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7/29/2019 HPE Nongenetic Risk Factors
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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 154C:7385 (2010)
A R T I C L E
Non-Genetic Risk Factors for HoloprosencephalyCANDICE Y. JOHNSON AND SONJA A. RASMUSSEN*
Holoprosencephaly (HPE) is a congenital defect of the brain characterized by incomplete cleavage of theembryonic forebrain into left and right hemispheres. Although a substantial proportion of cases of HPE can beattributed to genetic abnormalities, the etiology in many cases remains unknown, with non-genetic risk factorsbelieved to be important contributors. Due to the low birth prevalence of this defect, it has proven difficultto conduct studies of sufficient size to identify risk factors with certainty. This article provides a summary of non-genetic risk factors for HPE that have been investigated in case reports and case series, animal studies, andepidemiologic studies, including maternal illnesses, therapeutic and non-therapeutic exposures, nutritionalfactors, and sociodemographic factors. The article also highlights challenges in study design andfurther areas forresearch to better understand the etiology of HPE. Published 2010 Wiley-Liss, Inc.{
KEY WORDS: holoprosencephaly; risk factors; teratogens; diabetes; salicylates; cholesterol
How to cite this article: Johnson CY, Rasmussen SA. 2010. Non-genetic risk factors forholoprosencephaly. Am J Med Genet Part C Semin Med Genet 154C:7385.
INTRODUCTION
Holoprosencephaly (HPE) is a congen-
ital defect of the brain characterized by
incomplete cleavage of the embryonic
forebraininto left andr ight hemispheres.
Affected persons often have accompany-
ing facial dysmorphology, ranging
from severe (e.g., cyclopia) to more mild
(e.g., mild hypotelorism or a single
central maxillary incisor) abnormalities,
although 10 20% of affected persons
have no facial abnormalities [Cohen,
1989a]. The prevalence at birth of
this condition is about 1 per 10,000
live births [Croen et al., 1996;
The prevalence at birth of this
condition is about 1 per
10,000 live births.
Rasmussen et al., 1996]. However, the
defect appears to occur much more
frequently earlier in pregnancy, with an
estimated rate of 4 per 1,000 conceptuses
[Matsunaga and Shiota, 1977], whichsuggests a high rate of fetal loss.
However, the defect
appears to occur much
more frequently earlier in
pregnancy, with an
estimated rate of 4 per
1,000 conceptuses, which
suggests a high rate of
fetal loss.
In most cases, the causes of HPE
are unknown. Genetic causes include
chromosome abnormalities and single
gene disorders [Munke et al., 1988;Cohen, 2006; Roessler and Muenke,
2010]. Among persons with HPE, about
2550% have chromosome abnormal-
ities and about 1825% have a mutation
in a single gene that causes syndromic
HPE [Muenke and Gropman, 2008].
The most commonly mutated gene in
persons with HPE is the sonic hedgehog
(SHH) gene, which codes for the sonic
hedgehog protein, a secreted protein
that plays a critical role in patterning of
the ventral neural tube, the anterior
posterior limb axis, and ventral somites
[Muenke and Gropman, 2008]. In
recent years, much progress has been
made in understanding genetic factors
involved in the etiology of HPE
[Bendavid et al., 2009; Bendavid et al.,
2010]. However, even among families in
whom a single gene has been shown
to increase the risk for HPE, the
phenotype varies significantly among
family members who carry the gene,
The findings and conclusions in this reportare those of the authors and do notnecessarily represent the official position of
the Centers for Disease Control and Preven-tion.
Candice Y. Johnson, M.Sc., is a doctoralstudent in the Department of Epidemiologyat Emory University and Guest Researcher atthe National Center on Birth Defects andDevelopmental Disabilities at the Centers forDisease Control and Prevention in Atlanta.She is interested in the epidemiology of birthdefects and the contributions of chronicillness during pregnancy to birth defectetiology.
Sonja A. Rasmussen, M.D., M.S., is apediatrician and clinical geneticist and cur-rently serves as Senior Scientist at theNational Center on Birth Defects andDevelopmental Disabilities at the Centersfor Disease Control and Prevention inAtlanta. Her research interests include theidentification of risk factors for birth defects,morbidity and mortality associated with birthdefects and genetic conditions, and theimpact of infections on the pregnant womanand her embryo or fetus.
*Correspondence to: Sonja A. Rasmussen,M.D., M.S., 1600 Clifton Road, MS E-86,CDC, Atlanta, GA 30333.E-mail: [email protected]
DOI 10.1002/ajmg.c.30242Publishedonline 26 January 2010 in Wiley
InterScience (www.interscience.wiley.com)
Published 2010 Wiley-Liss, Inc.{This article is a US Government work and, as such, is inthe public domain in the United States of America.
7/29/2019 HPE Nongenetic Risk Factors
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including some family members with a
normal brain [Roessler et al., 1996;
Solomon et al., 2010], a finding that
supports a role for other genetic and
non-genetic factors [Ming and Muenke,
2002].
Evidence that supports the involve-
ment of certain non-genetic risk factors
is available from several sources, includ-
ing case reports/series, experimental
studies using animal models, and epi-
demiologic studies. Each of these has an
important role to play in better under-
standing non-genetic risk factors for
HPE, but each has its own strengths
and limitations [Rasmussen et al., 2007].
Case reports can alert investigators to
potential adverse effects of a particular
exposure so that the exposure can be
further investigated in an epidemiologicstudy or experimental animal model.
