Download Drug Effects on the Fetus and Breast-Fed Infant

Drug Effects on the Fetus and Breast-Fed Infant
GERALD G. BRIGGS, BPharm
Women's Hospital, Long Beach Memorial Medical Center, Long Beach, California
CLINICAL OBSTETRICS AND GYNECOLOGY 2002;45:6-21
A major dilemma facing anyone who prescribes, dispenses, or administers drugs
to a woman of childbearing age is that the patient may be or may become
pregnant. This dilemma is heightened by the realization that drugs can and do
adversely effect the embryo, fetus, and newborn. Fortunately, most medicinal
agents produce no measurable effect on the developing offspring and, thus, are
relatively safe during pregnancy. Drug-induced teratogenicity and toxicity are
limited to a few therapeutic agents. Awareness of these agents can be an
effective means of diminishing the anxiety of prescribing for a woman who is or
may become pregnant. Communication of this information to the patient can also
lessen the anxiety she may experience when she is taking the therapy.
A second important consideration is knowledge of the background incidence of
birth defects, their various causes, and the percentage of the total that are
believed to be drug-induced. The incidence of congenital malformations among
live births is approximately 5–6% after long-term follow-up.
1–3
Approximately half of these are diagnosed shortly after birth. The causes of
birth defects and the approximate percentage of each are single major mutant
genes (15–20%), chromosomal aberrations (5%), multifactorial (polygene–
environmental factor interactions) (20%), environmental factors (maternal
conditions and diseases, deformations, radiation, hyperthermia, chemicals,
drugs) (10%), and unknown (up to 65%).4–6 The combined incidence of birth
defects resulting from radiation, hyperthermia, chemicals, and drugs is thought to
be less than 1%6 but has been estimated in the past to be as high as 3%.4
Teratogen-induced congenital anomalies usually involve a combination of minor
and major malformations.7 Underreporting of adverse outcomes is most likely
common, therefore, because most drug-induced malformations are characterized
by a pattern of minor anomalies rather than a single major defect. 7 Part of the
reason for this discrepancy is that the diagnosis of minor malformations is very
difficult unless exposed offspring are studied in a systematic fashion with
standardized physical examinations. Moreover, the long-term effects of drugs on
neurobehavior are rarely studied. Henceforth, the terms “birth defects,”
“anomalies,” or “congenital malformations” will be used to refer only to major
structural anomalies unless otherwise stated.
The definitions used for major and minor malformations are as follows: major—
“a defect that has either cosmetic or functional significance to the child”; minor—
“a defect that occurs infrequently (in less than 4% of the population) but that has
neither cosmetic nor functional significance to the child.”7 Deformations are
defined as “abnormal form, shape or position of a part of the body caused by
mechanical forces.”8
A second dilemma facing health professionals is the woman who requires
pharmacologic therapy while breast feeding. In most cases, there is less concern
about the possible toxicity from drugs in breast milk because the adverse
consequences are usually transient, quickly observable, and far less severe than
an analogous situation during gestation. However, there are some drugs (eg,
antineoplastics, radiopharmaceuticals, drugs of abuse) that may injure the
nursing infant without causing easily recognizable signs and symptoms. Thus,
agents with this potential should be absolutely avoided during breast feeding.
This paper is designed to serve two objectives: to provide sufficient information to
clinicians and other health professionals concerning the risks of drug-induced
teratogenicity and toxicity in the embryo, fetus, or newborn; and to provide
adequate information to health professionals concerning the adverse effects in
the nursing infant from drugs excreted into breast milk. In both of these
situations, the information should serve as a foundation to counsel pregnant and
lactating women on the risks of toxicity to their offspring from therapeutic drugs.
To have maximum effectiveness, however, a system of close communication
between the patient and her health-care providers must be established and
maintained.
Counseling Women About Drugs in Pregnancy
The counseling of women who are of childbearing age should be based on
accurate information and is one of the primary objectives of this paper. This
knowledge base should include agents known to cause malformations or toxicity,
the critical periods for the adverse outcomes, an estimate of the magnitude of
risk, and the types of malformations or toxicity (
Table 1). Typically, the critical period is the period of organogenesis (5–10 weeks
after the last menstrual period, or 20–55 days after conception), but it can be at
any time during gestation. The risk estimates apply only to populations, not to
individual pregnancies, because many of the drug-induced adverse outcomes
are genetically determined.
Table 1. Drugs That Cause Toxicity in the Fetus and/or Newborn
As previously stated, most medications pose little if any measurable risk to the
embryo or fetus when consumed at therapeutic doses at any time in gestation.
Moreover, drug-induced teratogenicity and toxicity are relatively rare and can
usually be avoided altogether by avoiding the known critical periods for toxic
drugs. However, many of the newer drugs have little or no reported human
pregnancy experience, so the estimation of pregnancy risk is difficult at best.
Three methods to reduce the risks arising from treating pregnant women with
drugs are readily apparent: try to use only those agents considered relatively
safe in pregnancy; if a drug known to be toxic must be used, avoid, if possible,
the critical period associated with the its toxicity; and use new drugs with no
human pregnancy experience only when necessary and only after careful review
of the potential risks and benefits.
