Available online at www.annclinlabsci.

org

99

Annals of Clinical & Laboratory Science, vol. 40, no. 2, 2010

Review:
Teratogenic Causes of Malformations

Enid Gilbert-Barness
Department of Pathology, Tampa General Hospital and University of South Florida College of Medicine,
Tampa, Florida
Abstract. Crucial morphogenetic processes during the blastogenesis period, which extends throughout
the first 4 wk of development, from fertilization until the end of the gastrulation stage (days 27 to 28
postconception), can be altered and result in structural abnormalities, including patterns of multiple
congenital anomalies (MCAs) arising from developmental field defects. Severe damage may cause death
of the product of conception or, because of the pluripotential nature of the cells, the damage may be
compensated allowing development to continue in a normal fashion. Most investigators believe that the
all-or-none rule applies to the first 2 wk of development. Because the fetus is less susceptible to morphologic
alterations when the developmental process of the majority of organs has been completed, the most
common anomalies associated with teratogenic exposures during the fetal period are fetal growth restriction
(intrauterine growth retardation) and mild errors of morphogenesis (abnormalities of phenogenesis), such
as epicanthic folds, clinodactyly, and others. Thus, teratogenic exposures result in a wide variety of effects
that range from infertility, prenatal onset growth restriction, structural defects, and functional CNS
abnormalities to miscarriage or fetal death.
Keywords: teratogens, malformations, disruptions, morphogenesis, environmental exposures
Introduction
It is estimated that approximately 10-15% of
congenital structural anomalies are the result of
the adverse effect of environmental factors on
prenatal development [1]. This means that
approximately 1 in 250 newborn infants have
structural defects caused by an environmental
exposure and, presumably, a larger number of
children have growth retardation or functional
abnormalities resulting from nongenetic causes, in
other words, from the effects of teratogens. A
teratogen is defined as any environmental factor
that can produce a permanent abnormality in
Address correspondence to Enid Gilbert-Barness, M.D.,
Tampa General Hospital, 1 Tampa General Circle, Tampa, FL
33606, USA; tel 813 844 7565; fax 813 844 1427; e-mail
egilbert@tgh.org.

structure or function, restriction of growth, or

death of the embryo or fetus. A dose-response
relationship should be demonstrated in animals or
humans so that the greater the exposure during
pregnancy, the more severe the phenotypic effects
on the fetus [2]. Factors comprise medications,
drugs, chemicals, and maternal conditions or
diseases, including infections. Time of exposure
and specificity are shown in Table 1. This
manuscript discusses the teratogenic effects of
well-documented environmental factors.
Brent [1] noted that it is inappropriate to label
an agent as teratogenic without characterizing the
dose, route of exposure, and stage of pregnancy
when the exposure occurred. This is because, as has
long been recognized, the effects of an environmental agent on the embryo or fetus depend on the
chemical or physical nature of the agent and several
other factors, such as dose, route, and length of

0091-7370/10/0200-0099. $5.60. 2010 by the Association of Clinical Scientists, Inc.

100 Annals of Clinical & Laboratory Science, vol. 40, no. 2, 2010
exposure; the developmental stage at which the
exposure occurs; the genetic susceptibility of the
mother and embryo or fetus; and the presence and
nature of concurrent exposures [3].
Teratogenic exposures during prenatal development cause disruptions regardless of the developmental stage or site of action. Most structural
defects caused by teratogenic exposures occur
during the embryonic period, which is when critical
developmental events are taking place and the
foundations of organ systems are being established
[4]. Different organ systems have different periods
of susceptibility to exogenous agents.
Radiation
Ionizing radiation can injure the developing
embryo due to cell death or chromosome injury.
There is no proof that human congenital malformations have been caused by diagnostic levels of
radiation. The most critical exposure period is 8-15
wk after fertilization [5,6]. Before implantation,
the mammalian embryo is insensitive to the
teratogenic and growth-retarding effects of
radiation and sensitive to the lethal effects [7-9].
The risks of 1-rad (0.10Gy) or 5-rad (0.05Gy) acute
exposure are far below the spontaneous risks of the
developing embryo because 15% of human embryos
abort, 2.7 - 3.0% of human embryos have major
malformations, 4% have intrauterine growth
retardation, and 8-10% have early- or late-stage
onset genetic disease. Permanent growth retardation
is more severe after midgestation radiation.

Because of its extended periods of organogenesis

and histogenesis, the central nervous system (CNS)
retains the greatest sensitivity of all organ systems
to the detrimental effects of radiation through the
later fetal stages. In utero radiation produces microcephaly and mental retardation. Later in life there
is increased incidence of hematopoietic malignancies and leukemia [10].
Infectious Agents
The lethal or developmental effects of infectious
agents are the result of mitotic inhibition, direct
cytotoxic effects, or a vascular disruptive event on
the embryo or fetus. However, a repair process may
result in scarring or calcification, which causes
further damage by interfering with histogenesis
[11,12]. Infections that do not result in congenital
malformations but do cause fetal or neonatal death
include enteroviruses (coxsackievirus, poliovirus
,and echovirus) and hepatitis, variola, vaccina, and
mumps viruses [13,14]. Non-radioactive in-situ
hybridization of formalin-fixed, paraffin-embedded
placental and fetal tissue, using virus-specific DNA
or RNA probes, is helpful for diagnosing fetal virus
infections such as cytomegalovirus, parvovirus
B-19, and varicella-zoster virus that cause fetal
hydrops, placentitis, and abortion [15].
Varicella. Varicella (or chickenpox) is a highly
infectious disease, usually occurring in childhood.
By adulthood, more than 95 percent of Americans
have had chickenpox. Eighty-five to ninety-five

Table 1. Time specificity of action of some human teratogens [190].

Teratogen
Rubella virus

Thalidomide
Hyperthermia
Male hormones (androgens)

Warfarin (coumadin)
Diethylstilbestrol



Radioiodine therapy
Goitrogens and iodides
Tetracycline

Fertilization Age (days)

0-60
0->129
21-40
18-30
<90
>90
<100
>100
>14
>98
>126
>65-70
>180
>120
>150

Malformation
Cataract or heart diseases more likely
Deafness
Reduction defects of extremities
Anencephaly
Clitoral hypertrophy and labial fusion
Clitoral hypertrophy
Hypoplasia of nose and stippling of epiphyses
Possible mental retardation
50% vaginal adenosis
30% vaginal adenosis
10% vaginal adenosis
Fetal thyroidectomy
Fetal goiter
Dental enamel staining of primary teeth
Staining of crowns of permanent teeth

Teratogenic causes of malformations

percent of pregnant women are immune to

chickenpox, which means that there is no need to
be concerned about this during pregnancy, even if
the woman is exposed to someone with chickenpox.
Nearly seven women out of 10,000 will develop
chickenpox during pregnancy, however, because
they are not immune [16].
The disease is caused by the varicella-zoster
virus (VZV), which is a form of the herpes virus.
Transmission occurs from person-to-person by
direct contact or through the air. Chickenpox is
contagious from 1 to 2 days before the appearance
of the rash until the blisters have dried and become
scabs. Once a person is exposed to the virus,
chickenpox may take up to 14 to 18 days to develop.
When a woman has a varicella infection during the
first 20 wk of pregnancy, there is a 2% chance that
the baby will have a group of defects called the
congenital varicella syndrome [16], which includes
scars, defects of muscle and bone, malformed and
paralyzed limbs, small head size, blindness,
seizures, and mental retardation. This syndrome is
rarely seen if the infection occurs after 20 wk of
pregnancy.
Another time that there is a concern about a
varicella infection is in the newborn period, if the
mother develops the rash during the period from 5
days before to 2 days after delivery. Between 25%
and 50% of newborns will be infected in this case,
and they develop a rash between 5 and 10 days
after birth. Up to 30% of infected babies will die if
not treated. If the mother develops a rash between
6 and 21 days before delivery, the baby faces some
risk of mild infection [17].
If the baby is treated immediately after birth
with an injection of VZIG (varicella-zoster immune
globulin), the infection can be prevented or the
severity lessened [16]. If a pregnant woman has
been exposed to someone with chickenpox, VZIG
can be given within 96 hr to prevent chickenpox or
lessen the severity [16]. It is important for pregnant
women to avoid exposure to anyone with
chickenpox if they are unsure that they are immune
to this infection.
Mumps virus. Mumps virus during pregnancy
does not cause malformations, but endocardial
fibroelastosis has been noted in infants with a

101

positive mumps antigen skin test; this relationship

has not been consistent [18].
Influenza virus. There is no compelling evidence
to incriminate influenza virus infection during
pregnancy as a cause of malformations [18].
Parvovirus. Human parvovirus B-19 is able to
cross the placenta and results in fetal infection,
which may occur whether the mother is symptomatic or asymptomatic. It is associated with a
higher than average fetal loss and may lead to
spontaneous abortion in the first trimester, hydrops
fetalis in the second trimester, and stillbirth at
term [19,20]. Generalized myocarditis, myositis of
skeletal muscles, and abnormalities of the eyes are
reported [21]. Human parvovirus B-19 has an
affinity for the erythropoietic tissue of the host and
is therefor associated with fetal anemia leading to
cardiac failure.
Other viral infections. Other viruses have not
resulted in congenital anomalies but have caused
significant fetal pathology. Poliovirus has been
associated with abortion, stillbirth, and meningomyelitis [22]; echovirus with disseminated viremia
[23]; variola and vaccinia with necrotizing
cutaneous and visceral infection; and hepatitis
virus with neonatal hepatitis [24].
Syphilis. It is believed that the fetus cannot be
infected with syphilis early in pregnancy because a
cytotrophoblastic layer of cells in the chorionic villi
of the placenta prevents the spirochete from passing
from maternal to fetal blood. This cell layer
disappears at the sixth month. Since the spirochete
usually does not reach the conceptus during the
first trimester, it is usually not a cause of abortion
[25]. However, there has been a report of syphilitic
endometritis causing first trimester abortion as a
potential infectious cause of fetal morbidity in
early gestation [26].
In untreated maternal syphilis of less than 2 yr
duration, about half of the infants are live-born
without infection. In untreated maternal syphilis
in the primary or secondary stages, 50% are
stillborn or die within 4 wk after birth. In
untreated maternal syphilis in the early part of the
tertiary stage, 20% to 60% of infants are normal,

