++
In weighing the possibility that a teratogen is responsible for
a child’s condition or defect, one of the most important
factors to consider is background risk. Every pregnancy
carries an approximate 3% risk that the fetus will be affected
with a major, life-affecting defect. Although this level of risk
can be increased by maternal teratogenic exposure, it cannot be
decreased. A common misconception is that a majority of birth defects
are the result of teratogenic exposure. However, teratogens cause
only about 3% of the clinically significant congenital
structural defects in humans. Because no teratogen affects all exposed fetuses,
there is probably an interaction between genes and environment necessary
to create teratogenicity.
++
To determine risk, the following factors must be assessed:
++
The time frame at which an exposure occurs during the pregnancy
is, arguably, the most important factor to consider when determining teratogenicity.
Contemporary understanding of embryology and embryopathy guides
this principle. For example, teratogenic exposure between days 15
and 28 after fertilization can be the cause of a neural tube defect,
because during this time neural tube closure occurs in the embryo.
Parallels can be drawn between teratogenic exposure and development
of virtually any other major organ or system. Thus, knowing that
the mother was exposed during a critical time for induction of the
child’s anomaly is vital when evaluating a child for possible
teratogenic effects.
++
Fortunately, threshold levels have been estimated for most known
human teratogens. For example, the dosage of methotrexate required for
therapeutic treatment of rheumatoid arthritis and psoriasis is considerably
below that which could induce fetal defects.
++
Most agents are transmitted to the fetus indirectly, through
maternal blood. Therefore, in order for the fetus to be affected,
an agent must have access to maternal blood. The amount of fetal
exposure to compounds concentrated in maternal blood is, therefore,
dependent on maternal blood levels. Isotretinoin, a known teratogen,
is directly absorbed into the maternal bloodstream, whereas tretinoin,
a topical vitamin A congener, has minimal maternal systemic absorption
and is not associated with an increased risk for birth defects.
++
Since functional as well as structural development of the fetus
can be affected by some teratogens, the duration of an exposure
can have a significant impact. For example, smoking more than 10
cigarettes each day can affect the growth of the fetus if the smoking
continues beyond the twelfth week of gestation. Alcohol can affect
functional brain development, and thus heavy consumption of alcohol
that continues beyond the first trimester is associated with developmental
and learning disorders.
+++
Confounding Variables
++
Confirmation of a specific drug, chemical, infection, or other
exposure as cause for an adverse outcome can be complicated by the
fact that multiple exposures often take place concurrently in the
same pregnancy. As an example, early investigations into caffeine
led researchers to hypothesize that its consumption during pregnancy
resulted in low-birth-weight infants. Later it was discovered that
immoderate coffee drinkers are also more likely to be immoderate tobacco
users; smoking was thus the confounding variable in lower birth
weight.
++
Studies of pregnancy outcomes in animals are not always predictive
of human outcomes, because teratogenic agents tend to demonstrate species-specific
effects. Genetic variability among species produces differences
in drug absorption, distribution, and metabolism. Extrapolating
from animal data to humans is problematic, because pharmacokinetic
profiles vary depending on the drug and species. For example, the
limb deficiency observed in children with thalidomide exposure is
not seen in the usual animal studies. Other differences may be credited
to animals’ ability to carry multiple fetuses and variations
in placental development and function. Although animal models are
useful in detecting the mechanisms by which known teratogens exert
their influence, such studies are not beneficial in determining
which agents are teratogenic in humans.
++
Most of the identified human teratogens show patterns of abnormalities
presenting as syndromes rather than isolated or nonspecific single
defects. Although statistically rare, these events have been the
hallmark by which teratogens have been “discovered.” Two
examples can illustrate this point.
++
Within three years of release of isotretinoin, three cases of
isotretinoin embryopathy characterized by isolated anotia, microtia,
and conotruncal heart defects were reported. All three infants had
a combination of these anomalies that is rarely seen, heightening
the statistical probability that there was a teratogenic agent involved.
Based on just three reports, isotretinoin was suspected as a human teratogen;
this was later established by epidemiologic and clinical investigations.
++
Case reports of malformations among children exposed to Bendectin,
a combination of pyridoxine (vitamin B6), doxylamine (Unisom),
and dicyclomine (Bentyl) in utero were reported, but no pattern
of defects could be detected. Epidemiologic analyses found the rate of
malformations in patients exposed to the drug was no higher than
the background risk of malformations. This demonstrated the lack of
teratogenicity of the product.
++
In summary, when assessing causation, the degree of certainty
of etiology depends on the rarity of the exposure and the distinctiveness
of the outcome: the rare exposure, rare outcome, astute clinician
model. Table 183-1 provides a complete list of known human
teratogens. What follows is a discussion of selected teratogens.