For each of the above methods, the risks and benefits should be carefully and
thoroughly discussed with the patient so that she is fully informed. It is an
important reality that many women will markedly overestimate the risk of
congenital malformations from a specific drug.9 Therefore, health professionals
need to invest adequate time and resources to overcome these misconceptions
and misinformation.
NONPREGNANT WOMAN WHO REQUIRES THERAPY AND MAY BECOME
PREGNANT
For the nonpregnant patient, the use of the safest drug, in terms of pregnancy
risk, is the best course of action, assuming that the safest drug also has
acceptable efficacy for the condition being treated. However, if therapy with a
potentially harmful drug is required, the patient should be informed of the risks if
she does conceive and plans made to modify her therapy if necessary.
Establishment of a system of close communication with the patient, if her
pregnancy status changes, would be ideal. Moreover, there are some toxic
agents (eg, acitretin, etretinate) that have such prolonged elimination times
(months or years) that they should not be prescribed to any woman who could
conceive in the foreseeable future (within 3 years). Special care should be taken
to exclude exposure to these agents in women who may become pregnant. For
especially potent human teratogens (eg, isotretinoin, thalidomide), continued
documentation that a sexually active woman is using effective contraceptive
methods and that she is not pregnant is vital to prevent inadvertent exposures.
One manufacturer of a potentially potent teratogenic agent with a prolonged
elimination time (leflunomide) has even designed a drug elimination procedure so
that systemic levels of the drug can be rapidly reduced in the event of an
inadvertent pregnancy. The importance of the above steps is evident in view of
the estimate that at least half of the pregnancies in North America are
unplanned.3 Consequently, patients should be counseled to contact their healthcare provider immediately if they miss a menstrual period or have other reason to
believe that they may be pregnant. In many cases there is time to discontinue
potentially toxic therapy because physiologic exchange (ie, substance transfer) is
not established between the mother and the embryo until about the fourth week
after conception.
PREGNANT WOMAN WHO REQUIRES DRUG THERAPY
Women who are pregnant and who need pharmacologic therapy require a more
urgent approach. Because of the apparently common misconception of the risks
of drug therapy during pregnancy, extra effort may be required to ensure the
patient's compliance with the prescribed therapy. This is imperative in maternal
conditions in which the disease itself is a greater risk factor for adverse
pregnancy outcome than the drug therapy may be (eg, epilepsy, asthma,
diabetes, severe hypertension, most infections). Counseling should include the
risks (maternal and embryo/fetal) of the disease in the absence of therapy or in
the presence of suboptimal treatment. Consideration should also be given to
delaying the treatment, if possible, so that it avoids the critical period for toxicity
or birth defects. Obviously, choosing a therapeutic agent that provides the lowest
known risk is important. Frequently, however, the best therapy is also one that
can produce defects or toxicity. In these cases, the benefits to the patient and her
pregnancy in relation to the risks of therapy should be clearly defined and
communicated to the patient. This involves discussing with her the reasons for
choosing a particular agent, the critical period in pregnancy for adverse drug
effects, the magnitude of the risk (actual percentages are important if known),
and the type of malformations or toxicity. The discussion should also reinforce
the risks of suboptimal therapy. If there is no human pregnancy experience, as is
the case with most new drugs, then the fetal risk must be inferred from animal
toxicity data and the experience, if any, with similar agents. Again, adequate time
must be given so that she understands that the treatment plan designed for her is
optimal. Consent of the patient is an important element of the treatment process
and is a major determinant in ensuring her eventual compliance.
PREGNANT WOMAN ALREADY RECEIVING DRUG THERAPY
Women who present for pregnancy care or who have a pregnancy diagnosed
and have been receiving drug therapy are common clinical situations. In some
cases, the drug exposure may have occurred during a portion or all of the critical
period. If it has not, then changing to a safer drug is indicated. A careful
assessment of the fetal condition should be conducted (eg, ultrasound) followed
by a discussion, in a calm and supportive manner, of the potential risks.
Knowledge of the drugs that are potentially teratogenic or toxic, their critical
periods of exposure, the magnitude of the risk, and the types of defects is crucial
in this situation, as is knowledge of the background risk. Many women elect to
terminate a wanted pregnancy out of fear of an adverse outcome, even if a
nonteratogen was involved. Therefore, she must receive and understand an
accurate assessment of the risk (with actual percentages if available) that has
been imposed on her pregnancy by the specific drug exposure. Such information
has been shown to significantly reduce the tendency for elective termination. 9
Counseling Women About Drugs and Breast Feeding
As a general rule, any drug that can be given safely to a neonate is probably safe
to use during breast feeding. The American Academy of Pediatrics periodically
publishes a review of drugs and chemicals in human milk to help health-care
professionals assess which agents can be safely used during lactation. The
latest review was published in 2001.
