be
inappropriate.
• Long-term effects of even small doses of drugs may yet be
discovered.
• Drugs are eliminated more slowly in the infant with
immature enzyme systems.
• Because the benefits of breastfeeding are well known, the
risk of drug exposure must be weighed against these benefits.
For drugs that require daily dosing during lactation, knowledge
of pharmacokinetics in breast milk may minimize the dose to
the infant. For example, dosing immediately after nursing
decreases the neonatal exposure because the blood level will
be at its nadir just before the next dose.
 Drugs Commonly Listed as Contraindicated During Breastfeeding

Cytotoxic Drugs That May Interfere With Cellular Metabolism of

the Nursing Infant
• Cyclosporine, doxorubicin, and cyclophosphamide might cause
immune suppression in the infant, although data are limited.
• After oral administration to a lactating patient with
choriocarcinoma, methotrexate was found in milk in low but
detectable
• levels. However, therapy with this drug would not in itself appear
to constitute a contraindication to breastfeeding.
Drugs of Abuse for Which Adverse Effects on the
Infant During Breastfeeding
• Amphetamines, cocaine, heroin, LSD, and phencyclidine

Radioactive Compounds That Require Temporary

Cessation of Breastfeeding
• The mother can attempt to store breast milk before the study, and
she should continue to pump to maintain milk production but
should discard the milk during therapy.
• Radiopharmaceuticals require variable intervals of interruption of
nursing.
TOBACCO
• Nicotine and its metabolite cotinine enter breast milk. Infants of
smoking mothers achieve significant serum concentrations of nicotine
even if they are not exposed to passive smoking; exposure to passive
smoking further raises the levels of nicotine.
• Women who smoke should be encouraged to stop during lactation as
well as during pregnancy.
Drugs for Which the Effect on Nursing Infants Is Unknown
but May Be of Concern

• Several classes of psychotropic drugs,

• Amiodarone (associated with hypothyroidism),
• Lamotrigine (potential for therapeutic serum concentration in the
infant),
• Metoclopramide (potential dopaminergic blocking, but no reported
detrimental effects),
• Metronidazole
• Antianxiety, antidepressant, and antipsychotic agents are sometimes
given to nursing mothers.
• Although no data are available about adverse effects in infants
exposed to these drugs through breast milk, they could theoretically
alter CNS function.
• Some psychoactive drugs have been reported to appear in breast milk
in levels that approach clinical significance (10% or more). These
include bupropion, fluoxetine, citalopram, sertraline, and venlafaxine
• Fluoxetine is excreted in breast milk at low levels, so the infant
receives approximately 6.7% of the maternal dose.

A bigger problem is postpartum depression exacerbated by fatigue, and

the benefits of nursing should be weighed against the negative effect on
bonding that would result from untreated postpartum depression.
Drugs Associated With Significant Effects in Some Nursing Infants
That Should Be Given to Nursing Mothers With Caution

• BROMOCRIPTINE: inhibitory effect on lactation, it should be

avoided unless the mother has taken it during the pregnancy.
• ERGOTAMINE used by some for migraine headache, and has been
associated with vomiting, diarrhea, and convulsions in the infant.
• Administration of an ergot alkaloid for the treatment of uterine
atony does not contraindicate lactation.
• LITHIUM
 Maternal Medication Usually Compatible With
Breastfeeding

• NARCOTICS, SEDATIVES, AND ANTICONVULSANTS

• In normal doses, carbamazepine, phenytoin, magnesium sulfate,
codeine, morphine, and meperidine do not cause any obvious
adverse effects in breastfed infants because the dose detectable in
the breast milk is approximately 1% to 2% of the mother’s dose.
CODEINE
Although the short-term use of codeine by a breastfeeding mother
appears to be harmless, in one case, a mother was breastfeeding
while taking codeine and acetaminophen for episiotomy pain. On
day 7, the infant was lethargic and had difficulty feeding, and died
on day 13. The mother was an ultra-rapid metabolizer who converted
codeine to morphine at a rapid rate.

• Because a mother’s status is rarely known, the use of any

codeine product should be restricted to less than 2 days.
• COLD PREPARATIONS
• No harmful effects have been noted from antihistamines or decongestants.