++
++
Few pregnancies progress to term without the use of at least
one medication, whether prescription or nonprescription drugs, herbal
remedies, or nutritional supplements. An average of three to four
medications are used during the course of a pregnancy, with analgesics
being the most commonly reported. About 30% of women are exposed
to a prescription medication during the first trimester of pregnancy.
Other common categories include cough and cold products, antacids,
antihistamines, antiemetics, psychotropics or sedatives, and antibiotics.
++
Valproic acid (Depakote) carries a 1% risk for a neural
tube defect (spina bifida) when fetal exposure occurs between 15
and 29 days after conception. Other fetal effects (craniofacial changes,
preaxial defects, and hypospadias) have also been described, but
the level of risk for these effects has not been established.
+++
Methotrexate/Aminopterin
++
Methotrexate can have a teratogenic effect when taken between
8 and 11 weeks after the last menstrual period at doses higher than
10 mg per week. The level of fetal risk after exposure to methotrexate
is not known. Craniosynostosis and craniofacial abnormalities (wide-spaced
eyes, broad nose, small chin, and flattened facies), and limb defects
(absent toes, webbed fingers, or shortened limbs) have been reported.
Based on cases in which aminopterin was used as an abortifacient
in high doses (12 mg or more per week), there is an increased risk
for spontaneous abortion, low birth weight, craniofacial abnormalities,
limb abnormalities, craniosynostosis, and possibly neural tube defects
(spina bifida or anencephaly). The level of risk for birth defects
associated with aminopterin use in the first trimester of pregnancy
is unknown.
++
Thalidomide was the first drug identified as a human teratogen.
When exposure to the drug occurs during days 34 to 50 of gestation
(3–6 LMP weeks), there is a risk of at least 20% for limb
reduction defects (missing segments of the arms and/or
legs) and ear malformations, including deafness. Because of its
effectiveness in treating some peripheral neuropathies associated with
Hansen disease, thalidomide was approved for marketing in the United
States in the summer of 1998. In an effort to avoid additional cases
of thalidomide embryopathy in children, the drug’s parent
company has established an extensive physician and pharmacy registration process
called the System for Thalidomide Education and Prescribing Safety
(S.T.E.P.S.) (http://www.thalomid.com/steps_program.aspx).
++
In most cases with maternal illnesses, risk to the fetus increases
with the severity of maternal disease and inadequate treatment,
emphasizing the necessity of rigorous medical oversight.
++
It is not known if there is a safe amount of alcohol that can
be consumed during any trimester of pregnancy. However, it is unlikely
that a single drink (12 ounces of beer/5 ounces of wine/1.5
ounces of hard liquor) during pregnancy would affect a fetus or
cause fetal alcohol spectrum disorders (FASD).
++
Binging is defined as drinking to the point of heavy intoxication
(being drunk), usually drinking more than 5 drinks (beer, wine,
or hard liquor) on any occasion. When a pregnant woman binges more
than 3 times in early pregnancy, there is a 15% to 50% risk
of miscarriage, a 10% to 15% risk of minor changes
in the face and an 8% to 10% risk of a minor heart
defect in the fetus. Binge drinking that continues beyond the fifth
month of pregnancy is associated with an increased risk for growth
delay and a risk of learning disabilities and behavior problems
in the child. Women who drink heavily (more than 3 to 4 drinks a
day) or binge weekly have a 15% to 50% risk of
miscarriage; a 10% to 15% chance of having a child
with minor facial defects, growth delay, and a 5% to 25% risk
of having a child with FASD.
++
The fetuses of alcoholic women (or women who experience health
problems or social problems related to their drinking) may be at
risk even if maternal alcohol consumption is less than the amounts
described.
++
Diagnosing FASD is complicated and should only be done after
ruling out other conditions that present with similar effects. For
instance, genetic conditions such as Williams syndrome, Cornelia
de Lange syndrome, and velocardiofacial syndrome (VCFS) all have similar
facial and growth characteristics.
+++
Diabetes Mellitus
Types I and II
++
Maternal diabetes mellitus is the most common cause of birth
defects. Mothers with insulin-dependent diabetes have an increased
risk for having a child with a congenital malformation. The level
of risk is dependant on the mother’s hemoglobin A1c level
(HbA1c) (Table 183-2).
++
++
The pattern of defects observed with the diabetic embryopathy
includes defects of the heart (transposition of the great arteries,
pulmonary stenosis, dextrocardia, patent ductus arteriosus), central
nervous system (hydrocephaly, microcephaly, holoprosencephaly, neural
tube defects), skeleton (sacral dysgenesis, caudal deficiency), and
kidneys (renal agenesis, hydronephrosis, multicystic displastic
kidneys). Improved control of glucose levels prior to conception
decreases the risk substantially and underscores the importance
of preconceptional counseling.
++
Primary infections of childhood diseases (eg, human parvovirus
B19 and varicella) are of concern in pregnancy. Fetal effects occur
only when the pregnant woman acquires the active infection. Even
then, only a small percentage of fetuses will contract the disease
and have an adverse outcome.