10
As can been seen in Table 2A, Table 2B and Table 2C, only a small number of
drugs are contraindicated during breast feeding or should be used cautiously
because of potentially serious toxicity. Because almost all drugs are excreted into
breast milk, those agents that are contraindicated are considered to pose an
unacceptable risk to a nursing infant. Some drugs have caused rare toxicity and
may require the measurement of blood concentrations in the infant. Most drugs,
however, are considered compatible with breast feeding. Because of the
importance of breast feeding in the long-term health of the infant, special care
should be taken during the counseling process to allay the fears of the mother
concerning exposing her infant to drugs via her breast milk.
Table 2A. Adverse Effects in the Nursing Infant From Drugs in Milk
Table 2B. Continued
Criteria for Establishing Teratogenicity
Various criteria have been proposed to determine whether an agent is a human
teratogen. These criteria can be summarized as follows: (a) exposure to the drug
at the critical time or times; (b) consistent findings by epidemiologic studies; (c)
case reports, especially of a specific defect or syndrome; (d) a rare exposure
associated with a rare defect; (e) evidence that the frequency of the specific
outcomes is associated with the introduction or withdrawal of the agent; (f)
teratogenicity in animals at doses equivalent to those in humans; and (g) biologic
plausibility.
5,11
A drug does not have to meet all of the criteria to establish it as a human
teratogen. One author, however, thought that at least three of the criteria (a, b,
and c or a, c, and d) were essential for proof of human teratogenicity. 5
Interpretation of Animal Reproduction Studies
New drugs released since 1966 have been required to undergo reproductive
testing in animals.
6
Many of these drugs exhibit dose-related teratogenicity, variations, and toxicity
in commonly used experimental animal species (mice, rats, and rabbits). Often,
however, the doses that cause malformations are much higher, based on a body
surface area or systemic exposure, than the human therapeutic dose. The
relationship of these very high doses to human malformations is tenuous at best,
and even less so when the teratogenic dose is also toxic to the mother.
Additionally, some species have a greater genetic tendency for certain types of
defects (eg, cleft lip and resorptions when some strains of mice are exposed to a
drug) than other species, so these outcomes cannot be readily extrapolated to
humans. Further, some agents are prodrugs that must undergo metabolism to
the active component (eg, leflunomide, oxcarbazepine, sulindac). If metabolism
of a prodrug is markedly different in an experimental species, then animal
reproduction studies should be conducted with the active metabolite if they are to
have any meaning in human reproduction.
For the newer agents, there are frequently few or no human pregnancy data,
particularly regarding exposures during the period of organogenesis. Few of
these drugs, however, at least at therapeutic doses, will prove to cause human
birth defects. Importantly, all established human teratogens, except angiotensinconverting enzyme (ACE) inhibitors and angiotensin II receptor blockers, are also
teratogenic in one or more animal species. Excluding these two drug classes,
only lithium and tetracycline fail to demonstrate concordance between human
and animal drug-induced malformations (ie, human birth defects mimic those
observed in animals).6 Thus, knowledge of animal reproduction tests, combined
with other criteria, can help determine the risk of human teratogenicity.
Placental Transfer of Drugs
Human placentas are hemochorial in that the fetal tissue is in direct contact with
the maternal blood.
12
Examples of other mammals with hemochorial placentas are the mouse, rat,
hamster, guinea pig, rabbit, and Rhesus monkey.6,12 A thin layer of trophoblast
cells separates the maternal and fetal blood vessels and serves as the exchange
surface between the two circulation systems. Almost all medications used for the
treatment or prevention of human disease cross the placenta. The most
important factor that determines the fetal drug concentration is the maternal drug
concentration. Drug and placenta factors that determine the rate and degree of
transfer, in addition to the maternal concentration, include the molecular weight,
lipid solubility, protein binding, degree of ionization at physiologic pH, placental
blood flow, and placental surface area (correlated with gestational age).
Placental metabolism may also be important for some agents (eg,
corticosteroids). Because transfer across the membrane is by passive diffusion
and thus is concentration-dependent, drugs may also cross from the fetus to the
mother. Drugs with molecular weights less than 1,000 cross readily, particularly
those less than 500. Near term, when the placental surface area is at its
maximum, the magnitude of drug transfer to the fetus is such that for most
agents the maternal and fetal concentrations reach near unity. 12,13
Factors Determining Excretion of Drugs in Breast Milk
Drugs are primarily excreted into breast milk by passive diffusion, the same
mechanism that occurs during placental transfer. Factors that determine the
amount of drug in milk are the drug concentration in the mother (dependent on
dose and maternal clearance rate), molecular weight, lipid solubility, protein
binding, and degree of ionization at physiologic pH.