However, in an individual case report or
case series, it is difficult to know if the
adverse effects are caused by the partic-
ular exposure or if the observed relation
is coincidental. Studies using an animal
model allow experimental manipulation
of the exposure while other factors (such
as genetic background) are held con-
stant; however, animal studies may not
always predict results in humans [Scialli
et al., 2004]. Epidemiologic studies of
HPE are challenging, given its low birth
prevalence, and only a few studies have
focused on identifying risk factors for
this defect. These studies have been
retrospective and have utilized a case
control study design. The studies are
often dependent on maternal recall of
exposures, which can be incomplete and
possibly biased because of knowledge of
the outcome (i.e., recall bias) [Kallen,
2005]. In addition, it may sometimes be
challenging to determine if a particular
exposure is the risk factor or whetheranother (confounding) factor may be
responsible for the observed increased
risk. In this manuscript, we will review
theevidence forcertain non-genetic risk
factors, includingdata from case reports/
series, animal models, and epidemio-
logic studies. In addition, we will discuss
key issues for consideration in future
studies in order to improve available
information on non-genetic risk factors
for HPE.
EPIDEMIOLOGIC STUDIESOF HOLOPROSENCEPHALY
We are aware of four casecontrol
studies that have focused on a spectrum
of non-genetic risk factors for HPE.
Because these studies have been used to
address a large number of risk factors,and thus will be referred to repeatedly
below, information about them is briefly
summarized here. In addition to these
studies, a few other epidemiologic
studies of specific risk factors (e.g.,
diabetes and obesity) have also some-
times included HPE as one of many
defects studied.
Human Embryo Center for
Teratological Studies
(Kyoto Embryo Study)
Between 1962 and 1974, a total of
36,380 conceptuses (resulting in 3,411
undamaged embryos) were collected by
Kyoto University in Japan from physi-
cians performing pregnancy termina-
tions [Matsunaga and Shiota, 1977].
Among the 3,411 embryos, 150 with
HPE were identified. A matched case
control study was conducted where
two non-cases were selected from the
undamaged embryos as controls and
matched to each HPE case on parityand month of last menstrual period.
Karyotyping wasnot performed, and the
proportion of cases with chromosomal
abnormalities is unknown. Physicians
performing pregnancy terminations
were asked to collect information on
the reproductive and exposure histories
of the mothers.
California Birth Defects
Monitoring Program (CBDMP)Forty-eight cases of non-syndromic
HPE (live births, fetal deaths
20 weeks gestation or pregnancy
terminations) were identified between
1993 and 1996 using data from the
CBDMP, a birth defects surveillance
system that uses active case ascertain-
ment methods that include review of
medical records at hospitals and genetics
clinics in 11 California counties [Croen
et al., 2000]. Infants with a chromosome
abnormality were excluded. Controls
were liveborn infants without birth
defects randomly selected from births
in the hospitals in the area. Motherswere
interviewed by telephone. Another epi-
demiologic study of HPE using data
from the CBDMP focused on cases
identified between 1983 and 1988 and
included 53 non-syndromic cases
[Croen et al., 1996].
Latin American Study of
Congenital
Malformations (ECLAMC)
Between 1967 and2000, 281livebornor
stillborn (birthweight 500 g) infants
with non-syndromic HPE were identi-
fied through the ECLAMC birth defects
surveillance system, a hospital-basedsystem that includes births in all South
American countries (except Guyanas)
[Orioli and Castilla, 2007]. Cases with
chromosome abnormalities or other
syndromes were excluded. Controls
were selected as the next non-mal-
formed child born in the same hospital
as the case, matched on sex. Mothers
were interviewed by the pediatrician
shortly after the birth.
National Birth Defects PreventionStudy (NBDPS)
The NBDPS is an ongoing, population-
based casecontrol study that ascertains
liveborn infants, fetal deaths (20
weeks gestation), and pregnancy termi-
nations with major birth defects through
birth defect surveillance systems in
10 regions of the United States [Yoon
et al., 2001; Miller et al., 2010]. Cases
with recognized single gene disorders
and chromosome abnormalities are
excluded [Rasmussen et al., 2003].Controls are liveborn infants without
birth defects selected from study catch-
ment areas. Mothers of case and control
infants are interviewed up to 2 years
after delivery. From 1997 through
2004, 74 cases of non-syndromic HPE
were identified [Miller et al., 2010].
Mothers with pre-existing diabetes were
excluded from the analysis of HPE
risk factors. Analyses were adjusted
for potential confounders including
74 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
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maternal age, education, race/ethnicity,
number of previous pregnancies, and
periconceptional use of aspirin and folic
acid.
MATERNAL ILLNESSES
Diabetes
Maternal diabetes is a well-recognized
risk factor for birth defects [Becerra
et al., 1990; Correa et al., 2008] and is
one of the most extensively studied
risk factors for HPE. HPE is estimated
to occur in 1% of births to
diabetic women [Barr et al., 1983].
Maternal diabetes is awell-recognized risk factor for
birth defects and is one of the
most extensively studied risk
factors for HPE. HPE is
estimated to occur in 1% of
births to diabetic women.
Surveillance data from the New York
State Congenital Malformations Regis-
try and data from a case series collected
by the Carter Centers for Brain
Research have noted the prevalence of
pre-existing diabetes among mothers of
children with HPE to be 6% and 9%,
respectively [Olsen et al., 1997; Sta-
shinko et al., 2004].