102 Annals of Clinical & Laboratory Science, vol. 40, no. 2, 2010
40% have congenital syphilis, 20% are born
prematurely, and 16% are stillborn or die within 4
wk after birth. In untreated syphilis in the late
part of the tertiary stage, 75% of babies are
unaffected, 10% have congenital syphilis, 9% are
born prematurely, 10% are stillborn, and 1% die
within 4 wk after birth [27].
Toxoplasmosis. Primary maternal infection with
Toxoplasma gondii occurs in 1 per 1000 pregnancies
in the United States [28]. Infection is disseminated
through the placenta to the offspring in 40%, with
maternal infection through the placenta. Malformations do not occur; however, hydrocephalus and
microcephaly result from chronic destructive
meningoencephalitis. Chorioretinitis may progress
to scarring and loss of vision. Hydrocephalus and
cerebral calcifications, hepatitis, and lymphadenopathy are the most common complications in
infants infected prenatally [29]. Organisms have
been recovered from the brain of a congenitally
infected infant after 5 yr.
Thermodisruptions
Hyperthermia is defined as a body temperature of
at least 38.9C and is an antimitotic teratogen after
exposure between weeks 4 and 14 [30-32]. In a
retrospective study, Smith et al [33] presented 21
patients who had been exposed during pregnancy
to hyperthermia caused by infections or by sauna
bathing. Severe mental deficiency, seizures in
infancy, microphthalmia, midface hypoplasia, and
mild distal limb abnormalities were associated
with hyperthermia [33]. Infants exposed to
maternal hyperthermia at 7 to 16 wk of gestation
have hypotonia, neurogenic arthrogryposis, or
CNS dysgenesis [34]. Shiota [34] studied 100
embryos with CNS defects and found that 18% of
mothers of anencephalic infants had experienced
hyperthermia at the critical embryonic stage [34].
Occipital encephalocele has also been related to
hyperthermia [35]. Embryonic studies in guinea
pigs and rats have highlighted the sensitivity of
brain growth to elevated temperatures [36-38].
Hypothermia is defined as a core body temperature
of less than 35C. Cardiopulmonary bypass in a

pregnant patient is associated with a fetal mortality

rate of 16% to 33%. One infant with multiple
congenital defects has been described. Another
infant had severe disruptive defects of the brain
and distal spinal cord, suggesting hypoperfusion
injuries related to hypothermia [39].
Toxic Metals
Lead. A woman who has had lead poisoning can
pass lead on to her fetus if she becomes pregnant,
even if she no longer is exposed to lead. This
happens because more than 90% of the lead may
be stored in bone and released into the bloodstream
years later. Blood Pb levels of 10 g/dl are
considered to be elevated but not dangerously high.
The term lead poisoning refers to blood Pb levels
50 g/dl. Deleterious effects of lead exposure have
not been convincingly shown to occur at blood Pb
levels 20 g/dl. Lead crosses the placenta as early
as the 12th to 14th weeks of gestation and
accumulates in fetal tissue [40-42]. The adverse
effects of lead include spontaneous abortion and
stillbirth. A small but significant increase in minor
malformations, including hemangiomas, lymphangiomas, hydroceles, skin tags, skin papillae, and
undescended testes, was seen in infants with high
lead levels in the umbilical blood [41-44]. The
VACTERL (vertebral, anal, cardiac, tracheoesophageal fistula, renal and limb abnormalities)
association has been reported with prenatal
exposure to high lead levels, similar to animal
models of lead teratogenicity [45].
Mercury. Organic forms of mercury are more toxic
than the inorganic forms. Methylmercury, the
most toxic organic form, causes severe brain
damage, as in Minamata disease, which occurred
in epidemic proportions on the Japanese island of
Minamata after maternal ingestion (by both
humans and cats) of methlymercury-contaminated
shellfish [46]. A similar exposure occurred in Iraq
after the ingestion of bread prepared from wheat
treated with methylmercury that was used as a
fungicide [47]. The blood Hg assay measures
exposure to all types of mercury, but because
mercury remains in the bloodstream for only a few
days after exposure, the test should be done soon

Teratogenic causes of malformations 103

after exposure. Most non-exposed people have

blood Hg levels of 0 to 2 g/dl. Levels >2.8 g/dl
are required to be reported to the state health
department. The assay can be influenced by eating
fish that contain mercury. Early effects of mercury
toxicity have been found when the blood Hg level
exceeds 3 g/dl [48]. Methylmercury poisoning
produces atrophy of the granular layer of the
cerebellum and spongiose softening in the visual
cortex and other cortical areas of the brain [47];
polyneuritis can also occur.
Lithium is used in the treatment of bipolar disorder.
If possible lithium should be withheld during the
first trimester of pregnancy and women taking
lithium should not breast feed their infants. The
ratio of lithium concentrations in umbilical cord
blood to maternal blood is uniform (mean 1.05
0.13). Infants with high lithium concentrations
(>0.64 mmol/L) at delivery have significantly lower
Apgar scores. High lithium concentrations at
delivery are associated with perinatal complications,
and lithium concentrations can be reduced by brief
suspension of therapy proximate to delivery.
Cardiovascular malformations, in particular
Ebstein anomaly and tricuspid atresia, have been
related to lithium exposure [49-52]. Infants exposed
in utero to lithium may experience transient
lethargy, hypotonia, cyanosis, poor feeding, and
poor respiratory efforts during the early neonatal
period [49]. Other defects that have been noted in
infants exposed to lithium in utero include
malformations of the CNS, ear, and ureter, altered
thyroid and cardiac function, and congenital goiter
[53]. Some abnormalities (mainly heart defects
such as Ebstein malformation) in the newborn
occur in 6% to 10% of pregnancies involving firsttrimester exposure to lithium [54,55].
Chemical Exposures
Polychlorinated and polybrominated biphenyls
(PCBs). PCBs have been used for more than 40
years as insulating fluids, heat exchangers,
plasticizers, and chemical additives, and they are
known to be worldwide pollutants. They have been
present in game fish caught in PCB-contaminated
waters [56]. Placental transfer of PCBs occurs in
humans [57]. Women suffering from PCB

poisoning have infants with parchment-like skin

with desquamation and brown discoloration (cola
baby), dark colored nails, conjunctivitis, low
birthweight, exophthalmos, and natal teeth.
Reduced birthweight and small head size with
hypotonicity and hyporeflexia are associated with
higher levels of exposure. There is no evidence of
reproductive risk to humans as long as occupational
exposures to PCBs are below the recommended
airborne levels of 0.0001 mg/m3 [58]. PCBs may
interfere with male reproductive function by
exerting estrogenic agonist/antagonist activity.
Toluene. Standards for a permissible exposure limit
(PEL) for toluene have been set by the U.S.
Occupational Safety and Health Administration
(OSHA) at 100 ppm (375 mg/m3), calculated as a
time weighted average over an 8-hr workday.
Toluene embryopathy includes prenatal and
postnatal growth deficiency, microcephaly,
anencephaly, developmental delay, cardiac and
limb defects, and craniofacial anomalies similar to
fetal alcohol syndrome (FAS) [57,59-67]. Phenotypic facial abnormalities similar to those of FAS
suggest a common mechanism of craniofacial
teratogenesis for toluene and alcohol attributed to
deficiency of craniofacial neuropeithelium and
mesodermal components due to increased
embryonic cell death [67].
Maternal Conditions
Obesity. During pregnancy, obesity is associated
with adverse outcomes that include macrosomia,
hypertension, pre-eclampsia, gestational diabetes
mellitus (GDM), and fetal death [68-72]. In
addition, many investigators have reported an
increased risk of birth defects.
Diabetes mellitus. Although hyperglycemia may
be key in the pathogenesis of diabetic embryopathy,
other factors contained in diabetic serum may also
contribute to the embryopathy [73]. Hyperglycemia
leads to inhibition of the myoinositol uptake that is
essential for embryonic development during
gastrulation and neurulation stages of embryogenesis [74,75]. Deficiency of myoinositol appears
to cause perturbations in the phosphoinositide
system that lead to abnormalities in the arachidonic
acid-prostaglandin pathway. The gastrulation and

104 Annals of Clinical & Laboratory Science, vol. 40, no. 2, 2010
neurulation stages of development are particularly
sensitive to hypoglycemia and result in growth
retardation as well as cranial and caudal neural
tube defects (NTDs). Obesity that occurs with a
number of metabolic abnormalities, including
abnormal glucose metabolism, is associated with a
higher risk of malformations. A possible role of
free oxygen radicals in diabetic teratogenicity has
been suggested. The pathogenesis of diabetic
embryopathy is heterogeneous [73,74]; maintenance of glucose homeostasis is important for the
prevention of diabetic embryopathy.
There is a correlation between elevated
hemoglobin A1c (HbA1c) levels and the incidence
of major congenital anomalies in infants of diabetic
mothers (IDMs) [76-80]. HbA1c is a normal,
minor hemoglobin that differs from HbA by the
addition of a glucose moiety to the amino-terminal
valine of the beta chain. Glycosylation of
hemoglobin A occurs during circulation of the red
cell and depends on the average concentration of
glucose to which the red cell is exposed during its
life cycle [81]. Measurement of HbA1c provides an
index of chronic glucose elevation, and therefore of
diabetes control [82]. HbA1c levels during
pregnancy that exceed 11.5% are associated with
congenital abnormalities in 66% of the offspring,
but levels below 9.5% are not associated with
increased frequency of anomalies in infants of
diabetic mothers [83]. Defects of the heart, central
nervous system (CNS), kidneys, and skeleton
predominate. Transposition of the great vessels,
ventricular septal defect (VSD), and dextrocardia
occur with greatest frequency. Anencephaly, spina
bifida, and hydrocephaly are the major CNS
malformations. Rare malformations include situs
inversus and caudal dysplasia, vertebral and renal
anomalies, imperforate anus, radius aplasia, renal
abnormalities including agenesis and dysplasia,
and other defects. Brain development is often
impaired and anomalies include those observed in
the VACTERL association. Minor physical
abnormalities include anteverted nares, flattened
nasal bridge, excess skin folds on the neck, and
tapered fingers with hyperconvex nails. Other
complications include hyperbilirubinemia, hypocalcemia, vascular thromboses (eg, renal vein
thrombosis), and respiratory distress syndrome.