14
Drugs that have a low molecular weight and are unionized and lipophilic pass
into milk to the greatest extent. The distribution of a drug between milk and
plasma can be characterized by the milk:plasma ratio. The ratio varies over time,
so the ideal ratio would be determined based on the respective concentration–
time curves (AUC), usually over 24 hours but sometimes less; however, ratios
based on single points are often reported. Because milk is slightly acidic (pH
about 7.2) compared with plasma (pH 7.4), the milk:plasma ratios are less than 1
for weak acids, approximately 1 for neutral compounds, and greater than 1 for
weak bases. Weak bases (eg, some beta-blockers) may accumulate in breast
milk from ion trapping. For drugs with data available, most have a milk:plasma
ratio of 1 or less, about 25% have ratios greater than 1, and about 15% have
ratios greater than 2.15
An estimation of the infant dose received via milk is important because this can
help to determine the effects of the drug in the nursing infant. Based on a typical
daily milk consumption of 150 mL/kg, and knowing the average amount of drug in
milk over a 24-hour period, the infant's dose can be compared with the mother's
dose or, if known, with the recommended dose for infants of similar age and
weight. Infant doses for many drugs, however, are not known, so the dose
consumed by the infant from milk is often expressed as a percentage of the
mother's weight-adjusted dose.16 Because for most drugs there is no information
about the no-effect dose in infants, one author arbitrarily assumed that levels of a
drug in milk were safe if they were 10% or less of the infant therapeutic dose or,
if not known, the adult dose standardized by weight. 15 However, this assumption
would not apply to drugs in which toxicity could be caused by very small
amounts.15
Drugs That Are Teratogenic in Humans
Of the thousands of drugs available for human use, only a few, are thought to be
teratogenic. Although of vital importance, defects and toxicity induced by drugs of
abuse (eg, cocaine, alcohol, cigarette smoking, toluene inhalation) are not
covered here because they are addressed in another article. Complete
avoidance during pregnancy of all teratogenic and toxic agents, including drugs
of abuse, is the best approach. However, some of these drugs are indicated for
pathologies commonly observed in women of childbearing age. Epilepsy,
asthma, severe hypertension, cancer, rheumatoid arthritis, and thyroid disease
are just a few examples of conditions that frequently require treatment during
pregnancy with drugs that are known to cause fetal harm. Pharmacologic
treatment of these conditions often improves the outcome of the pregnancy in
comparison to no treatment or suboptimal treatment. Thus, the patient must be
informed of the risk:benefit ratio and she and her partner must understand and
agree with the decision to treat.
In the section below, reference to gestational weeks implies dating from the first
day of the last menstrual period (LMP). Three common abbreviations used are
CNS (central nervous system), NTD (neural tube defects), and IUGR
(intrauterine growth retardation). Three reference books have been used to
assemble the information cited.
5,6,17
ANDROGENIC HORMONES
Critical Period: labial fusion (8th to 13th gestational week), clitoral
hypertrophy (second and third trimesters)
Magnitude of Risk: unknown
Mechanism: hormonal
Defects and Toxicity: masculinization of female fetus (female
pseudohermaphroditism) characterized by a normal XX karyotype and
internal female reproductive organs but ambiguous external genitalia; no
fetal effects if exposure is stopped before onset of androgen receptor
sensitivity in eighth gestational week; no adverse effects reported in males
ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS
Critical Period: second and third trimesters
Magnitude of Risk: unknown; dose-and duration-dependent
Mechanism: decreased fetal angiotensin II results in renal impairment and
hypotension
Defects and Toxicity: fetus—renal impairment/anuria resulting in
oligohydramnios; IUGR; renal tubular dysplasia; hypocalvaria
(oligohydramnios allows the uterus to press on top of the fetal head;
combined with fetal hypotension, the uterine pressure prevents blood flow
to that portion of the fetal skull, resulting in the defect; classified as a
deformation); persistent patent ductus arteriosus; stillbirths; newborn—
anuria and hypotension that is resistant to both volume expansion and
pressor agents; renal failure may require hemodialysis
Comment: Monitoring of amniotic fluids levels is recommended, but fetal
renal impairment (as indicated by oligohydramnios) may not be reversible.