Results from a mouse model are
consistent with the observations from
these case series. In one study, pregnant
mice were given streptozotocin intra-
peritoneally on gestational day 2 to
induce diabetes, and the rate of severalcongenital anomalies (including HPE)
among offspring was observed. Diabetic
mice had an increased risk of delivering
offspring with HPE; this risk was
reduced among mice treated with insu-
lin. To observe the interaction between
diabetes and ethanol, the authors also
exposed the pregnant diabetic mice to
ethanol, and a decrease in the rate of
HPE was observed. This led the authors
to hypothesize that ethanol exposure
might result in increased pregnancy
loss of severely malformed embryos
[Padmanabhan and Shafiullah, 2004].
Four epidemiologic studies of pre-
existing diabetes [Croen et al., 2000;
Anderson et al., 2005; Orioli and
Castilla, 2007; Correa et al., 2008] and
three of four studies of gestational
diabetes [Martinez-Frias et al., 1998;
Croen et al., 2000; Anderson et al.,
2005; Correa et al., 2008] have observed
the prevalence of diabetes among moth-
ers of infants with HPE to be at least
twice as high as among control mothers
(Table I). In the study using CBDMP
data, the increased risk associated
with ever having diabetes was mainly
observed among mothers who reported
taking insulin to treat their diabetes
(odds ratio [OR] 10.2, 95% confidenceinterval [CI] 1.939.4 for mother taking
insulin, OR 0.8, 95% CI 0.22.8 for
those not taking insulin) [Croen et al.,
2000]. A study using data from the
NBDPS noted that the association
between HPE and pregestational diabe-
tes to be stronger when HPE occurred
with other unrelated birth defects (OR
16.2; 95% CI 1.6163.9), compared to
when HPE occurred as an isolated defect
(OR 6.0, 95% CI 0.749.8) [Correa
et al., 2008]. However, CIs were wide
because the number of cases with HPE
was small.
Despite the fact that diabetes is a
well-recognized risk factor for HPE and
other birth defects, its mechanism of
action as a teratogen is not well under-
stood. Hyperglycemia, oxidative stress,
and other metabolic disturbances
have been investigated as potential
mechanisms for diabetic teratogenesis
[Kousseff, 1999; Ornoy, 2007]. Better
understanding of the mechanism
could lead to improved therapeuticoptions for pregnant women with dia-
betes to reduce their risk for birth
defects; although reduced risks of
birth defects appear to be achievable
through better preconceptional care and
glycemic control of diabetes during
pregnancy, diabetic women continue
to have an increased risk for having
children with birth defects [Suhonen
et al., 2000; Ray et al., 2001; Platt et al.,
2002].
Infections
A variety of infections have beenreported
among mothers of infants with HPE [see
Cohen and Shiota, 2002 for a review].
Congenital cytomegalovirus (CMV)
infection has been described as a possible
cause of HPE in several case reports andcase series [Barr et al., 1983; Byrne et al.,
1987; Rasmussen et al., 1996; Kilic and
Yazici, 2005]. However, documentation
of congenital CMV was incomplete in
several of these cases. Other infections
noted in mothers who have had a child
with HPEincludeone case where rubella
was suspected in the mother, who had a
rash and high fever during the first weeks
of fetal development [Khudr and Olding,
1973], and two infants with HPE and
trisomy 13 who showed evidence of
herpes simplex virus and of congenital
syphilis [Rasmussen et al., 1996]. As with
CMV, documentation of these congenital
infections was incomplete.
Three epidemiologic studies have
investigated risk of HPE among mothers
with respiratory illnesses, respiratory
infections, or influenza during preg-
nancy. While the study from ECLAMC
identified an increased risk among
mothers with influenza (OR 2.8, 95%
CI 1.07.9) and an increased risk among
mothers with respiratory illness wasreported using data from CBDMP (OR
2.0, 95% CI 0.94.5) [Croen et al., 2000;
Orioli and Castilla, 2007], a subsequent
study from NBDPS found no association
with respiratory infection or with fever
during pregnancy [Miller et al., 2010].
Studies using data from NBDPS
and CBDMP have each suggested an
increased risk of HPE among mothers
with sexually transmitted infections.
NBDPS investigators reported an OR
of 2.1 (95% CI 0.95.1) for any sexuallytransmitted infection [Miller et al.,
2010], while CBDMP researchers
reported a prevalence of genital herpes
or chlamydia of 4/48 among HPE case
mothers and 2/107 among control
mothers [Croen et al., 2000].