Caudal dysplasia syndrome, with varying degrees

of sacral agenesis, is sometimes associated with
defects of the palate and branchial arches and
occurs in 1% of diabetic offspring [84,85].
Hypothyroidism in infants occurs when the fetal
thyroid gland has been suppressed by antithyroid
drugs (propylthiouracil, carbimazole, iodides),
radioactive iodine [86] or possibly maternal
antibodies [87]. Transfer of maternal thyroxin to
the fetus is negligible during early pregnancy.
During the final weeks of pregnancy, thyroidbinding globulin (TBG) may compete for thyroxin.
Triiodothyronine is less bound by TBG and can
more freely cross the placenta.
Hyperthyroidism during pregnancy is usually due
to Graves disease. The presence of thyroidstimulating globulins may result in thyrotoxicity in
the fetus and newborn regardless of the treatment
of maternal disease. Neonatal thyrotoxicosis is
usually a transient phenomenon lasting several
months. Affected infants have goiter, exophthalmos,
restlessness, tachycardia, periorbital edema,
ravenous appetite, hyperthermia, cardiomegaly,
cardiac failure, and hepatosplenomegaly [88].
Hyperparathyroidism. Infants of mothers with
untreated hypoparathyroidism may have transient
hyperparathyroidism during the fetal and neonatal
periods [89]. The fetal parathyroid hyperplasia that
occurs in response to low maternal and fetal serum
calcium concentration is mediated by the maternal
parathyroid dysfunction. Bone demineralization
and subperiosteal reabsorption occurs in the long
bones. IUGR, pulmonary artery stenosis, VSD,
and muscle hypotonia also occur.
Cretinism and iodine deficiency. Iodine deficiency
is the cause of endemic goiter and cretinism due to
deficiency or of insufficient availability of thyroxine
at the feto-placental level. There is a role of maternal
T4 in neurological embryogenesis, before the onset
of fetal thyroid function and, therefore, its
protective role in fetal thyroid failure. In early
pregnancy, iodine deficiency induces a critical
decrease of T4 levels with consequent TSH increase
responsible for hypothyroidism in about 50% of
iodine-deficient pregnant women. Congenital

Teratogenic causes of malformations 105

Table 2. Characteristics of the fetal alcohol syndrome [191]
Affected System

Frequent Anomalies

Occasional Anomalies

Growth Deficiency
Prenatal
<2 SD for length and weight
Postnatal
<2 SD for length and weight

Disproportionately diminished adipose tissue
CNS Dysfunction
Intellectual
Mild to moderate mental retardation
Neurologic
Microcephaly*
Behavioral
Poor coordination, hypoptonia

Irritability in infancy*

Hyperactivity in childhood
Dermatoglyphics

Prominent thenar crease

Nearly absent proximal transverse crease

Abrupt turning of distal transverse crease

into second interdigital space

Fourth interdigital loop
Facial Characteristics
Eyes
Short palpebral fissures*
Nose
Short, upturned

Hypoplastic philtrum*
Maxilla
Hypoplastic
Mouth
Thin upper cermilion*

Retrognathia in infancy

Micrognathia or prognathia in adolescence
Associated Anomalies
Eyes
Ptosis, strabismus, epicanthal folds
Myopia, clinical microphthalmia, blepharophimosis
Ears
Posterior rotation
Poorly formed concha
Mouth
Prominent lateral palatine ridges
Cleft lip or cleft palate,

Small teeth with faulty enamel
Cardiac system
Murmurs, especially in early
Ventricular septal defects,

childhood, often atrial septal defect
Great vessels anomalies, tetralogy of Fallot
Urogenital system
Labial hypoplasia
Hypospadias, small rotated kidneys, hydronephrosis
Cutaneous system
Hemangiomas, nail hypoplasia
Hirsutism in infancy
Skeletal system
Aberrant palmar crease, pectus excavatum
Limited joint movements (eg, fingers and elbows),

Synostosis, pectus carinatum, bifid xiphoid
Klippel-Feil anomaly, scoliosis
Muscular system
Hernias of diaphragm, umbilicus, or groin

Diastasis recti
Central nervous system
Errors in neuronal migration
Cortical nuclear white matter dysplasia,

Rudimentary cerebellum,

Dysplastic brainstem, hydrophobia, lissencephaly
*Reported in 26%-50% of patients; Reported in 1%-25% of patients; SD, standard deviation.

hypothryoidism associated with deafness and

mental retardation is found in the offspring of
hypothyroid mothers. Deafness persists in spite of
thyroid replacement therapy. Developmental
changes in the brain and cerebellum have been
described [90].
Fetal iodine deficiency results in cretinism
characterized by mental retardation, spastic
diplegia, deafness, and strabismus [91,92]. It
requires severe maternal iodine deficiency (less
than 20 g/day) during the first half of gestation,
which occurs primarily in Northern Italy and in
mountainous areas of New Guinea, the Himalayas,
and the Andes.

Myotonic dystrophy. The myotonic dystrophy gene

contains a segment of CTG repeats that tends to
amplify in each generation [87-89]. Infants born
of women with myotonic dystrophy may show fetal
hypokinesia and generalized weakness, and may
experience difficulty in respiration and feeding.
The facies characteristically shows tenting of the
upper lip, ptosis, absence of movement, and
anterior cupping of the pinnas. Clubfoot is often
present and postnatal growth is slow.
Phenylketonuria.
Maternal
phenylketonuria
(PKU) leads to defects that include intrauterine

106 Annals of Clinical & Laboratory Science, vol. 40, no. 2, 2010
and postnatal growth retardation, cardiovascular
defects, dislocated hips, and other anomalies [9395]. Infants of mothers with PKU are heterozygous,
and because phenylketonuric heterozygotes are
generally normal, the defect in the fetus must be
attributed to the maternal metabolic disturbance.
These effects are directly related to the maternal
phenylalalnine level. When the level exceeds 20
mg/ml, 92% of infants have mental retardation;
73%, microcephaly; 40%, IUGR; and 12%,
cardiac malformations. One-fourth of pregnancies
abort spontaneously.
Ethanol, Smoking, and Various Drugs
Fetal Alcohol Syndrome (FAS). Patients with FAS
must have three characteristics: prenatal and
postnatal growth retardation (>2 SD for length
and weight), facial anomalies, and CNS dysfunction
(Table 2). The full picture of FAS usually occurs in
babies born to alcoholic mothers, or those who
drink regularly or binge-drink. However, no
amount of alcohol is safe. Even light or moderate
drinking can affect the developing fetus.
Acetaldehyde is implicated as the cause of FAS
through its inhibiting effects on DNA synthesis,
placental amino acid transport, and development
of the fetal brain [96-98]. The biologic basis for
FAS is related to genetic polymorphisms identified
for alcohol dehydrogenase (ADH), which converts
alcohol to acetaldehyde, and acetaldehyde
dehydrogenase (ALDH2), which converts acetaldehyde to acetate. Genetic differences in ADH alleles
make some infants exposed to the same level of
alcohol in utero more likely to have longer or higher
levels of exposure to acetaldehyde. This may
explain the greater frequency in American blacks
and Native Americans.
Structural and functional impairments occur
in up to one half of infants born to alcoholic
women who drink heavily. Functional and growth
disturbances without other morphologic changes
can occur in infants whose mothers drink
moderately (1 to 2 oz of absolute ethanol daily). No
malformations have been documented in infants of
mothers who drink <1 oz of absolute ethanol daily.
However, the risk of spontaneous abortion is twice
the normal rate in women who drink 1 oz of

ethanol twice a week [99]. Binge drinking in the

first trimester may be a cause of fetotoxicity [100].
In view of the limited understanding of the effects
of prenatal exposure to alcohol, abstinence from
alcohol during pregnancy is a wise precaution.

Chloroquine. Minimal knowledge is available of
the effects of chloroquine malarial prophylaxis
used during pregnancy. Van Allen and colleagues
[101] studied the effects of chloroquine on women
in Tanzania who were taking 500 mg/wk from the
time they became pregnant. Malformations in
three half-siblings included up-slanting palpebral
fissures, flat philtrum, thin upper lip, and brachydactyly of the fifth finger. Maternal chloroquine
use during pregnancy may be associated with
auditory, vestibular, retinal, and other neurologic
dysfunction in children.
Tobacco smoking. Nicotine is a vasoconstrictor that
results in uterine vascular constriction and
intrauterine growth retardation (IUGR) through
decreased perfusion of fetal tissues [102]. It is a
cholinergic agonist and a constituent of tobacco.
Cigarette smoking during pregnancy raises the risk
of perinatal mortality and morbidity [103]. The
increased mortality is attributed to abruptio
placentae, placenta previa, spontaneous abortion,
prematurity, and IUGR [104].
Carbon monoxide from cigarette smoke also
crosses the placenta and produces an increase in
blood carboxyhemoglobin (HbCO) levels; there is
a longer half-life of HbCO in fetal blood than in
maternal blood [105-107].
Marijuana. The active ingredient of marijuana is
8,9-tetrahydrocannabinol, which is fat soluble,
crosses the placenta easily, and may persist in the
fetus for as long as 30 days [108-110]. Growth
retardation and malformations are reported after
marijuana use during pregnancy, especially in the
first trimester. However, other potentially teratogenic drugs are often used by women who smoke
marijuana. Increased risk of nonlymphoblastic
leukemia has been reported [111].
Lysergic acid diethylamide (LSD). Children born
to mothers who used LSD before or during
pregnancy have had a variety of anomalies. Defects

Teratogenic causes of malformations

107

Table 3. Manifestations in isotretinoin embryopathy [192].