ANGIOTENSIN II RECEPTOR ANTAGONISTS
Critical Period: second and third trimesters
Magnitude of Risk: unknown; dose-and duration-dependent
Mechanism: blocks angiotensin II at receptor site; net effect is the same
as ACE inhibitors
Defects and Toxicity: losartan, valsartan—renal toxicity (anhydramnios),
hypoplastic lungs, IUGR, skull hypoplasia, stillbirth (defects and toxicity
are identical to those observed with ACE inhibitors)
ANTICOAGULANTS (WARFARIN)
Critical Period: sixth to ninth week, fetal warfarin syndrome (FWS);
throughout
gestation,
CNS
defects
Magnitude of Risk: 5% to 10% (has been as high as 50% in some studies)
for FWS (facial anomalies and epiphyseal stippling); 4% to 5% for CNS
and
other
defects
Mechanism: vitamin K deficiency in embryo; microhemorrhage and
scarring
(CNS
defects)
Defects and Toxicity: FWS—most common characteristics are nasal
hypoplasia (depressed nose with flattened, upturned appearance,
commonly results in neonatal respiratory distress secondary to upper
airway obstruction) and stippled epiphyses; other defects are IUGR, eye
defects (when exposure also occurs in second and third trimesters),
hypoplasia of extremities, congenital heart disease, and CNS damage
(mental retardation, spasticity, seizures, scoliosis, deafness and hearing
loss, and death)
ANTICONVULSANTS
Critical Period: first trimester (malformations), third trimester (early
hemorrhagic
disease
of
newborn)
Magnitude of Risk: two-to threefold increase over risk from epilepsy alone;
12% to 15% for anticonvulsant drug therapy; 1% to 2% NTD (valproic
acid);
1%
NTD
(carbamazepine)
Mechanism: probably multifactorial (polygene–drug interaction); folic acid
deficiency may contribute; carbamazepine, phenytoin, and valproic acid
produce toxic epoxide metabolites; if fetus is homozygous for low epoxide
hydrolase activity, then high risk for embryopathy (multifactorial); early
hemorrhagic disease of the newborn may result from depletion of vitamin
K
stores
in
fetus
Defects and Toxicity: carbamazepine—NTD (1%), minor craniofacial
defects, fingernail hypoplasia, and developmental delay; mephobarbital—
cardiac defects, cleft lip/palate; paramethadione (see trimethadione);
phenobarbital—cardiac defects, cleft lip/palate, hypoplasia of midface and
fingers, microcephaly, IUGR, impaired cognitive development, and early
hemorrhagic disease of the newborn; phenytoin—fetal hydantoin
syndrome, includes craniofacial defects and limb defects (eg, fingernail
hypoplasia) and early hemorrhagic disease of the newborn; primidone—
similar to phenobarbital; trimethadione—fetal trimethadione syndrome
(includes some cases of paramethadione), cardiac septal, craniofacial,
and genitourinary defects, IUGR, postnatal growth deficiency, and mental
retardation; valproic acid/valproate—NTD (1%–2%) (exposure between
the 17th and 30th day after fertilization), craniofacial, digit, and urogenital
defects, IUGR, retarded psychomotor development
ANTIDEPRESSANTS (LITHIUM)
Critical Period: first trimester (cardiac defects), third trimester (newborn
toxicity)
Magnitude of Risk: less than 1% to 8% (cardiac defects); less than 1%
(Ebstein's anomaly)
Mechanism: Unknown
Defects and Toxicity: cardiac defects, including Ebstein's anomaly;
transient toxicity in newborns has included cyanosis, hypotonia, thyroid
suppression with goiter, bradycardia, atrial flutter, cardiomegaly,
electrocardiogram abnormalities (T-wave inversion), hepatomegaly,
gastrointestinal bleeding, diabetes insipidus (may be prolonged),
polyhydramnios, shock, and seizures
ANTI-INFECTIVES
Aminoglycosides (Kanamycin and Streptomycin)
Critical Period: throughout pregnancy
Magnitude of Risk: low, probably less than 3%; dose-and durationdependent
Mechanism: direct toxicity of eighth cranial nerve
Defects and Toxicity: hearing loss/deafness; combination therapy with
other ototoxic agents increases risk
Comment: Although eighth cranial nerve damage and renal impairment
may occur with all aminoglycosides, this toxicity has not been associated
with other members of this class. This most likely reflects greater attention
to maternal serum levels and shorter courses of therapy.
Fluconazole
Critical Period: first trimester
Magnitude of Risk: unknown, dose-related (400 mg/day or greater)
Mechanism: unknown
Defects and Toxicity: brachycephaly, craniosynostosis, proptosis, low
nasal bridge, cleft palate, femoral bowing, thin ribs and long bones, joint
contractures, cardiac malformations
Quinine (High-Dose)
Critical Period: first trimester
Magnitude of risk: observed only after use of toxic doses in unsuccessful
abortion attempts
Mechanism: unknown
Defects and Toxicity: CNS anomalies (hydrocephalus, deafness, optic
nerve damage) and limb defects most frequent; other defects involved the
face, heart, and gastrointestinal and urogenital systems
Tetracycline
Critical Period: beyond fourth month
Magnitude of Risk: unknown, duration-dependent
Mechanism: chelation; drug forms a complex with calcium orthophosphate
and is incorporated into bones and teeth undergoing calcification; complex
is permanent in teeth because remodeling and calcium exchange do not
occur after calcification is completed
Defects and Toxicity: intense yellow-gold fluorescence of mineralized
skeletal structures and teeth; impairment of bone growth may occur but is
not clinically significant
CORTICOSTEROIDS, SYSTEMIC (ALL MEMBERS OF CLASS)
Critical Period: before 10 weeks after LMP (oral clefts), IUGR (throughout
gestation)