High Blood Pressure
Associations between HPE and mater-
nal high blood pressure have been
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 75
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TABLEI.EpidemiologicStudiesofHoloprosencephalyandPre-ExistingandGestationalDiabetes
Study
Stud
ydesign
Sourceofcaseandexposureinformation
Numberofcases
OR(95%CI)
Comments
Pre-existingdiabetes
Correaetal.[2008]
Population-based
case
control
study
NationalBirthDefectsPreventionStudy,
19972003,throughbirthdefects
surveillancesystemsandmaternalinterview
Isolated:42,
multiple:19
Isolated:6.00(0.7249.76),
multiple:16.16
(1.59163.88)
Excluded
recognized
syndrom
iccases,adjustedfor
age,rac
e/ethnicity,prenatal
care,bo
dymassindex,study
center,householdincome
OrioliandCastilla
[2007]
Hospital-based
case
control
study
LatinAmericanCollaborativeStudyon
CongenitalMalformation
s,19672000,
throughhospital-basedre
gistryandmaternal
interview
Allcases:281,
isolated:182
Allcases:3.5(0.916.2),
isolated:1.9(0.49.7)
Matchedonsex,location,
andtim
eofbirth,excluding
chromo
somalabnormalities
Andersonetal.[2005]
Population-based
case
control
study
TexasBirthDefectsMonito
ringProgram,
19972001,throughbirthdefects
surveillanceandmaternalinterview
57
46.6(9.5230)
Adjustedforethnicity,body
massindex,age,education,
smoking,alcoholuse,folic
aciduse
Croenetal.[2000]
Population-based-
based
case
contro
lstudy
CaliforniaBirthDefectsMonitoringProgram,
19931996throughmed
icalrecordreview
andmaternalinterview
48
All:2.0(0.85.2),taking
medication:10.2
(1.939.4),no
medication:0.8(0.22.8)
Excluded
caseswith
chromo
somalabnormalities
Gestationaldiabetes
Correaetal.[2008]
Population-based
case
control
study
NationalBirthDefectsPreventionStudy,
19972003,throughbirthdefects
surveillancesystemsandmaternalinterview
42
0.76(0.105.75)
Isolatedcases,excluded
recognizedsyndromiccases,
adjusted
forage,race/
ethnicit
y,prenatalcare,body
massindex,studycenter,
householdincome
Andersonetal.[2005]
Population-based
case
control
study
TexasBirthDefectsMonito
ringProgram,
19972001,throughbirthdefects
surveillanceandmaternalinterview
47
2.9(1.08.4)
Adjustedforethnicity,body
massindex,age,education,
smoking,alcoholuse,folic
aciduse
Croenetal.[2000]
Population-based
case
control
study
CaliforniaBirthDefectsMonitoringProgram,
19931996throughmed
icalrecordreview
andmaternalinterview
48
2.0(0.75.3)
Excluded
caseswith
chromo
somalabnormalities
Martinez-Friasetal.
[1998]
Hospital-based
case
control
study
LatinAmericanCollaborativeStudyon
CongenitalMalformation
s,19761995,
throughhospital-basedre
gistryandmaternal
interview
109
3.27(1.297.77)
Matchedonsex,location,
andtim
eofbirth
OR,oddsratio;CI,confidenceinte
rval.
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investigated in epidemiologic studies
using data from the NBDPS and
CBDMP, neither of which identified
an association [Croen et al., 2000; Miller
et al., 2010].
Anemia
An increased risk of HPE to mothers
with anemia was reported using data
from the CBDMP (OR 3.4, 95% CI
1.011.8) [Croen et al., 2000], although
a subsequent study using data from
ECLAMC found no such association
(OR 0.9, 95% CI 0.15.9) [Orioli and
Castilla, 2007] The ECLAMCstudyalso
examined HPE and use of iron supple-
ments during pregnancy, and no associ-
ation was seen [Orioli and Castilla,
2007].
Other Maternal Illnesses
and Injuries
Researchers used CBDMP data to
investigate associations between HPE
and skin problems, allergies, urinary
tract infection, and injury. No associa-
tions were identified [Croen et al.,
2000]. A single case of lobar HPE has
been reported born to a mother with
phenylketonuria who had high phenyl-
alanine levels throughout the first 8
10 weeks of pregnancy [Keller et al.,
2000].
MATERNAL THERAPEUTICEXPOSURES
Salicylates, Including Aspirin
Three case reports of children with HPE
among mothers taking large doses of
aspirin during early pregnancy have
been described, and two additional cases
have been described born to mothers
taking sodium salicylate and sulfasalazine
(Table II) [Khudr and Olding, 1973;
Benawra et al., 1980; Agapitos et al.,
1986; Koyama et al., 1996; Sezgin et al.,
2002]. In these cases, the mothers had
additional potential risk factors such as
parental consanguinity [Sezgin et al.,2002], smoking [Benawra et al., 1980],
and useof other medications [Khudr and
Olding, 1973; Koyama et al., 1996]
(Table II).
Salicylate use has been investigated
in three epidemiologic studies with
inconsistent results. Findings from the
CBDMP and NBDPS showed that
mothers who have had a child with
HPE were over twice as likely to have
taken aspirin or salicylates during early
pregnancy (Table III) [Croen et al.,
2000; Miller et al., 2010], whereas the
study from ECLAMC showed no asso-
ciation [Orioli and Castilla, 2007].
Findings from the CBDMP
and NBDPS showed that
mothers who have had a childwith HPE were over twice as
likely to have taken aspirin or
salicylates during early
pregnancy (Table III), whereas
the study from ECLAMC
showed no association.
As with all studies showing a relation
between use of a medication and birthdefects, it is important to consider
whether the observed association
between salicylates and HPE observed
in some studies is related to the medi-
cation itself or to the indication for
which the medication was used.
Other Analgesics
One case report has described HPE in an
infant born to a mother who took
acetaminophen in her second trimester
of pregnancy, but the mother had also
TABLE II. Case Reports of Holoprosencephaly Where Maternal Salicylate Use Was Reported
Study Maternal characteristics Salicylate exposure Diagnosis
Other reported exposures
or risk factors
Sezgin et al. [2002] 38-year-old with 2
healthy children
Aspirin 500g twice daily for
1 week during first trimester
Cyclopia, astomia, agnathia
(46, XX)
Consanguinity (parents first
cousins)
Agapitos et al. [1986] 41-year-old G2P1 Aspirin up to 4 g/day during
first trimester
Cyclopia, proboscis, multiple
other birth defects, no
chromosomal studies available
Advanced age of mother (41)
and father (56)
Benawra et al. [1980] 20-year-old G2P0 Aspirin 34.5 g/day during firsttrimester Cyclopia, polypoid proboscis,multiple other birth defects,
normal chromosomes
Acetaminophen 610 tablets/day during second trimester,
smoking 2 packs/day
throughout pregnancy
Khudr and
Olding [1973]
22-year-old G2P1 Sodium salicylate 3.6 g/day for
7 days during first trimester
Cyclopia, proboscis,
low-set ears
Viremia during week 3 of fetal
development, treatment with
high-dose penicillin G
procaine, cortisone
Koyama et al. [1996] 32-year-old G0P0 with
Crohns disease
Sulfasalazine 3 g/day before and
during pregnancy
Semilobar holoprosencephaly
(46, XX)
Ferrostatin (Fe) 100 mg/day,
kernac (plant extract)
240 mg/day, protective drug
for gastritis or gastric ulcer,
artificial insemination
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taken aspirin in the first trimester
and smoked throughout pregnancy
[Benawra et al., 1980]. Results from
the NBDPS found a weak association
between acetaminophen use during
pregnancy and HPE (OR 1.5, 95% CI
0.92.5), but no association with
ibuprofen use [Miller et al., 2010].