+++
Human Parvovirus
B19/Fifth Disease
++
There have been no confirmed reports of congenital anomalies
related to maternal parvovirus infection. Hydrops occurs in 10% of fetuses
whose mothers contract this infection during pregnancy. The critical
time for fetal effects is between 12 and 26 LMP weeks.
++
When a pregnant woman contracts varicella (chickenpox) during
the first trimester, the risk of fetal effects is approximately
1%. If the infection occurs prior to or during limb bud formation,
limb reduction defects can result. Other effects of varicella include
chorioretinitis, scarring of the skin with muscle atrophy, and a
possibility of developmental delay, which is less well established
than the eye, skin, and limb effects (see Chapter 314).
++
Given the growing number of chemical agents being developed or
sold for both home and industrial environments, pregnant women are
increasingly vulnerable to chemical exposures. Although many such
compounds do not appear to be teratogenic to humans, limited human
data exist to develop risk assessment. In most cases, however, maternal
poisoning is necessary for a teratogenic effect to occur. Some selected chemical
teratogens are described below.
++
Methylmercury is an organic compound that can accumulate in animals
(eg, fish) that are subsequently consumed by humans. When a pregnant woman
develops symptoms of methylmercury poisoning, there is a concern
for prenatal encephalopathy at any stage of the pregnancy. Recent reports
of high levels of methylmercury in fish have created confusing messages
regarding the safety of fish consumption. Nearly all fish contain
trace amounts of methylmercury. Federal agencies recommend limiting
fish to 6 ounces weekly for women who are pregnant or lactating. Pregnant
or breast-feeding women should avoid eating large fish (shark, swordfish,
king mackerel, and tilefish) because they live a long time, feed
on smaller fish, and have the highest levels of methlymercury. For
the current recommendations on fish consumption see the Federal Drug Administration
Web site at http://www.fda.gov/fdac/reprints/mercury.html.
++
Studies of solvent exposure in an occupational setting have shown
pregnancy loss when mothers are exposed to high does for long periods and
have symptoms of toxicity (lightheadedness and headaches). In the
absence of these signs of toxicity, no adverse fetal effects have
been confirmed. The fetal effects of solvent abuse are discussed
in the following section.
++
With the exception of alcohol and possibly cocaine and solvents,
no substance of abuse has been conclusively associated with an increased risk
of birth defects. However, reversible toxicity and/or withdrawal
symptoms may occur in newborns whose mothers abuse certain drugs throughout
the pregnancy or in large doses near the time of delivery. Substance
abuse throughout pregnancy has been associated with an increased
risk for intrauterine growth retardation, prematurity, and low birth
weight regardless of the particular substance abused. Also, with
needle use, an increased risk for transmission of pathogens such
as human immunodeficiency virus (HIV) or hepatitis B, C, and D can
cause adverse health effects for both the mother and infant.
++
Investigative evidence shows a greater risk of low birth weight
commensurate with the number of cigarettes smoked during pregnancy.
Evidence also suggests that heavy maternal smoking (more than 10
cigarettes/day) is associated with an increased risk for
miscarriage, premature delivery, and stillbirth.
++
With cocaine use during pregnancy, an increased risk for abruptio
placentae, which can result in a miscarriage, stillbirth, or premature
delivery, occurs. Used near delivery, cocaine can also be associated
with an increased risk for intracranial hemorrhage. Infants whose
mothers use cocaine continuously throughout pregnancy or in large amounts
near the time of delivery may be at an increased risk for irritability,
tremulousness, and muscle rigidity, which usually develop several days
after birth, resolve quickly, and seem to have no long-term effects
on the infant or child.
++
Case reports suggest an association between maternal solvent
abuse and pregnancy loss, intrauterine growth retardation, prematurity,
microcephaly, and developmental delay. However, the magnitude of
risk remains unknown.
++
Most infants exposed to drugs in utero will not have physical
signs of problems, but there are concerns that fetal drug exposure
can lead to behavioral problems later in childhood. To date, no conclusive
studies have been able to confirm this link, but it is presumed
that at least a portion of these infants are at risk for learning
and behavioral problems. Socioeconomic elements that can accompany
maternal substance abuse (ie, inadequate parenting skills, poverty,
lack of education) may ultimately prove to have as significant an
impact on the long-term outcomes for these children as the physiological
consequences.
++
Although information is available regarding maternal exposures
during pregnancy, limited information exists surrounding outcomes
from paternal exposures. There is concern that environmental exposures
could affect the egg or sperm cells. However, studies of such mutagenic
exposures do not reveal an increased risk of birth defects; damage
of the germ cells appears only to affect the fertility of those
cells. Semen studies of men exposed to known teratogens did not
suggest an increased risk of malformations. In addition, concentration
of the agent in semen does not appear to have systemic effects in
women and therefore does not affect the pregnancy, except when an
infection is transmitted to the mother through the semen.