Magnitude of Risk: background risk for nonsyndromic cleft lip with or
without cleft palate is 0.1–0.2%; may be increased two-to sevenfold;
unknown for IUGR, but prolonged therapy is required
Mechanism: unknown
Defects and Toxicity: nonsyndromic cleft lip with or without cleft palate;
IUGR (about 300–400 g)
DIAGNOSTICS AND ANTIDOTES
Methylene Blue (Intra-amniotic Injection)
Critical Period: second and third trimesters
Magnitude of Risk: about 20% for jejunal–ileal atresias
Mechanism: vascular disruption due to arterial constriction, but cannot
exclude methemoglobinemia-or hemolytic anemia-induced hypoxia
shunting blood away from the intestine or a direct toxic effect of the dye
when swallowed with amniotic fluid
Defects and Toxicity: jejunal and ileal atresias; fetal death has occurred;
newborn toxicity includes hyperbilirubinemia, hemolytic anemia with or
without Heinz body formation, methemoglobinemia, and deep blue
staining of skin
Penicillamine
Critical Period: unknown
Magnitude of Risk: unknown, probably less than 5%
Mechanism: chelation of metals (eg, copper)
Defects and Toxicity: cutis laxa; limiting dose to 1 g/d or less during
gestation may reduce risk; if cesarean section is planned, limit dose to 250
mg/day for 6 weeks before delivery and after surgery until wound healing
is complete
SYNTHETIC ESTROGENS (DIETHYLSTILBESTROL)
Critical Period: 10 to 13 weeks of gestation (highest risk of vaginal
adenocarcinoma but some risk up to 18 weeks); up to 20 weeks (genital
malformations)
Magnitude of Risk: less than 0.1% (about 350–450 cases of vaginal
cancer); unknown for genital malformations
Mechanism: possible inhibition of upward growth of vaginal plate or
stimulation of müllerian epithelium so that it persists in the developing
vagina
Defects and Toxicity: female: lower müllerian tract—vaginal adenosis,
vaginal and cervical clear cell adenocarcinoma (more than 90% occur
after 14 years of age), cervical and vaginal fornix defects, cockscomb
(hood, transverse ridge of cervix), collar (rim, hood, transverse ridge of
cervix), pseudopolyp, hypoplastic cervix, altered fornix of vagina; vaginal
defects (exclusive of fornix)—incomplete transverse and/or longitudinal
septum; upper Müllerian tract—uterine structural defects, fallopian tube
defects; male: epididymal cysts, hypotrophic testis, microphallus,
varicocele, capsular induration, altered semen (decreased count,
concentration, motility, and morphology)
GASTROINTESTINAL AGENT (MISOPROSTOL)
Critical Period: highest risk occurs with exposure in weeks 6 to 8, but any
time during first trimester conveys some risk
Magnitude of Risk: up to seven times background risk for Möbius
syndrome and other malformations; almost all adverse outcomes have
been related to unsuccessful abortion attempts with large, sometimes
massive doses (orally, vaginally, or both); only a few cases have been
reported when the drug was used for its approved indication
Mechanism: vascular disruption caused by uterine contractions;
deformation
Defects and Toxicity: vaginal bleeding, abortion; if abortion does not
occur, reported defects include Möbius syndrome (sixth and seventh
nerve palsies), defect of cranium and overlying scalp, cleft lip/palate,
ocular hypertelorism, arthrogryposis (multiple nonprogressive congenital
joint contractures; may be a result of neurologic impaired leg movement;
in addition, bilateral talipes equinovarus is a common feature), terminal
transverse-limb defects (missing metacarpals and phalanges, hypoplasia
of the thumbs and fingers), syndactyly, limb constriction ring or skin scars,
and hydrocephalus
IMMUNOMODULATOR (THALIDOMIDE)
Critical Period: days 34 to 50 days after LMP (20–36 days after
conception); critical maternal dose is at least 100 mg
Magnitude of Risk: 20–50%
Mechanism: one current theory is that thalidomide, or its metabolite,
intercalates into DNA of specific promoter regions of genes that code for
proteins involved in normal limb development, thereby inhibiting
transcription of these genes and disrupting development of new blood
vessels, resulting in truncation of limbs
Defects and Toxicity: limb defects—bilateral amelia or phocomelia of
upper and lower limbs and various lesser degrees of reduction defects;
osteochondritis of femoral head; laxity of cruciate ligaments in knee joints;
other skeletal defects—malformations of spine, shoulder, hip/pelvis, and
jaw; craniofacial—multiple defects of eyes, ears, face and skull, tongue,
nose (including choanal atresia), teeth, midline hemangioma or nevus;
CNS—facial nerve palsy, hydrocephalus, NTD, epilepsy, autism, Marcus
Gunn phenomenon (jaw winking syndrome), crocodile-tear syndrome;
major organs—multiple malformations of respiratory, cardiovascular,
gastrointestinal, and genitourinary systems; miscellaneous—excessive
sweating, inguinal hernias
ANTITHYROID AGENTS
Iodine
Critical Period: second and third trimesters
Magnitude of Risk: dose-and duration-dependent
Mechanism: inhibition of fetal thyroid gland with compensatory
hypertrophy
Defects and Toxicity: hypothyroidism, goiter, may cause tracheal
compression in newborn
Methimazole and Carbimazole
Critical Period: up to 9 weeks after LMP
Magnitude of Risk: unknown but probably low
Mechanism: possible phenotype (polygene–drug interaction)
Defects and Toxicity: a pattern of rare congenital malformations, possibly
indicating a phenotype, that consists of some or all of the following: scalp
(aplasia cutis congenita) or patchy hair defects, choanal atresia,