Abnormality

Manifestations

Brain
Brain (occasional)
Brain function
Craniofacial

Heart

Hydrocephalus, leptomeningeal, heterotopias, vermis hypoplasia, Dandy-Walker, corticospinal tract malformations

Gyral defects including grade 3 lissencephaly, regional pachygyria, subcortical heterotopias
Severe or profound mental retardation, hypotonia, diminished deep tendon reflexes (absent or abnormal)
Low-set, small or atretic, malformed ears; small or atretic external auditory meatus; microphthalmia; telecanthus;
epicanthal folds; low nasal bridge; small jaw, sometimes with U-shaped cleft palate (Robin sequence)
Ventricular septal defect, truncus arteriosus, double-outlet right ventricle; interrupted aortic arch; patent ductus arteriosus

of the limbs, eyes, CNS, and arthrogryposis may

be present [112]. The assessment of the effects of
LSD use during pregnancy has been difficult, since
the womens lifestyle may include use of alcohol
and other drugs, poor medical care, and
malnutrition. There is no indication that the risk of
congenital anomalies is great [113]. LSD-induced
chromosomal damage may last up to 2 years but is
sometimes transient [114,115]. There is no evidence
that paternal exposure to LSD in small doses before
conception is associated with increased rates of
spontaneous abortion, premature birth, or birth
defects [116,117].
Sedatives. Increased frequencies of cleft lip, cleft
palate, and congenital heart disease have been
reported after maternal phenobarbital exposure
[118]. Benzodiazepine-containing drugs, taken in
large amounts, may produce IUGR, cleft lip, and
facial features that resemble the findings of FAS
[2,119], although studies have shown little or no
increase in congenital anomalies.
Isotretinoin (accutane, retin-A, retinoic acid)
(Table 3). The risk of fetal abnormality when
isotretinoin is taken by a pregnant woman is 25%
[118]. The critical period of exposure is 4 to 10 wk
of gestation. The defects include hydrocephalus,
microcephaly, cerebellar dysgenesis, depressed
nasal bridge, microtia or absent external ears, cleft
palate, anomalies of the aortic arch, cardiac defects
(including ventricular septal defect, atrial septal
defect, tetralogy of Fallot), and hypoplastic adrenal
cortex [120-122]. Spontaneous abortion is also
increased. A pregnancy-prevention program has
been implemented in women of child-bearing age
receiving isotreitinoin [123]. Use of topical retinoic
acid has not been associated with fetal malformations. Like its congener isotretinoin, etretinate
can cause CNS, cardiovascular, and skeletal

malformations [124]. In contrast to isotretinoin,

etretinate is bound to lipoproteins and persists in
the circulation for years after use.
Thalidomide (Table 4). Thalidomide was used
clinically in the 1960s. It caused limb reduction
defects, facial hemangiomas, esophageal and
duodenal atresia, cardiac defects (eg, tetralogy of
Fallot), renal agenesis, urinary tract anomalies,
Table 4. Abnormalities in thalidomide embryopathy [193]
Skeletal defects
Absent radii
Hand
Limited extension, club hand, hypoplastic
or fused phalanges, finger syndactyly, carpal hypoplasia or
fusion, radial deviation
Ulna
Short and malformed, unilaterally or bilaterally absent
Humerus
Hypoplastic, absent
Shoulder girdle
Abnormally formed with absent glenoid, fossa and acromion
process, hypoplastic scapula and clavicle
Hips
Unilaterally or bilaterally dislocated
Legs
Coxa valga, femoral torsion, tibial torsion, bilateral or
unilateral stiff knee, abnormal tibiofibular joint, dislocated
patella(e)
Feet
Overriding fifth toe, calcaneovalgus deformity
Ribs
Asymmetric first rib, cervical rib
Spine
Cervical spina bifida, fused cervical spine
Mandibular hypoplasia
Maxillary hypoplasia
Cardiac anomalies
Tetratology of Fallot, atrial septal defect, patent foramen ovale,
dextrocardia, congestive heart failure leading to death
Systolic murmur, cardiomegaly
Suspected congenital heart disease
Other abnormalities
Apparently low-set ears, malformations extending to microtia
Urogenital anomalies
Micrognathia
Meckel diverticulum
Uterine anomalies

108 Annals of Clinical & Laboratory Science, vol. 40, no. 2, 2010
genital defects, dental anomalies, ear anomalies,
facial palsy, ophthalmoplegia, anophthalmia,
microphthalmia, and coloboma [125,126]. Cleft
palate was a rare occurence and the CNS was not
affected. The children had normal intelligence.
The sensitive period for production of human
thalidomide birth defects was 23 to 28 days postconception, with the critical period no longer than
14 days. About 20% of pregnancies exposed during
this period resulted in infants with anomalies, the
most notable of which were limb defects ranging
from triphalangeal thumb to tetra-amelia or
phocomelia of the upper and lower limbs, at times
with preaxial polydactyly of six or seven toes per
foot [125].
McCredie [127-129] postulated interference
with neural crest-based sclerotomal organization as
the pathogenetic basis of the limb malformations.
McCredie and coworkers [125,130] expanded their
studies of the visceral anomalies in infants who
died with multiple congenital anomalies with
longitudinal limb defects by attempting to
determine whether neural crest injury would
impair development of structures supplied by the
sensory autonomic nerves derived from the injured
zone of the neural crest. Application of sclerotomal
and viscerotomal maps to the autopsy data showed
a neuroanatomic correlation in 89% of cases. The
authors proposed a developmental correlation
within a multiple congenital anomaly syndrome
on the basis of neurotomes or embryonic
developmental fields with common regional
innervation. Thalidomide is an inhibitor of
angiogenesis; its antiangiogenic activity correlates
with its teratogenicity [131].
Folic acid deficiency and folic acid antagonists.
Folic acid deficiency has been observed in a high
percentage of women who have had infants with a
neural tube defect (NTD); folic acid antagonists
also may result in NTDs. Deficiency of folic acid
appears to result in up to 70% of NTDs, particularly
anencephaly [132]. The US Food and Drug
Administration (FDA) recommends fortifying
food with adequate levels of folic acid. Periconceptional daily intake of 0.4 mg of folic acid
(the dose commonly contained in over-the-counter
multivitamin preparations) reduces the risk of

NTDs by approximately 60% [133]. The US Public

Health Service (PHS) recommends that all women
of childbearing age in the United States who are
capable of becoming pregnant should consume 0.4
mg of folic acid per day in order to reduce their risk
of having a pregnancy affected with spina bifida or
other NTDs [134]. Because the effects of high
intakes are not well known but include masking
the diagnosis of vitamin B12 deficiency, care should
be taken to keep total folate consumption at <1 mg
per day. Women who had a prior NTD-affected
pregnancy are at high risk of having a subsequent
affected pregnancy.
Ergotamine. Ergotamine is a natural alkaloid of
ergot that causes smooth muscle contraction. The
constrictive effects of ergotamine on fetal blood
vessels may be responsible for IUGR and jejunal
atresia [135]. No adverse effect on pregnancy was
found in women who took ergotamine for the
treatment of migraine [136,137]. A report from the
database of the Hungarian Case-Control
Surveillance of Congenital Anomalies (1980-1986)
showed that of 9460 children born to mothers
exposed to ergotamine in the first 3 months of
pregnancy, three had NTDs [136]. Controlled
studies on ergotamine use during pregnancy have
not been reported.
Metronidazole (Flagyl). Metronidazole is an antibiotic and antiprotozoal agent commonly used to
treat gynecologic infections. It has been associated
with birth defects in isolated cases [138]. However,
most published reports indicate that use of this
drug during pregnancy is not associated with an
increase of malformations, spontaneous abortions,
stillbirths, or prematurity [139-141].
Cocaine. Cocaine is metabolized very slowly in the
fetus because the fetus has low plasma cholinesterase
activity [142]. Cocaine blocks the presynaptic
reuptake of neurotransmitters at nerve terminals,
which results in increased levels of norepinephrine
and dopamine [143]. It may alter the availability
and utilization of calcium, and reduce blood flow
from the uterus to the placenta. The complications
of abruptio placentae, cerebral hemorrhage, IUGR,
limb defects, bowel atresia, and necrotizing
enterocolitis appear to be related to vascular