• ANTIHYPERTENSIVES
• THIAZIDES
• β-BLOCKERS
• Atenolol is concentrated in breast milk to about three times the plasma
level. Thus, infants must be monitored closely for bradycardia. Propranolol
is a safer alternative.
• Clonidine concentrations in milk are almost twice the maternal serum
levels. Neurologic and laboratory parameters in the infants of treated
mothers are similar to those of controls.
• ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
• Captopril use has shown no effects on nursing infants.
• CALCIUM CHANNEL BLOCKERS
• Nifedipine is excreted into breast milk at a concentration of less than 5% of
the maternal dose, and verapamil is excreted at an even lower level. Neither
have caused adverse effects in the infant.
• ANTICOAGULANTS
• Heparin does not cross into milk and is not active orally.
• Studies show that warfarin appears only in insignificant quantities in breast
milk.
• Thus, with careful monitoring of maternal prothrombin time and of
neonatal prothrombin times to ensure lack of drug accumulation, warfarin
may be safely administered to nursing mothers.
• CORTICOSTEROIDS
• DIGOXIN
• ANTIBIOTICS
• Penicillin derivatives are safe in nursing mothers. In susceptible
individuals or with prolonged therapy, diarrhea and candidiasis are
concerns.
• Dicloxacillin & Cephalosporins appear only in trace amounts in
milk
• Tooth staining or delayed bone growth from tetracyclines have not
been reported after the drug was taken by a breastfeeding mother.
• Sulfonamides only appear in small amounts in breast milk and are
ordinarily not contraindicated during nursing.
• However, the drug is best avoided in premature, ill, or stressed
infants in whom hyperbilirubinemia may be a problem, because
the drug may displace bilirubin from binding sites on albumin.
• On the other hand, sulfasalazine was not detected in the breast milk
of.
• Gentamicin is detected in low levels which would not be expected to
cause clinical effects.
• Nitrofurantoin is excreted into breast milk in very low concentrations.
• Erythromycin is excreted into breast milk in small amounts, although
no reports of adverse effects on infants reported.
• Azithromycin & Clindamycin also appears in breast milk in low
concentrations. And nursing is usually continued during
administration of these drug.
• There are no reported adverse effects on the breastfed infant when
isoniazid is administered to nursing mothers, and its use is considered
to be compatible with breastfeeding
• ACYCLOVIR
• ANTIFUNGAL AGENTS:
• No data are available on the effects of nystatin, miconazole, or
clotrimazole in breast milk. However, with only small amounts
absorbed vaginally and poor oral bioavailability, this would not be
expected to be a clinical problem.
• ORAL CONTRACEPTIVES: Estrogen and progestin combination
oral contraceptives cause dose-related suppression of milk production.
Lactation is inhibited to a lesser degree if the pill is started about 3
weeks postpartum and with lower doses of estrogen than 50 μg.
Although the magnitude of the change is low, it still may be of
nutritional importance, particularly in malnourished mothers.
• No consistent long-term adverse effects on growth and
development have been described.
• ACOG(American College of Obstetricians and Gynecologists )
recommends placement of the etonogestrel contraceptive implant 4
weeks or more after childbirth.
• Progestin only contraceptives do not cause alteration of breast milk
composition or volume, making them ideal for the breastfeeding
mother. When the infant is weaned, the mother should be switched to
combined oral contraceptives for maximum contraceptive efficacy.
• Evidence indicates that norgestrel is metabolized, rather than
accumulated, by infants, and to date, no adverse effects have been
identified as a result of progestational agents taken by the mother.
• ALCOHOL
• Alcohol levels in breast milk are similar to those in maternal blood.
No evidence suggests that occasional ingestion of alcohol by a
lactating mother is harmful to the breastfed infant.
• However, one study showed that ethanol ingested chronically through
breast milk might have a detrimental effect on motor development but
not mental development.
• Also, alcohol in breast milk has an immediate effect on the odor of the
milk, and this may decrease the amount of milk the infant consumes.
PROPYLTHIOURACIL
• Several infants studied up to 5 months of age show no changes in
thyroid parameters. Lactating mothers on PTU can thus continue
nursing with close supervision of the infant.
• PTU has been preferred over methimazole because of its high protein
binding (80%) and lower breast milk concentrations. However,
recently it has been observed that liver injury is higher with PTU than
with methimazole, but no cases of liver damage in infants of nursing
mothers taking PTU have been reported
H2–RECEPTOR BLOCKERS
• In theory, H2-receptor antagonists such as ranitidine and cimetidine
might suppress gastric acidity and cause CNS stimulation in the infant,
but these effects have not been confirmed.
• Famotidine, nizatidine, and roxatidine are less concentrated in breast
milk and may be preferable in nursing mothers.
CAFFEINE
• Caffeine has been reported to have no adverse effects on the nursing
infant, even if the mother consumes five cups of coffee per day.
 FDA’S RULE OF PREGNANCY AND LACTATION
LABELING (DRUGS) FINAL RULE