Antiepileptic Medications
Kotzot et al. [1993] reported an infant
with HPE whose mother was treated
with phenytoin and primidone. In
addition to HPE, the infant had features
of fetal hydantoin syndrome, including
hypertelorism, midfacial hypoplasia, and
hypoplastic distal phalanges and nails of
the fingers and toes [Kotzot et al., 1993].
To address this possible association, a
review of infants born at Boston area
hospitals who were exposed to antiepi-
leptic medications was performed, and
one case of HPE was recorded among
112 antiepileptic-exposed pregnancies.
However, in a subsequent analysis of 453
antiepileptic-exposed pregnancies, no
cases with HPE were identified [Holmes
and Harvey, 1994]. Rosa subsequently
reviewed reports of adverse events to the
U.S. Food and Drug Administration
(FDA). He identified seven cases ofsuspected HPE including the case
reported by Kotzot et al. [1993]
among mothers taking antiepileptic
drugs during pregnancy, including car-
bamazepine, valproate, phenytoin, and
primidone (used alone or in combina-
tion) [Rosa, 1995]. The proportion of
infants with HPE was higher among
antiepileptic users than in mothers
exposed to medications other than
anticonvulsants.
Retinoic Acid
In a series of 154 mothers with prenatal
exposure to isotretinoin, a retinoic
acid derivative used to treat severe acne,
21 had a child with a birth defect, one of
whom had HPE [Lammer et al., 1985].
Between 1969 and 1993, 25 cases of
birth defects delivered following first-
trimester exposure to topical tretinoin
(all-trans-retinoic acid), a medication
TABLEIII.EpidemiologicStudiesofHoloprosencephalyandMaternalSalicy
lateUseinEarlyPregnancy
Study
Studydesign
Sourceofcaseandexposure
information
Exposure
Numberofcases
OR(95%CI)
C
omments
Milleretal.
[2010]
Population-based
casecontrol
study
NBDPS,19972004,
throughbirthdefects
surveillanceandmaternal
interview
Aspirinduring
periconceptionalperiod
Allcases:72,
isolated:50
Allcases:3.4(1.66.9),
isolated:2.0(0.75.5)
Adjustedfor
age,race/ethnicity,
education,
previous
pregnancie
s,folicacid,or
multivitam
inuse;excluded
knownsyn
dromiccasesand
thosewhosemothershad
pre-existingdiabetes
Orioliand
Castilla[2007]
Hospital-based
casecontrol
study
ECLAMC,19672000,
throughhospital-based
birthdefectsregistryand
maternalinterview
Aspirinorsalicylates
Allcases:105,
isolated:65
Allcases:0.6(0.31.1),
isolated:0.7(0.31.6)
Matchedon
sex,location,
andtimeo
fbirth,excluded
caseswith
chromosomal
abnormalities
Croenetal.[2000]Population-based
casecontrol
study
CBDMP,19931996,
throughmedicalrecord
reviewandmaternal
interview
Aspirinorsalicylatesduring
periconceptionalperiod
48
2.5(0.87.9)
Excludedcaseswithchromosomal
abnormalities
OR,oddsratio;CI,confidenceinterval.
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used for treatment of acne and of
aging and sun-damaged skin, were
reported to the FDA. Five of these
25 had HPE, compared to 19 cases of
HPE occurring in the 8,700 reports
where the exposure was notretinoicacid
[Rosa, 1994].
Animal models also support a pos-
sible relation between prenatal exposure
to retinoic acid and HPE. Oral admin-
istration of all-trans-retinoic acid in
early pregnancy (gestational day 7) to
inbred mice has produced a range of
craniofacial phenotypes consistent with
HPE [Kalter, 1992; Sulik et al., 1995;
Lipinski et al., 2010].
Antibiotics
Case reports have described use ofantibiotics among mothers who have
had a child with HPE, including
penicillin procaine [Khudr and Olding,
1973], ampicillin [Garzozi and Barkay,
1985], and trimethoprimsulfamethox-
azole [Ronen, 1992]. In the Kyoto
embryo study, 0.8% of case mothers
and 1.2% of control mothers reported
using antibiotics during pregnancy
[Matsunaga and Shiota, 1977].
Hormones
Case reports have described the use
of several different hormones during
early pregnancy among mothers who
have had a child with HPE, including
allyloestrenol and dihydrogesterone
[Stabile et al., 1985], oral contraceptives
[Ronen and Andrews, 1991], and
cortisone [Khudr and Olding, 1973],
although most motherstaking these hor-
mones were taking other medications.