esophageal atresia with tracheoesophageal fistula, minor facial anomalies
(short up-slanting palpebral fissures, epicanthal folds, small nose and
mouth, short philtrum), hypoplastic (hypothelia) or absent (athelia) nipples,
psychomotor delay; goiter
VITAMIN A DERIVATIVES
Etretinate and Acitretin
Critical Period: day 15 after conception to end of first trimester
(same as isotretinoin)
Magnitude of Risk: unknown; may be same as isotretinoin
Mechanism: unknown; may be same as isotretinoin
Defects and Toxicity: upper/lower limb reduction defects, other skeletal
anomalies (multiple synostoses, hip, cervical vertebrae), NTD and CNS
defects (meningomyelocele, meningoencephalocele, peripheral facial
nerve paresis), head (microcephaly, small mandible), facial dysmorphia
(asymmetric nares, microtia or low-set, protruding ears with malformed
antihelices, and enlarged, keyhole-shaped entrances to external ear
canals), strabismus, cardiac malformations (including tetralogy of Fallot),
syndactylies, and poor head control
Comment: Acitretin, an active metabolite of etretinate, undergoes
interconversion to 13-cis-acitretin, also an active metabolite. In addition,
when alcohol is consumed when acitretin is still in the system, acitretin
may be converted back to etretinate, which has a very long elimination
half-life (mean 120 days, but may be as long as 168 days). Therefore,
current recommendations state that alcohol consumption should be
avoided during therapy and for 2 months after cessation of therapy.
Moreover, because of the prolonged elimination times of etretinate,
acitretin, and 13-cis-acitretin, effective contraception should be used for at
least 3 years after stopping acitretin and etretinate therapy.
Isotretinoin
Critical Period: day 15 after conception to end of first trimester
Magnitude of Risk: 30–50%; teratogenic dose range less than 0.2 to 1.5
mg/kg/day
Mechanism: disruption of initial differentiation and migration of cephalic
neural
crest
cells
Defects and Toxicity: spontaneous abortions (may be most common
adverse outcome); CNS—hydrocephalus, facial nerve (seventh) palsy,
posterior fossa structure defects, cortical and cerebellar defects, cortical
blindness, optic nerve hypoplasia, retinal defects, microphthalmia;
craniofacial—facial dysmorphism, microtia or anotia, low-set ears,
agenesis or marked stenosis of external ear canals, micrognathia, small
mouth, microcephaly, depressed nasal bridge, triangular skull, cleft palate,
hypertelorism; cardiovascular—transposition of great vessels, tetralogy of
Fallot, double-outlet right ventricle, truncus arteriosus communis,
ventricular septal defect, atrial septal defect, interrupted or hypoplastic
aortic arch, retroesophageal right subclavian artery; thymic gland
defects—ectopia, hypoplasia, or aplasia; miscellaneous defects (sporadic
occurrence)—spina bifida, nystagmus, hepatic abnormality, hydroureter,
decreased muscle tone, large scrotal sac, simian crease, limb reduction
defects
Drugs That Cause Toxic Effects in the Fetus or Newborn
As shown in
Table 1, pharmacologic therapy during pregnancy can produce, in addition to
birth defects, fetal and neonatal toxicity. This toxicity is an extension of a drug's
pharmacologic effects and as a rule is identical to the toxicity observed in
patients treated directly with the drug. As above, drugs of abuse are not
discussed. Fortunately, most toxicity is transient or reversible when exposure to
the offending drug is stopped. Toxicity in the fetus or newborn is frequently the
result of prolonged, continuous use of the drug by the mother. However, there
are notable exceptions to this rule. For example, abortions produced by
mifepristone and misoprostol, bradycardia resulting from drug-induced maternal
hypotension, and fetal/newborn toxicity associated with the use of narcotic
analgesics close to delivery (eg, sinusoidal fetal heart rate patterns, newborn
respiratory depression, and neonatal neurobehavioral dysfunction) may all occur
with single doses or very brief therapeutic courses. Therefore, when a woman
requires drug therapy during pregnancy, particularly continuous therapy, the
lowest possible dose should be used, and close attention should be given to
detect any signs and symptoms of toxicity.
Adverse Effects in the Infant From Drugs in Milk
As the physiologic process that governs the placental crossing of drugs to the
embryo and fetus is similar to the excretion of drugs into breast milk, so the
toxicity produced in the embryo and fetus is similar to the toxicity produced in the
nursing infant. In other words, the toxic effects of a drug during lactation are
specifically related to the pharmacologic characteristics of the drug. Six drugs of
abuse (amphetamines, cocaine, ethanol, heroin, marijuana, and PCP) have been
covered here because they are not covered elsewhere. With the exception of
those agents contraindicated during nursing, the toxicity of most drugs is
transient and reversible. Alert health professionals and mothers are the best
defense against allowing this toxicity to become long-lasting or to cause
permanent harm. Having said that, however, few studies have been conducted
on the consequences of exposure in milk to neuroactive drugs on long-term
neurobehavior. Psychotropic agents change the brain chemistry of the mother
and may so in a nursing infant. That this may occur during a rapidly changing
and very vulnerable period of infant neurodevelopment heightens the concern.