Teratogenic causes of malformations 109

disruption [144]. Cocaine-exposed fetuses also

have increased incidences of prematurity, microcephaly, and sudden infant death [145].
Phenytoin (hydantoin, dilantin). Phenytoin is a
medication used to treat epilepsy. If taken by the
mother in the first trimester, there is a small risk for
a combination of birth defects known as the fetal
hydantoin syndrome. The pattern of anomalies
consists of developmental delay or frank mental
deficiency, dysmorphic craniofacial features, and
hypoplasia of the distal phalanges. The presence of
major phenytoin-associated birth defects in a child
correlates with an inability of lymphocytes to
detoxify the drug. There appears to be genetic
susceptibility to phenytoin fetal toxicity. Twins
have been discordant for manifestations of the
hydantoin syndrome [146]. The risk of developmental disturbance in phenytoin-exposed children
ranges from 1% to 11%. Chronic exposure presents
a maximum of 10% risk for the full syndrome and
a maximum of 30% risk for some anomalies
[147,148].
Trimethadioine, paramethadione. Maternal use of
these drugs results in spontaneous abortion in onefourth of pregnancies. Most liveborn infants have
prenatal and postnatal growth deficiency, developmental delay, malformations, and distinctive facies,
including brachycephaly with midfacial hypoplasia,
V-shaped eyebrows with or without synophrys,
broad nasal bridge, arched or cleft palate, and
malpositioned ears, with anterior cupping and/or
excessive folding of the superior helices [149].
Cardiovascular defects, particularly septal defects
and tetralogy of Fallot, renal malformations,
tracheoesophageal anomalies, hernias, and hypospadias are common. Survivors often have mild to
moderate mental retardation and speech impairment [149].
Warfarin (dicumarol, coumarin derivatives).
Women with a history of thromboembolic disease
or artificial heart valves often require long-term
anticoagulant therapy. There is an estimated 25%
risk for affected infants after exposure during the
period from 8 to 14 weeks of pregnancy. Warfarin
inhibits the formation of carboxyglutamyl from

glutamyl residues, decreasing the ability of proteins

to bind calcium [150]. Choanal stenosis may occur.
Calcific stippling occurs primarily in the tarsals,
proximal femurs, and paravertebral processes.
Brachydactyly and small nails, with greater severity
in the upper limbs, has been present in about onehalf of affected infants. Optic atrophy, microphthalmia and blindness can result from exposure
during the first or second trimester. Brain anomalies
include microcephaly, optic atrophy, visual impairment, seizures, hypotonia, and mental retardation.
Inhibition of calcium binding by proteins during a
critical period of ossification may explain the nasal
hypoplasia, stippled calcification, and skeletal
abnormalities of warfarin embryopathy [150].
Angiotensin-converting enzyme (ACE) inhibitors.
Captopril crosses the human placenta. Its use and
that of other ACE inhibitors is associated with
spontaneous abortions, intrauterine and neonatal
deaths, neonatal respiratory distress, limb and
CNS defects, patent ductus arteriosus (PDA),
oligohydramnios, and calcarial hypoplasia, as well
as renal tubular dysplasia [151].
Statins. The statins are hypolipidemic drugs used
to lower serum cholesterol levels in people who
have or are at risk for cardiovascular disease
[152,153]. Statins inhibit 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase, the
enzyme that catalyzes formation of mevalonate
from HMG-CoA, the rate-limiting step in the
mevalonate pathway of cholesterol biosynthesis.
Cholesterol, an integral part of cell membranes, is
critical for embryonic and fetal development. It
also is the precursor of steroid hormones and is
essential for the activation and propagation of
hedgehog signaling, which regulates critical events
during development, including patterning of the
CNS [154-157]. The FDA designated these drugs
in pregnancy category X [153] and, therefore, their
use is contraindicated in women who are or may
become pregnant. Because approximately 50% of
pregnancies in the United States are unplanned
[158-160], early pregnancies may be unknowingly
exposed to them.
Because of the recognition of various patterns
of congenital abnormalities (CA) resulting from

110 Annals of Clinical & Laboratory Science, vol. 40, no. 2, 2010
deficient de novo cholesterol synthesis [161-163],
concern has been raised about the potential effect
of prenatal use of statins on embryonic and fetal
development. These patterns include the SmithLemli-Opitz syndrome; two Smith-Lemli-Opitzlike syndromes, desmosterolosis and lathosterolosis;
and two skeletal dysplasia syndromes with
dermatologic manifestations, X-linked dominant
chondrodysplasia punctata type 2 and congenital
hemidysplasia with ichthyosiform erythroderma
and limb defects (Child syndrome) [162,163]. At
present, no controlled studies have shown teratogenicity of statins in humans. However, case
reports [164,165] and a case series reported by
Edison and Muenke [166] have suggested that
statins may have teratogenic effects.
Assisted Reproductive Technologies
In addition to the problems inherent in multiple
pregnancies, children conceived by assisted
reproductive technologies (ART) have increased
risks for low-birth weight (LBW) and preterm
delivery [2,167,168]. Data on birth defects are
inconclusive because most available studies, which
generally are observational and based on small
sample sizes, do not have the power to control for
confounding factors, such as parental age, causes
of infertility, the multiple technical variables of the
ART regimens, and the causal heterogeneity of
infertility [169-172]. In contrast to early reports
showing a lack of association between ART and an
increased rate of birth defects [173-177], more
recent and larger studies [178-183], including three
meta-analyses [184-186], indicate that children
conceived by ART are more likely to have a CA
than children conceived spontaneously. Anomalies
with the strongest associations include hypospadias
and other genitourinary defects. Nasal tube defects
(NTDs), gastrointestinal anomalies, CHDs, and
chromosomal abnormalities may occur [178-183].
Hansen et al [184] reviewed 25 reported studies;
two-thirds of them showed 25% or greater risk for
birth defects in children conceived by ART.

that spermicides should not affect the developing

pregnancy, since their task is to prevent pregnancy
to begin with. Studies during the 1970s and 1980s
suggested that spermicides might cause some birth
defects. Subsequent studies, however, have shown
no association between the use of spermicides and
an increased risk for birth defects [2,187].
Acetaminophen. Acetaminophen is the active
ingredient of some pain relievers. Thousands of
women have taken acetaminophen-containing
pain relievers during pregnancy and there has been
no association with an increased risk of birth
defects, when used at or below the recommended
dosage [2,188].
Prenatal vitamins. Vitamins are prescribed when a
woman becomes pregnant to supplement her diet
to meet the growing nutritional needs of pregnancy.
The amounts of vitamins contained in prenatal
vitamin pills are calculated to address some of the
biological changes that happen when a woman is
pregnant, such as increased blood volume. When
used at the recommended dosage, prenatal vitamins
do not increase the risk of birth defects [2,189].
Microwave ovens. There are two types of radiation:
ionizing and non-ionizing radiation. X-rays are an
example of ionizing radiation, while ultraviolet
rays (sunlight) and microwaves are examples of
non-ionizing radiation. Non-ionizing radiation is
not teratogenic. Microwaving of food during
pregnancy is not known to increase the risks for
birth defects or health problems [2].
Summary
This manuscript summarizes the well-documented
teratogenic causes of fetal malformations due to
prenatal exposures and includes some examples of
agents that have been suspected but are found to be
nonteratogenic.
References

Examples of Nonteratogenic Agents

1.

Spermicides. Spermicides are agents that impair

the ability of sperm to fertilize an egg. This suggests

2.

Brent RL. The cause and prevention of human birth defects:

what have we learned in the past 50 years? Congenit Anom
(Kyoto) 2001;41:3-21.
Frias JL, Gilbert-Barness E. Human teratogens: current controversies. Advanc Pediat 2008;55:171-211.

Teratogenic causes of malformations 111

3.

4.
5.
6.
7.
8.
9.
10.

11.
12.
13.
14.
15.

16.
17.
18.
19.
20.

21.
22.
23.
24.

25.
26.

27.

Wilson JG. Current status of teratology. General principles and

mechanisms derived from animal studies. In: Handbook of
Teratology (Wilson JG, Fraser FC, Eds), Plenum Press, New
York, 1977; vol 1, pp 147-174.
Gilbert SF. Developmental Biology, 7th ed, Sinauer Associates,
Sunderland, MA, 2003; pp 694-696.
Barish RJ. In-flight radiation exposure during pregnancy.
Obstet Gynecol 2004;103:1326-1330.
Fattibene P, Mazzei F, Muccetelli C, Risica S. Prenatal
exposure to ionizing radiation: sources, effects, and regulatory
aspects. Acta Pediatr 1999;88:693-702.
Robert CJ, Lowe CR. Where have all the conceptions gone?
Lancet 1975;1:498.
Brent RL. Methods of evaluating the alleged teratogenicity of
environmental agents. Prog Clin Biol Res 1985;163C:191-195.
Larsen JW Jr, Greendale K. Letter to the editor: ACOG
technical bulletin. Teratology 1985;32:493-496.
Brent RL. Utilization of developmental basic science principles
in the evaluation of reproductive risks from pre- and postconception environmental radiation exposures, Teratology
1999;59:182-204.
Hall JG. Genomic imprinting. Arch Dis Child 1990;65:1013.
Newell M-L, McIntyre J. Congenital and Perinatal Infections:
Prevention, Diagnosis and Treatment, Cambridge Univ Press,
Cambridge, 2000; pp 3-14.
Marecki MA, Bozzette M. Infections in the perinatal period.
J Perinat Neonatal Nurs 2008;22:173-174.
Beckman DA, Brent RL. Mechanism of known environmental
teratogens: drugs and chemicals, Clin Perinatal 1986;13:649687.
Mehraein Y, Rehder H, Draeger HG, Froster-Iskenius UG,
Schwinger E, Holzgreve W. Diagnosis of fetal virus infections
by in-situ hybridization. Geburtshilfe Frauenheilkd 1991;51:
984-989.
Paryani SG, Arvin AM. Intrauterine infection with varicellazoster virus after maternal varicella. NEJM 1986;314:15421546.
Alber C. Neonatal varicella. Am J Dis Child 1964;107:492494.
Stevenson RE. The environmental basis of human anomalies.
In: Human Malformations (Stevenson RE, Ed), Oxford Univ
Press, New York, 1993; p 37.
Carrington D. Maternal serum alpha-fetoprotein: a marker of
fetal aplastic crisis during intrauterine human parvovirus
infection, Lancet 1987;1:433-435.
Schwartz TF, Nerlich A, Hottentrager B, Jager G, Weist I,
Kantimm S, Ruggendorf H, Schultz M, Gloning KP, Schramm
T. Parvovirus B19 infection of the fetus. Histology and in-situ
hybridization. Am J Clin Pathol 1991;96:121-126.
Weiland HT. Parvovirus B19 associated with fetal abnormality,
Lancet 1987;1:682-683.
Siegel M, Greenberg M. Poliomyelitis in pregnancy: effect on
fetus and newborn infant. J Pediatr 1956;49:280-288.
Moss PD, Hefferman CK, Thurston JG. Enteroviruses and
congenital abnormalities, Br Med J 1967;1:110-111.
Lin HH, Lee TY, Chen DS, Sung TL, Ohto H, Etoh T,
Kawana T, Mizuno M. Transplacental leakage of HBeAgpositive maternal blood as the most likely route in causing
intrauterine infection with hepatitis B virus. J Pediatr 1987;111:
877-881.
Ingall D, Norin L. Syphilis. In: Infectious Diseases of the
Fetus and Newborn Infant, 5th ed (Remington JS, Klein JO,
Eds), Philadelphia, Saunders, 2006; pp 643-681.
Lee WK, Schwartz DA, Rice RJ, Larsen SA. Syphilitic endometritis causing first trimester abortion: a potential infectious
cause of fetal morbidity in early gestation. South Med J
1994;87:1259-1261.
Harter CA, Benirschke K. Fetal syphilis in the first trimester.
Am J Obstet Gynecol 1976;124:705-711.