Use of sex hormones was associated
with an increased risk of HPE in thestudy using data from ECLAMC (OR
3.7, 95% CI 1.311.0) [Orioli and
Castilla, 2007]. An elevated risk was also
seen in NBOPS among mothers using
progesterone before or during the first
trimester of programming, although the
insert was not statistically significant
(OR 2.3, 75%, CI 0.77.3) [Miller et
al., 2010]. In the Kyoto embryo study,
23% of case mothers had taken proges-
tagens during early pregnancy compared
to 15% of control mothers [Matsunaga
and Shiota, 1977], while investigators
from CBDMP found no association
between HPE and use of birth control
pills [Croen et al., 2000].
Alkaloids Including Cyclopamineand Jervine
In sheep and several other animal
species, consumption of the corn lily
Veratum californicum in early pregnancy
was associated with malformations
characteristic of HPE in the offspring
[Coventry et al., 1998; Hovhannisyan
et al., 2009; Welch et al., 2009].
In sheep and several other
animal species, consumption
of the corn lily Veratum
californicum in early pregnancy
was associated with
malformations characteristic of
HPE in the offspring.
Cyclopamine and jervine have since
been identified as the primary terato-
genic components of the corn lily plant.These alkaloids are structural analogs of
cholesterol and act by inhibiting hedge-
hog signaling [Hovhannisyan et al.,
2009]. These components and related
compounds are under investigation as
therapeutic agents for treatment of
psoriasis and several malignancies [Tas
and Avci, 2004; Feldmann et al., 2008;
Garber, 2008; Von Hoff et al., 2009]. We
are not aware of any reports of human
exposures to these alkaloids during
pregnancy.
Statins
Several pieces of evidence have led to
concerns that maternal exposure to
statins, which are used to lower choles-
terol levels, might raise the risk for HPE.
These include the fact that some genetic
conditions with defects in cholesterol
metabolism include HPE as a feature in
about 5% of cases [Kelley et al., 1996;
Incardona and Roelink, 2000], inhib-
ition of cholesterol biosynthesis has
previously been shown to result in
HPE in animal studies [Kolf-Clauw
et al., 1997; Roux et al., 2000], and
cholesterol is required for hedgehog
signaling, a pathway which is critical in
embryonic development and has
been implicated in HPE [Roessler and
Muenke, 2003; Edison and Muenke,
2004b]. One report of 52 statin-exposed
pregnancies reported to the FDA iden-
tified 20 mothers who had a child with a
major malformation, including 1 with
HPE [Edison and Muenke, 2004a,b,
2005]. However, among 22 mothers
participating in the NBDPS and the
Slone Epidemiology Center Birth
Defects Study who were exposed to
statins during pregnancy and had a child
with a major birth defect, none had aninfant with HPE [Petersen et al., 2008].
Analyses using a casecontrol design
have not been possible because of the
low frequency of exposure to statins
during pregnancy.
Other Medications
Case reports and case series have
described a wide variety of medication
use during pregnancy among mothers
who have had a child with HPE,
including methotrexate (used for cancertreatment and as an abortifacient) [Seid-
ahmed et al., 2006], tranexamic acid
(used for the treatment of excessive
bleeding) [Garzozi and Barkay, 1985],
chlordiazepoxide (a benzodiazepine
derivative used for the treatment of
anxiety) [Ronen and Andrews, 1991],
imipramine (a tricyclic antidepressant)
[Ronen and Andrews, 1991], lithium
(used in the treatment of bipolar
disorder) [Rasmussen et al., 1996], and
dimenhydrinate (an over-the-countermedication used to treat nausea and
motion sickness) [Ronen, 1992]. A
higher prevalence of medication use
overall among case mothers compared
to control mothers was observed in the
Kyoto embryo study [Matsunaga and
Shiota, 1977].
Fertility Treatments
Use of artificial insemination has been
reported in a case of HPE, although the
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mother had other potential risk factors
such as use of salicylates and other
medications during pregnancy [Koyama
et al., 1996]. Data from the NBDPS
suggest an increased risk of HPE among
mothers who have undergone assisted
reproductive technologies (OR 4.2,
95% CI 1.313.7), but not for fertility
treatments overall (OR 0.9, 95% CI
0.32.9) [Miller et al., 2010].
Medical Exposures
No association between HPE and
X-rays or scans during pregnancy was
observed by NBDPS or CBDMP inves-
tigators [Croen et al., 2000; Miller et al.,
2010]. Data from CBDMP were also
used to investigate whether HPE was
associated with surgery during preg-nancy, and no association was seen
[Croen et al., 2000].
MATERNALNON-THERAPEUTICEXPOSURES
Alcohol
Several case reports have implicated
heavy alcohol consumption during the
first trimester of pregnancy as a cause of
HPE, although many of the reported
mothers had other potential risk factors
such as smoking and medication use
[Bonnemann and Meinecke, 1990;
Ronen and Andrews, 1991; Coulter
et al., 1993; Rasmussen et al., 1996].
Animal studies have supported a
role for maternal alcohol exposure in the
etiology of HPE. Acute maternal etha-
nol exposure at an early stage (gastrula-
tion) in embryonic development in mice
has been shown to induce a spectrum of
facial abnormalities consistent with HPE[Sulik and Johnston, 1982; Webster
et al., 1983]. In a study of weekly
Animal studies have supported
a role for maternal alcohol
exposure in the etiology of
HPE. Acute maternal ethanol
exposure at an early stage
(gastrulation) in embryonic
development in mice has been
shown to induce a spectrum of
facial abnormalities consistent
with HPE.
administration of ethanol throughout
gestation to pregnant pigtail macaques,
HPE was observed in a single fetus
[Siebert et al., 1991]. Brief ethanol
exposure of zebrafish during early gas-
trulation has been shown to induce
cyclopia [Blader and Strahle, 1998].