• The PLLR requires changes to the content and format of information

presented on prescription drug labels in the Physician Labeling Rule
(PLR) format to assist health care providers in assessing benefit versus
risk and subsequent counseling of pregnant women and nursing
mothers who must take medication, allowing them to make informed
and educated decisions for themselves and their children.
The PLLR removes pregnancy letter categories – A, B, C, D and X.

Category Risk Examples

A Adequate and well-controlled studies in pregnant women have Doxylamine
failed to demonstrate a risk to the fetus in the first trimester of Folic acid
pregnancy. Levothyroxine

B Animal reproduction studies have failed to demonstrate a risk Amoxicillin

to the fetus, and there are no adequate and well-controlled Loratadine
studies in pregnant women, or animal reproduction studies Ondansetron
have shown adverse effects, but well-controlled studies in
pregnant women have shown no adverse effects to the fetus.

C Animal reproduction studies have shown an adverse effect on Fluconazole

the fetus, or there are no animal reproduction studies and no Metoprolol
well-controlled studies in humans. Sertraline

D Positive evidence of fetal risk, but benefits may outweigh risks. Lisinopril
Lithium
Phenytoin

X Positive evidence of fetal risk, and risks clearly outweigh any Methotrexate
possible benefit. Simvastatin
Warfarin

Table 1: Pregnancy Categories Prior to New Pregnancy and Lactation Labeling Rule
The Problem with Letters
• Pregnancy letter category system was overly simplistic
• Misinterpreted as a grading system
• A drug with adverse information in animals could be labeled as the
same category as a drug with no animal information
• Example: Pregnancy Category C
• Animal reproduction studies have shown an adverse effect on the fetus,
• There are no AWC studies in humans, BUT the benefits from the use of
• The drug in pregnant women may be acceptable despite its potential risks
• Studies in pregnant women and animals are not available
The New System
• Instead of using an arbitrary lettering system, the PLLR provides detailed
risk summaries and more comprehensive information derived from
clinical experience (if available), animal data, and concerns related to the
pharmacologic activity of the drug.
• In addition, the label includes information on the risks associated with
untreated illness.
• This information helps to put the potential effects of the drug into
perspective with the goal of providing a more individualized risk-benefit
analysis.
• In addition, the PLLR will also reduce the “innocent until proven guilty”
phenomenon, where newer, untested drugs with no known harmful side
effects were perceived to be safer (Category B) than tested drugs with
possible or known side effects (Category C).
 The A, B, C, D and X risk categories, in use since 1979, are now
replaced with narrative sections and subsections to include:

For Pregnancy (includes For Lactation (includes For Females and Males of
Labor and Delivery): Nursing Mothers): Reproductive Potential
• Risk Summary (includes Labor and
•Pregnancy Exposure
Delivery):
Registry • Clinical Considerations
• Pregnancy Testing
•Risk Summary • Data
• Contraception
•Clinical Considerations
• Infertility
•Data
REFERENCES
• Center for Drug Evaluation and Research. (n.d.). Pllr labeleing final
rule. U.S. Food and Drug Administration.
https://www.fda.gov/drugs/labeling-information-drug-products/preg
nancy-and-lactation-labeling-drugs-final-rule
• Gabbe. (2016). Obstetrics: Normal and problem pregnancies. Elsevier.