28. Sever JL, Ellenberg JH, Ley AC, Madden DL, Fuccillo DA,
Tzan NR, Edmonds DM. Toxoplasmosis: maternal and
pediatric findings in 23,000 pregnancies. Pediatrics 1988;82:
181-192.
29. Giannoulis C, Zournatzi B, Giomisi A, Diza E, Tzafettas I.
Toxoplasmosis during pregnancy: a case report and review of
literature. Hippokratia 2008;12:139-143.
30. Plect H, Graham JM, Smith DW. Central nervous system and
facial defects associated with maternal hyperthermia at 4 to 14
weeks gestation. Pediatrics 1981;67:785-789.
31. Li DK, Janevic T, Odouli R, Liu L. Hot tub use during pregnancy and the risk of miscarriage. Am J Epidemiol 2003;158:
931-937.
32. Edwards MJ. Hyperthermia and fever during pregnancy. Birth
Defects Res A Clin Mol Teratol 2006;76:507-516.
33. Smith DW, Clarren SK, Harvey MAS. Hyperthermia as a
possible teratogenic agent. J Pediatr 1978;92:878-883.
34. Shiota K. Neural tube defects and maternal hyperthermia in
early pregnancy: epidemiology in a human embryonic
population. Am J Med Genet 1982;12:281-288.
35. Fisher NL, Smith DW. Hyperthermia as a possible cause of
occipital encephalocoele. Clin Res 1980;28:116A.
36. Edwards MJ. Congenital defects in guinea pigs: fetal
resorptions, abortions and malformations following induced
hyperthermia during gestation. Teratology 1969;2:313-328.
37. Edwards MJ. Congenital defects in guinea pigs following
induced hyperthermia during gestation. Arch Pathol 1967;84:
42-48.
38. Edwards MJ. The experimental production of clubfoot in
guinea pigs by maternal hyperthermia during gestation. J
Pathol 1971;103:49-53.
39. Jones MC, Kosaki K, Bird LM. Disruptive defects of the brain
and spinal cord as a consequence of cardiopulmonary bypass
and hypothermia at 18 weeks gestation. Proc Greenwood
Genet Ctr 1995;14:58-62.
40. Wang YY, Sui KK, Li H, Ma HY. The effects of lead exposure
on placental NF-kappaB expression and the consequences for
gestation. Reprod Toxicol 2009;27:190-195.
41. Gomaa A, Hu H, Bellinger D, Schwartz J, Tsaih SW,
Gonzalvo-Cossio T, Schnaas L, Peterson K, Aro A, HernandezAvila M. Maternal bone lead as an independent risk factor for
fetal neurotoxicity: a prospective study. Pediatrics 2002;110:
110-118.
42. Rischitelli G, Nygren P, Bougatsos C, Freeman M, Helfand M.
Screening for elevated lead levels in childhood and pregnancy:
an updated summary of evidence for the U.S. Preventive
Services Task Force. Pediatrics 2006;118:1867-1895.
43. Goldhaber MK, Polen MR, Hiatt RA. The risk of miscarriage
and birth defects among women who use video display
terminals during pregnancy. Am J Ind Med, 1988;13:695-706.
44. AMA Council on Scientific Affairs. Effects of toxic chemicals
on the reproductive system. JAMA 1985;253:3431-3437.
45. Levine F, Muenke F. VACTERL association with high prenatal
lead exposure: similarities to animal models to lead teratogenicity. Pediatrics 1991;87:390-392.
46. Murakami U. The effect of organic mercury on intrauterine
life. Adv Exp Med Biol 1971;27:301-306.
47. Amin-zaki L, Majeed MA, Elhassani SB, Clarkson TW,
Greenwood MR, Doherty RA. Prenatal methylmercury
poisoning; clinical observations over five years. Am J Dis Child
1979;133:172-177.
48. Murata K, Dakeishi M, Shimada M, Satoh H. Assessment of
intrauterine methylmercury exposure affecting child development messages from the newborn. Tohoku J Exp Med 2007;
213:187-202.
49. Warkany J. Teratogen update: lithium. Teratology 1988;38:593597.
50. Cohen LS, Friedman JM, Jefferson JW, Johnson EM, Weiner
ML. A re-evaluation of risk of in utero exposure to lithium.
JAMA 1994;271:146-150.

112 Annals of Clinical & Laboratory Science, vol. 40, no. 2, 2010
51. Jacobson SJ. Prospective multicentre study of pregnancy
outcome after lithium exposure during first trimester. Lancet
1992;339:530-533.
52. Berkowitz RL. Handbook for Prescribing Medications During
Pregnancy, 2nd ed, Little, Brown, Boston, 1986, pp 79.
53. Schou M. Occurrence of goiter during lithium treatment. Br
Med J 1968;3:710.
54. Giles JJ, Bannigan JG. Teratogenic and developmental effects
of lithium. Curr Pharm Des 2006;12:1531-1541.
55. Cohen LS, Friedman JM, Jefferson JW, Johnson EM, Weiner
ML. A reevaluation of risk of in utero exposure to lithium.
JAMA 1994;271:146-150.
56. Longo LD. Environmental pollution and pregnancy; risks and
uncertainties for the fetus and infant. Am J Obstet Gynecol
1980;137:162-173.
57. Beckman DA, Brent RL. Mechanism of teratogenesis. Annu
Rev Pharmacol Toxicol 1984;24:482-500.
58. Jacobson JL, Jacobson SM. Teratogen update: polychlorinated
biphenyls. Teratology 1997;55:338-347.
59. Arnold GL, Wilkens-Haug L. Toluene embryopathy
syndromes. Am J Hum Genet 1990;47:A46.
60. Hersh JH, Podruch PE, Roger G, Weisskopf B. Toluene
embryopathy. J Pediatr 1985;106:922-927.
61. Costa LG, Guizzetti M, Burry M, Oberdoerster J. Developmental neurotoxicity: do similar phenotypes indicate a
common mode of action? A comparison of fetal alcohol
syndrome, toluene embryopathy and maternal phenylketonuria.
Toxicol Lett 2002;127:197-205.
62. deSilva VA, Malheiros LR, Paumgartten FL, deSarego M, Riul
TR, Golovattei MA. Developmental toxicity of in utero
exposure to toluene on malnourished and well nourished rats.
Toxicology 1990;64:155-168.
63. Donald JM, Hooper K, Hopenhayn-Rich C. Reproductive and
developmental toxicity of toluene: a review. Environ Health
Perspect 1991;94:237-244.
64. Utidjian HM. Excerpts from criteria for a recommended
standard: occupational exposure to toluene. J Occup Med
1974;16:107-109.
65. McDonald JC. Chemical exposures at work in early pregnancy
and congenital defect: a case reference study. Br J Ind Med
1987;44:527-533.
66. Hersh JH. A toluene embryopathy, two new cases. J Med Genet
1989;26:233-237.
67. Pearson MA, Hoyne HE, Seaver LH, Rimsza ME. Toluene
embryopathy: delineation of the phenotype and comparison
with fetal alcohol syndrome. Pediatrics 1994;93:211-215.
68. Naeye RL. Maternal body weight and pregnancy outcome. Am
J Clin Nutr 1990;52:273-279.
69. Baeten JM, Bukusi EA, Lambe M. Pregnancy complications
and outcomes among overweight and obese nulliparous
women. Am J Public Health 2001;91:436-440.
70. Stephansson O, Dickman PW, Johansson A, Chattingius S.
Maternal weight, pregnancy weight gain, and the risk of
antepartum stillbirth. Am J Obstet Gynecol 2001;184:463469.
71. Andreasen KR, Andersen ML, Schantz AL. Obesity and
pregnancy. Acta Obstet Gynecol Scand 2004;83:1022-1029.
72. Cedergren MI, Selbing AJ, Kallen BA. Risk factors for cardiovascular malformation: a study based on prospectively collected
data. Scand Work Environ Health 2002;28:12-17.
73. Sadler TW, Hunter ES III, Wynn RE, Phillips LS. Evidence
for multifactorial origin of diabetes-induced embryopathies.
Diabetes 1989;38:70-74.
74. Sadler TW, Denno KM, Hunger ES III. Effects of altered
maternal metabolism during gastrulation and neurulation
stages of embryogenesis. Ann NY Acad Sci 1993;678:48-61.
75. Baker L, Piddington R. Diabetic embryopathy: a selective
review of recent trends. Diabetes Complicat 1993;7:204-212.