Animal models have also been used to
provide insight into the mechanism by
which alcohol produces these abnor-
malities in animals. These studies suggestthat ethanol exposure results in pertur-
bation of expression of certain devel-
opmental genes at a critical period in
development [Blader and Strahle, 1998;
Higashiyama et al., 2007].
However, results of epidemiologic
studies of maternal alcohol use during
pregnancy have been inconsistent. An
elevated risk (OR 2.0, 95% CI 0.94.5)
was seen inthe study using CBDMP data
[Croen et al., 2000], but researchers
using data from NBDPS and the
Kyoto embryo study found no associa-
tion between alcohol use and HPE
[Matsunaga and Shiota, 1977; Miller
et al., 2010]. Using data from CBDMP,
investigators noted an increased risk of
HPE when mothers consumed alcohol
and also smoked during pregnancy (OR
5.4, 95% CI 1.420.0) [Croen et al.,
2000].
Smoking
Several case reports have describedheavy smoking during pregnancy
among mothers who had children with
HPE, although most mothers had other
potential risk factors such as alcohol
intake and medication use [Benawra
et al., 1980; Burck et al., 1982; Ronen
and Andrews, 1991]. Three epidemio-
logic studies have investigated the role of
smoking as a potential r isk factor for
HPE, with conflicting results. CBDMP
researchers found a fourfold increased
risk (OR 4.1, 95% CI 1.412.0)
[Croen et al., 2000], whereas investiga-
tors from the NBDPS and the Kyoto
embryo study saw no association
[Matsunaga and Shiota, 1977; Miller
et al., 2010].
Illicit Drugs
Among mothers of infants with HPE
identified through the New York State
Congenital Malformations Registry,
medical records indicated that 3 of 82
used cocaine or marijuana during preg-
nancy [Olsen et al., 1997]. Maternal
marijuana use has been described in
a case report of HPE, although this
mother had also consumed alcohol
heavily during pregnancy [Coulter
et al., 1993]. No association between
HPE and maternal illicit drug use has
been seen in epidemiologic studies using
data from NBPDS and CBDMP [Croen
et al., 2000; Miller et al., 2010].
NUTRITIONAL FACTORS
Body Mass Index
Three studies have investigated associa-
tions between body mass index (BMI)
and HPE. Increased risks were observed
in studies using data from CBDMP (OR
1.5, 95% CI 0.64.0 for BMI >29 kg/
m2 vs. BMI 29 kg/m2) and from the
Texas Birth Defects Registry (OR 1.4,
95% CI 0.53.8 for BMI 30.0 kg/m2
vs. BMI 18.524.9kg/m2, adjusted for
ethnicity, age, education, smoking, alco-
hol use, and folic acid use and excluding
mothers with pre-existing diabetes),
although CIs were wide and included
the null value [Croen et al., 2000;
Anderson et al., 2005]. The study from
NBDPS, which also excluded women
with diabetes from the analysis, found noassociation between maternal pre-preg-
nancy obesity and HPE (OR 0.8, 95%
CI 0.41.6 for BMI 30.0 kg/m2 vs.
BMI 18.524.9 kg/m2, adjusted for
age, race/ethnicity, education, previous
pregnancies, folic acid use, and aspirin
use) [Miller et al., 2010]. The
Texas study also investigated interactions
between gestational diabetes and obesity
and observed that obesity alone
(BMI 30.0kg/m2 compared to BMI
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[Matsunaga and Shiota, 1977; Croen
et al., 2000].
Gravidity
Increased risk among mothers with high
gravidity has been observed by CBDMP
(OR 2.1, 95% CI 0.76.4 for gravidity 4vs. 1) and ECLAMC (OR 1.71, 95% CI
0.943.10 for gravidity 4 or more vs.
3 or less) investigators [Croen et al.,
2000; Orioli and Castilla, 2007]. Based
on data from NBDPS, no statistically
significant association was observed
between gravidity and HPE, although
risk tended to increase with increasing
gravidity [Miller et al., 2010].
Previous Pregnancy Loss
No association was observed betweenHPE and previous pregnancy loss in
epidemiologic studies from CBDMP,
ECLAMC, and NBDPS [Croen et al.,
2000; Orioli and Castilla, 2007; Miller
et al., 2010]. The Kyoto embryo study
observed more miscarriages among case
mothers compared to control mothers
(29.5% vs. 21.0%), although the differ-
ence was not statistically significant
[Matsunaga and Shiota, 1977].
Pregnancy Intention
NBDPS investigators identified an
increased risk for mothers whose pre-
gnancies were unintended compared to
those that were intended (OR 1.9, 95%
CI 1.03.6), but not for mothers whose
pregnancies were mistimed [Milleret al.,
2010].
Season of Conception
Month of conception of HPE cases
appeared to peak in March and has a
low in September in the Kyoto embryostudy, although this finding was not
statistically significant [Matsunaga and
Shiota, 1977].
SOCIODEMOGRAPHICFACTORS
Age
Maternal age has been inconsistently
associated with HPE, with some studies
finding lower risks among young
mothers and higher risks among older
mothers [Kallen et al., 1992; Orioli and
Castilla, 2007], others finding increased
risk among both younger and older
mothers [Rasmussen et al., 1996; For-
rester and Merz, 2000], and other studies
finding no association with age [Matsu-
naga and Shiota, 1977; Croen et al.,
2000; Miller et al., 2010]. Some of this
variation may be due to inclusion of
infants with chromosome abnormalities
(including trisomies) in some studies of
HPE. No association between HPE and
paternal age was seen in the three
studies that investigated this association
[Matsunaga and Shiota, 1977; Croen
et al., 1996; Orioli and Castilla, 2007].