The American Academy of Pediatrics has recognized this potential toxicity by
placing antianxiety, antidepressant, and antipsychotic agents in a special
category that exemplifies their concerns for long-term consequences.
Fortunately, the few studies that have examined the effects on infant
neurobehavior from exposure to psychoactive drugs in milk have not discovered
long-term toxicity. This is reassuring, but more studies in this regard are
warranted.
Conclusion
The best defense against drug-induced teratogenicity and toxicity during both
pregnancy and lactation is knowledgeable and alert health-care professionals
and patients. This combination can be very effective in preventing disasters in
pregnancy and in nursing infants. There are a wide variety of resources available
to professionals and the lay public that provide information on these subjects.
Although the overall effectiveness of these resources is not entirely known, they
do appear to be effective. The absence of pregnancy disasters similar in
magnitude to the one that occurred with thalidomide 40 years ago appears to be
evidence that the system is working. However, preventable congenital defects
still occur. Although their actual numbers are small in relation to the total, a
further reduction is certainly achievable, and so much remains to be
accomplished.
To reiterate, steps can be taken to lessen the dilemma posed by prescribing,
dispensing, and administering drugs to women who are or who may become
pregnant or who are breast feeding. First, health-care professionals providing
services to this population should be knowledgeable about the background risk
and the risk that a drug represents to the embryo, fetus, or newborn. They should
also know which drugs should be absolutely avoided during lactation and which,
although compatible with breast feeding, may cause toxicity. Second, this
information must be communicated to the patient in such a manner that she
clearly understands the risks and benefits of therapy. Additionally, she needs to
appreciate the risks of not properly treating her condition. Third, a system should
be set up between the patient and her health care provider to assure close
communication in the event her pregnancy status changes while she is receiving
drug therapy. Although adherence to this type of system may be difficult, it
should be a major factor in improving patient compliance and lessening the
anxiety of medication use in this population. Moreover, it will assist in achieving a
worthy and obtainable goal: the prevention of unnecessary poor outcomes in
pregnancy and during breast feeding.
References
1. Oakley Jr. GP Frequency of human congenital malformations. Clin
Perinatol 1986;13:545–54.
2. Hook EB, Regal RR. Representative and misrepresentative associations
of birth defects in livebirths. Am J Epidemiol 1993;137:660–75.
3. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med
1998;338:1128–37.
4. Kalter H, Warkany J. Congenital malformations. Etiologic factors and their
role in prevention. N Engl J Med 1983;308:424–31.
5. Shepard TH. Catalog of Teratogenic Agents. 10th ed. Baltimore: Johns
Hopkins University Press; 2001.
6. Schardein JL. Chemically Induced Birth Defects. 3d ed. New York: Marcel
Dekker; 2000.
7. Chambers CD, Braddock SR, Briggs GG, et al. Post-marketing
surveillance for human teratogenicity: a model approach. Teratology 2001
(in press).
8. Martinez-Frias ML, Bermejo E, Frias JL. Analysis of deformations in
26,810 consecutive infants with congenital defects. Am J Med Genet
1999;84:365–8.
9. Koren G, Bologa M, Pastuszak A. How women perceive teratogenic risk
and what they do about it. Ann NY Acad Sci 1993;678:317–24.
10. Committee on Drugs, American Academy of Pediatrics. The transfer of
drugs and other chemicals into human milk. Pediatrics 2001;108:776–789.
11. Brent RL. Method of evaluating alleged human teratogens [editorial].
Teratology 1978;17:83.
12. Sastry BVR. Techniques to study human placental transport. Adv Drug
Deliver Rev 1999;38:17–39.
13. Garland M. Pharmacology of drug transfer across the placenta. Obstet
Gynecol Clin North Am 1998;25:21–42.
14. Agatonovic-Kustrin S, Tucker IG, Zecevic M, et al. Prediction of drug
transfer into human milk from theoretically derived descriptors. Anal Chim
Acta 2000;418:181–95.
15. Ito S. Drug therapy breast-feeding women. N Engl J Med 2000;343:118–
26.
16. Atkinson HC, Begg EJ, Darlow BA. Drugs in human milk. Clinical
pharmacokinetic considerations. Clin Pharmacokinet 1988;14:217–40.
17. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. A
Reference Guide to Fetal and Neonatal Risk. 6th ed. Philadelphia:
Lippincott Williams & Wilkins; 2001.
Correspondence: Gerald G. Briggs, B Pharm, 9802 Saline Drive, Huntington
Beach, CA 92646
Clin
Obstet
Copyright
©
All rights reserved
2002
Gynecol
Lippincott
2002
Williams
March;45(1):6-21
&
Wilkins