76. Miller E, Hare JW. Elevated maternal hemoglobin A1c in early

pregnancy and major congenital anomalies in infants of
diabetic mothers. NEJM 1981;304:1331-1334.
77. Zhao Z, Reece EA. Experimental mechanisms of diabetic
embryopathy and strategies for developing therapeutic
interventions. J Soc Gynecol Invest 2005;12:549-557.
78. Loeken MR. Advances in understanding the molecular causes
of diabetes induced birth defects. J Soc Gynecol Invest 2006;
13:2-10.
79. Reece RA, Ji I, Wu YK, Zhao Z. Characterization of differential
gene expression profiles in diabetic embryopathy using DNA
microarray analysis. Am J Obstet Gynecol 2006;195:10751080.
80. de Vigan, Verite V, Vodovar V. Diabetes and congenital
anomalies data from Paris registry of congenital anomalies.
1985-1987. Reprod Toxicol 2000;14:76.
81. Bunn HF, Haney DN, Kamin S, Gabbay H, Gallop PM. The
biosynthesis of human hemoglobin A1c: slow glycosylation of
hemoglobin in vivo. J Clin Invest 1976;57:1652-1659.
82. Dunn PJ, Cole RA, Soeldner JS, Gleason RE, Kwa E,
Firoozabadi H, Younger D, Graham CA. Temporal relationships of glycosylated hemoglobin concentrations to glucose
control in diabetes. Diabetologia 1979;17:213.
83. Nielsen GL, Sorensen HT, Nielsen PH, Sabroe S. Glycosylated
hemoglobin as predictor of adverse fetal outcome in type I
diabetic pregnancies. Acta Diabetol 1997;34:217-222.
84. Kucera J. Rate and type of congenital anomalies among
offspring of diabetic women. J Reprod Med 1971;7:73-82.
85. Passarge E. Congenital malformation and maternal diabetes.
Lancet 1965;1:324-325.
86. Burrow GN, Bartsocas C, Klatskin EH, Grunt JA. Children
exposed in utero to propylthiouracil: subsequent intellectual
and physical development. Am J Dis Child 1968;116;161-165.
87. Sutherland JM, Esselborn VM, Burket RL, Skillman TB,
Benson JT. Familial nongoitrous cretinism apparently due to
maternal antithyroid antibody. NEJM 1960;263:336.
88. Polak M. Hyperthyroidism in early infancy: pathogenesis,
clinical features and diagnosis with a focus on neonatal
hyperthyroidism. Thyroid 1998;8:1171-1177.
89. Landing BH, Kamoshita S. Congenital hyperparathyroidism
secondary to maternal hypoparathyroidism. J Pediatr 1970;77:
842-847.
90. Potter A, Phillips II JA. Endocrine organs. In: Human
Malformations and Related Anomalies, 2nd ed (Stevenson RE,
Hall JG, Goodman RM, Eds), Oxford Univ Press, New York,
2006; pp 1355.
91. Connolly KJ, Pharoah POD, Hetzel BS. Fetal iodine deficiency
and motor performance during childhood. Lancet 1979;2:11491151.
92. Hetzel BS, Hay ID. Thyroid function, iodine nutrition, and
fetal brain development. Clin Endocrinol 1979;11:445-460.
93. Yu JS, OHalloran MT. Children of mothers with phenylketonuria. Lancet 1970;1:210-212.
94. Maillot F, Lilburn M, Baudin J, Morley DW, Lee PJ. Factors
influencing outcomes in the offspring of mothers with
phenylketonuria during pregnancy: the importance of variation
in maternal blood phenylalanine. Am J Clin Nutr 2008;88:700705.
95. National Institutes of Health Consensus Development Conference Statement. Phenylketonuria: screening and management.
Pediatrics 201;108:972-982.
96. Kumar SP. Fetal alcohol syndrome, mechanisms of teratogenesis. Ann Clin Lab Sci 1982;12:254-257.
97. Jones KL. Smiths Recognizable Patterns of Human Malformations, 6th ed, Elsevier Saunders, Philadelphia, 2006; pp 491494.
98. CDC. Fetal alcohol syndrome: Alaska, Arizona, Colorado, New
York, 1995-1997. Morb Mortal Wkly Rep 2002;51:433-435.

Teratogenic causes of malformations 113

99. Shepard TH. Catalog of Teratogenic Agents, 7th ed, John
Hopkins Univ Press, Baltimore, 1992; pp 156-160.
100. Streissguth AP, Landesman-Dwyer S, Martin JC, Smith DW.
Teratogenic effects of alcohol in humans and laboratory
animals. Science 1980;290:353.
101. Van Allen M, Jilek-Aall L, Rwiza HT. Possible fetal chloroquine
syndrome. Proc Greenwood Genet Ctr 1995;14:15.
102. Trease GE, Evans WC. The pharmacological action of plant
drugs. In: Pharmacognosy, 12th ed (Trease GE, Evans WC,
Eds), Bailliere Tindall, London, 1983; pp 147-154.
103. Landesman-Dwyer S, Landesman-Dwyer IE. Smoking during
pregnancy. Teratology 1979;19:119-125.
104. Naeye RL. Environmental influences on the embryo and early
fetus. In: Disorders of the Placenta, Fetus and Neonate:
Diagnosis and Clinical Significance (Naeye RL, Ed), MosbyYear Book, St. Louis, 1989; pp 77-89.
105. Bureau MA, Monette J, Shapcott D, Pare C, Mathieu JL,
Lippe J, Blovin D, Berthiaume Y , Begin R. Carboxyhemoglobin
concentration in fetal cord blood and in blood of mothers who
smoked during labor. Pediatrics 1982;69:371-373.
106. Chung KC, Kowalski CP, Kim HM, Buchman SR. Maternal
cigarette smoking during pregnancy and the risk of having a
child with cleft lip/palate. Plast Reconstr Surg 2000;105:485491.
107. Meyer KA, Williams P, Hernandez-Diaz S, Chattinquis S.
Smoking and the risk of oral clefts: exploring the impact of
study designs. Epidemiology 2004:15:671-678.
108. Idanpaan-Heikkila J, Fritchie GE, Englert LF, Ho BT, McIsaac
WM. Placental transfer of tritiated-1-tetrahydrocannabinol.
NEJM 1969;281:330.
109. Klausner HA, Dingell JV. The metabolism and excretion of
delta-9-tetrahydocannabinol in the rat. Life Sci 1971;10:49-59.
110. Kreuz DS, Axelrod J. Delta-9-tetrahydrocannabinol: localization in body fat. Science 1973;179:391.
111. Robison LL, Buckley JD, Daigle AE, Wells R, Benjamin D,
Arthur DC, Hammond GD. Maternal drug use and risk of
childhood nonlymphoblastic leukemia among offspring: an
epidemiologic investigation implicating marijuana. Cancer
1989;63:1904-1911.
112. Zellweger H, McDonald IS, Abbo G. Is lysergic-acid-diethylamide a teratogen? Lancet 1967;2:1066-1068.
113. Golbus MS. Teratology for the obstetrician: current status,
Obstet Gynecol 1980;55:269-277.
114. Irwin S, Egozcue J. Chromosomal abnormalities in leukocytes
from LSD-25 users. Science 1967;157:313-314.
115. Hungerford DA, Taylor KM, Shagass C. Cytogenic effects of
LSD-25 therapy in man. JAMA 1968;206:2287-2291.
116. Dishotsky NI, Loughman WD, Mogar RE, Lipscomb WR.
LSD and genetic damage. Science 1971;172:431-440.
117. Hecht F, Beals RK, Lee MH, Jollys H, Roberts P. Lysergicacid-diethylamide and cannabis as possible teratogens in man.
Lancet 1968;2:1087.
118. Brook JD, McCurrach ME, Harley HG. Molecular basis of
myotonic dystrophy: expansion of a trinucleotide (CTG) repeat
at the 3-end of a transcript encoding a protein kinase family
member. Cell 1992;68:799-808.
119. Garcia-Bournissen F, Tsur L, Goldstein LH, Stanoselsky A,
Avner M, Asrar F, Berkovitch M, Straface G, Koren G, De
Santis M. Fetal exposure to isotretinoin: an international
problem. Reprod Toxicol 2008;1:124-128.
120. Wilhite CC. Isotretinoin-induced craniofacial malformations
in humans and hamsters. J Craniofac Genet Dev Biol 1986;
2(suppl):193.
121. Teratology Society. Recommendations for vitamin A use
during pregnancy. Teratology 1987;35:269.
122. Lammer EJ. Retinoic acid embryopathy. NEJM 1985;313:837.
123. Mitchell AA, Van Bennekon CM, Louik C. A pregnancyprevention program in women of child-bearing age receiving
isotretinoin. NEJM 1995;333:101-106