Race/Ethnicity
Higher risks of HPE among non-white
compared to white mothers have been
observed in four studies conducted in
the United States and United Kingdom
[Rasmussen et al., 1996; Olsen et al.,
1997; Croen et al., 2000; Ong et al.,
2007], while in a study in Hawaii, a
greater risk among Far East Asians was
seen, compared to Pacific Islanders (RR
3.01, 95% CI 1.305.94) [Forrester and
Merz, 2000]. No association was iden-
tified between paternal race/ethnicity
and HPE in the one study that investi-
gated this association [Croen et al.,
2000].
CBDMP investigators observed an
elevated risk among mothers born out-
side the United States or Mexico (OR
3.1, 95% CI 1.18.6) [Croen et al.,
2000], while the analysis using data from
the NBDPS found no increased risk to
mothers born outside the United States
[Miller et al., 2010].
Socioeconomic Status
Mothers with less than a high school
education had a higher risk of HPE
compared to mothers with a high school
education by investigators using data
from CBDMP (OR 2.1, 95% CI 0.8
6.0) and from NBDPS (OR 2.5, 95% CI
1.15.6) [Croen et al., 2000; Miller
et al., 2010]. NBDPS investigators also
noted a slightly increased risk for
mothers with lower income (OR 1.5,
95% CI 0.82.8), whereas the study
using ECLAMC data found no asso-
ciation between HPE and socioeco-
nomic status [Orioli and Castilla, 2007;
Miller et al., 2010].
CONCLUSIONS
Few non-genetic risk factors for HPE
have been definitively identified to date,
with diabetes being among the most
commonly studied and the risk factor
that has resulted in the strongest associ-
ations, with fairly consistent results
between studies. Other potential r isk
Few non-genetic risk factors forHPE have been definitively
identified to date, with diabetes
being among the most
commonly studied and the risk
factor that has resulted in the
strongest associations, with
fairly consistent results
between studies.
factors that may warrant further study
include salicylate use, respiratory and
sexually transmitted infections, and use
of assisted reproductive technologies,
which have been identified in epide-
miologic studies as possibly associated
with increased r isk of HPE, and quality
of diet and use of multivitamin supple-
ments, which may be associated with a
decreased risk.
Caution is needed, however, in
interpreting the results of epidemiologicstudies of HPE. Since the prevalence of
HPE is much higher among embryos (4
per 1,000) [Matsunaga and Shiota, 1977]
than among live births (1 per 10,000)
[Croen et al., 1996; Rasmussen et al.,
1996], studying potential risk factors
among live births or fetuses at 20 weeks
or greater gestational age, as is com-
monly done, may result in the identi-
fication of exposures which are in fact
not risk factors for HPE, but risk factors
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for survival of the fetus long enough for
detection of the anomaly.
Small sample size leading to low
power to detect an effect is another
consequence of the low birth prevalence
of HPE, which results in unstable effect
estimates and wide CIs. These wide CIs,
which frequently contain the null value
(OR 1), make it difficult to identify
which exposures may be true non-
genetic risk factors for HPE as opposed
to merely findings observed by chance.
In this article some associations whose
CIs include the null are referred to as
potential risk factors when the effect
estimate was fairly large or when more
than one study found similar results;
however, further research will be needed
to determine whether these are true risk
factors or not.Failure to exclude infants with
conditions of genetic etiology (e.g.,
chromosome abnormalities and single
gene disorders) presents another
challenge to studying non-genetic risk
factors for HPE. Studies using etiolog-
ically heterogeneous case groups may
hamper identification of potential non-
genetic r isk factors [Rasmussen et al.,
2003]. For example, inclusion of differ-
ent proportions of cases with chromo-
somal anomalies may be responsible for
the variability seen in studies of the
association between maternal age and
HPE. Similarly, given that maternal
diabetes has been identified as a strong
risk factor for HPE, studies aiming to
identify other risk factors for HPE may
benefit from exclusion of infants with
diabetic mothers from the analysis.
Another key factor in these studies
is ensuring that all infants actually have
HPE. Older studies often depended on
facial phenotype for diagnosis of HPE,
but some infants with HPE have normalfacies [Cohen, 1989a] and some infants
with mild facial features consistent with
HPE may not have HPE [Cohen,
1989a,b]. Given the current widespread
availability of neuroimaging, future
studies should require that imaging
studies (or pathologic analysis in
deceased infants) documenting HPE be
available. However, even when neuro-
imaging is available, other brain defects
may be mistaken for HPE: 19% of scans
sent to the Carter Centers for Brain
Research were found to not have
HPE after review by radiologists with
expertise in HPE [Stashinko et al.,
2004].
One consequence of a stricter case
definition is further reduction in num-
berof cases available for study. Analysis of
the interaction between genetic and
non-genetic risk factors will also be
important, since some genotypes may
increase the risk for HPE after certain
exposures, but these studies will require
even larger sample sizes. Future studies
will likely require collaboration between
multiple investigators to reach a sample
size large enough to identify non-
genetic risk factors for HPE.
ACKNOWLEDGMENTS
We would like to thank Dr. Jaime Fras
for his helpful comments on an earlier
draft of the manuscript.
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