124. Barbero P, Lotersztein V, Bronberg R, Perez M, Alba L.

Acitretin embryopathy: a case report. Birth Defects Res A Clin
Mol Teratol 2004;70:831-833.
125. North K, McCredie J. Neurotomes and birth defects: a neuroanatomic method of interpretation of multiple congenital
malformations. Am J Med Genet 1987;3(suppl):29-42.
126. Henkel L, Willert HE. Dysmelia: a classification and pattern of
malformation in a group of congenital defects of the limbs. J
Bone Joint Surg 1969;51B:399.
127. McCredie J. Embryonic neuropathy: a hypothesis of neural
crest injury as the pathogenesis of congenital malformations.
Med J Aust 1974;1:159-163.
128. McCredie J. Neural crest defects: a neuroanatomic basis for
classification of multiple malformations related to phocomelia.
J Neurol Sci 1976;28:373-387.
129. McCredie JM. Comments on Proposed mechanisms of action
in thalidomide embryopathy. Teratology 1990;41:239-242.
130. McCredie J, North K, de Iongh R. Thalidomide deformities and
their nerve supply. J Anat 1984;139:397-410.
131. DAmato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide
is an inhibitor of angiogenesis. PNAS USA 1994;91:40824085.
132. Werler MM, Shaprio S, Mitchell AA. Periconceptional folic
acid exposure and risk of occurrent neural tube defects. JAMA
1993;269:1257-1261.
133. Czeizel AE. Periconceptional folic acid and multivitamin
supplementation for the prevention of neural tube defects and
other congenital abnormalities. Birth Defects Res A Clin Mol
Teratol 2009;85:260-268.
134. Harris MJ. Insights into prevention of human neural tube
defects by folic acid arising from consideration of mouse
mutants. Birth Defects Res A Clin Mol Teratol 2008;85:331335.
135. Graham JM Jr, Stephens TD, Shepard TH. Jejunal atresia
associated with cafergot ingestion during pregnancy. Clin
Pediatr 1983;22:226-228.
136. Czeizel A. Teratogenicity of ergotamine. J Med Genet 1989;
26:69-70.
137. Knapp P, Lenz W, Nowack E. Multiple congenital abnormalities. Lancet 1962;2:725-728.
138. Greenberg F. Possible metronidazole teratogenicity and
clefting. Am J Med Genet 1985;22:825.
139. Morgan I. Metronidazole treatment in pregnancy. Int J
Gynaecol Obstet 1978;15:501-502.
140. Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G.
Safety of metronidazole in pregnancy: a meta-analysis. Am J
Obstet Gynecol 1995;172:525-529.
141. Murphy A, Jones E. Use of oral metronidazole in pregnancy:
risks, benefits and practice guidelines. J Nurse Midwifery
1994;39:214-220.
142. Cregler LL, Mark H. Medical complications of cocaine abuse.
NEJM 1986;315:1495-1500.
143. Hodach RJ, Hodach AE, Fallon JE, Folts JD, Bruyere HJ,
Gilbert EF. The role of beta-adrenergic activity in the
production of cardiac and aortic arch anomalies in the chick
embryo. Teratology 1975;12:33-45.
144. Little BB. Cocaine abuse during pregnancy: maternal and fetal
implications. Obstet Gynecol 1989;73:157-160.
145. Volpe JJ. Mechanisms of disease: effect of cocaine use on the
fetus. NEJM 1992;327:399-407.
146. Frias JL, Gilbert-Barness E. Teratogenic disruptions. In:
Potters Pathology of Fetus, Infant, and Child (Gilbert-Barness
E, Ed), Mosby-Elsevier, Philadelphia, 2007, pp 155.
147. Meadow R. Anticonvulsants in pregnancy. Arch Dis Child
1991;66:62-65.
148. Speidel BD, Meadow SR. Maternal epilepsy and abnormalities
of the fetus and newborn. Lancet 1972;2:839-843.
149. Friedman JM. Effects of drugs and other chemicals on fetal
growth. Growth Genet 1992;8:1-5.

114 Annals of Clinical & Laboratory Science, vol. 40, no. 2, 2010
150. Pauli RM. Mechanisms of bone and cartilage maldevelopment
in the warfarin embryopathy. Pathol Immunopathol Res 1988;
7:107-112.
151. Brent RL, Beckman DA. Angiotensin-converting enzyme
inhibitors, an embryopathic class of drugs with unique
properties: information for clinical teratology counselors.
Teratology 1991;43:543-546.
152. Collins R, Armitage J, Parish S. Heart protection study
collaborative group. Lancet 2003;361:2005-2016.
153. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G,
Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R.
Efficacy and safety of cholesterol-lowering treatment:
prospective data-analysis of data from 90,056 participants in
14 randomized trials of statins. Lancet 2005;366:1267-1278.
154. Ming JE, Roessler E, Muenke M. Human developmental
disorders and the sonic hedgehog pathway. Mol Med Today
1998;4:343-349.
155. Murone M, Rosenthal A, de Sauvage FJ. Hedgehog signal
transduction: from flies to vertebrates. Exp Cell Res 1999;
253:25-33.
156. Incardona JP, Roelink H. The role of cholesterol in Shh
signaling and teratogen-induced holoprosencephaly. Cell Mol
Life Sci 2000;57:1709-1719.
157. Cohen MM, Shiata K. Teratogenesis of holoprosencephaly. Am
J Med Genet 2002;109:1-15.
158. Trussell J. The cost of unintended pregnancy in the United
States. Contraception 2007;75:168-170.
159. Forrest JD. Epidemiology of unintended pregnancy and
contraceptive use. Am J Obstet Gynecol 1994;170:1485-1489.
160. Irons M, Elias ER, Salen G, Tint GS, Batta AK. Defective
cholesterol biosynthesis in Smith-Lemli-Opitz syndrome.
Lancet 1993;341:1414.
161. Herman GE. Disorders of cholesterol biosynthesis: prototypic
metabolic malformation syndromes. Hum Mol Genet 2003;12:
75-88.
162. Kelley RI. Inborn errors of cholesterol biosynthesis. Adv
Pediatr 2000;47:1-52.
163. Porter FD. Human malformation syndromes due to inborn
errors of cholesterol synthesis. Curr Opin Pediatr 2003;15:607613.
164. Ghidini A, Sicherer S, Willner J. Congenital abnormalities
(VATER) in baby born to mother using lovastatin. Lancet
1992;339:1416-1417.
165. Hayes A, Gilbert A, Lopez G, Miller WA. Mevacor: a new
teratogen? Am J Hum Genet 1995;57(suppl 4):A92.
166. Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following
gestational exposure to statins. Am J Med Genet 2004;131:287298.
167. Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal
outcome of singletons and twins after assisted conception: a
systematic review of controlled studies. BMJ 2004;328:261.
168. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox
LS. Low and very low birth weight in infants conceived with
use of assisted reproductive technology. NEJM 2002;346:731737.
169. Reddy UM, Wapner RJ, Rebar RW, Tasca RJ. Infertility,
assisted reproductive technologies, and adverse pregnancy
outcomes. Obstet Gynecol 2007;109:967-977.
170. Mitchell AA. Infertility treatment: more risks and challenges.
NEJM 2002;346:769-770.
171. Schieve LA, Rasmussen SA, Reefhuis J. Risk of birth defects
among children conceived with assisted reproductive
techniques: providing an epidemiologic context to the data.
Fertil Steril 2005;84:1320-1324.
172. Sutcliff AG, Ludwig M. Outcome of assisted reproduction.
Lancet 2007;370:351-359.
173. Rufat P, Olivennes F, de Mouzon J, Dehan M, Frydman R.
Task force report on the outcome of pregnancies and children

conceived by in vitro fertilization (France: 1987-1989). Fertil

Steril 1994;61:324-330.
174. Dhont M, de Neubourg F, van der Elstand J, DeSutter P.
Perinatal outcome of pregnancies after assisted reproduction: a
case-control study. J Assist Reprod Genet 1997;14:575-580.
175. Olivennes F, Kerbrat V, Rufat P, Blanchet V, Fanchin R,
Hazout A. Follow-up of a cohort of 422 children aged 6 to 13
years conceived by in vitro fertilization. Fertil Steril 1997;67:
284-289.
176. Bergh T, Ericson A, Hillensjo T, Nygren KG, Wennerholm
UB. Deliveries and children born after in-vitro fertilization in
Sweden 1982-95: a retrospective cohort study. Lancet 1999;
354:1579-1585.
177. Van Steirteghem A, Bonduelle M, Devroey P, Liegaers I.
Follow-up of children born after ICSI. Hum Reprod Update
2002;8:111-116.
178. Ludwig M, Katalinic A. Malformation rate in fetuses and
children conceived after intracytoplasmic sperm injection
(ICSI): results of a prospective cohort study. Reprod Biomed
Online 2002;5:171-178.
179. Hansen M, Kurinczuk JJ, Bower C, Webb S. Risk of major
birth defects after the intracytoplasmic sperm injection and in
nitro fertilization. NEJM 2002;346:725-730.
180. Katalinic A, Rosch C, Ludwig M. Pregnancy course and
outcome after intracytoplasmic sperm injection: a controlled,
prospective cohort study. Fertil Steril 2004;81:1604-1616.
181. Klemetti R, Gissler M, Sevon T, Koivurova S, Ritvanen A,
Hemminki E. Children born after assisted fertilization have an
increased rate of major congenital anomalies. Fertil Steril
2005;84:1300-1307.
182. Olson CK, Keppler-Noreuil KM, Romitti PA, Budelier WT,
Ruan G, Sparks AE, Voorhis BJ. In vitro fertilization is
associated with an increase in major birth defects. Fertil Steril
2005;84:1308-1315.
183. Nygren KG, Finnstrom O, Kallen B, Olausson PO. Populationbased Swedish studies of outcomes after in vitro fertilization.
Acta Obstet Gynecol Scand 2007;86:774-782.
184. Hansen M, Bower C, Milne E, deKlerk N, Kurinczuk JJ.
Assisted reproductive technologies and the risk of birth defects:
a systemic review. Hum Reprod 2005;20:328-338.
185. Rimm AA, Katayama AC, Diaz M, Katayama KP. A metaanalysis of controlled studies comparing major malformation
rates in IVF and ICSI infants with naturally conceived
children. J Assist Reprod Genet 2004;21:437-443.
186. Lie RT, Lyngstadaas A, Orstavik KH, Bakketeig LS, Jacobsen
G, Tanbo T. Birth defects in children conceived by ICSI
compared with children conceived by other methods; a metaanalysis. Int J Epideiol 2005;34:696-701.
187. Phillips O, Simpson J. Spermicides, hormonal contraception
and congenital malformations. Adv Contracept 1999;6:141167.
188. Feldkamp ML, Meyer RE, Krikov S, Botto LD. Acetaminophen
use in pregnancy and risk of birth defects: findings from the
National Birth Defects Prevention Study. Obstet Gynecol
2010;115:109-115.
189. Shah PS, Ohlsson A. Determinants of low birth weight and
preterm births. CMAJ 2009;180:99-108.
190. Shepard TH. Human teratogens: how can we sort them out?
Ann NY Acad Sci 1986;477:105-115.
191. Wattendorf DJ, Muenke M. Fetal alcohol spectrum disorders.
Am Fam Physician 2005;72:279-282.
192. Kawashima H, Ohno I, Ueno Ym, Nakaya S, Kato E.
Syndrome of microtia and aortic anomalies resembling
isotretinoin embryopathy. J Pediatr 1987;111:738-740.
193. Knobloch J, Shaughnessy JD Jr, Ruther U. Thalidomide
induces limb deformities by perturbing the Bmp/Dkk1/Wnt
signaling pathway. FASEB 2007;21:1410-1421.