2003 Wiley-Liss, Inc.

Birth Defects Research (Part A) 67:10021007 (2003)

Mobius Sequence in Children Exposed In Utero to

Misoprostol: Neuropathological Study of Three Cases
Maria Joaquina Marques-Dias,1* Claudette H. Gonzalez,2 and Sergio Rosemberg3
1
Departments of Neurology and Pediatrics, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil
2
Department of Biology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil
3
Department of Pathology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil
Received 10 January 2000; Accepted 25 August 2003

BACKGROUND: Misoprostol exposure in the rst trimester of pregnancy has been related to congenital malformations, particularly the
Mobius sequence and terminal transverse limb defects. CASES: Neuropathological ndings of three patients with Mobius sequence related
to misoprostol are reported. No previous pathological studies have shown these abnormalities to be associated with misoprostol exposure
in utero. The brain stem was cut serially, from the rostral mesencephalum to the caudal aspect of the medulla, and all fragments were
stained with hematoxylin-eosin and cresyl violet. Old ischemic-anoxic foci of gliosis, with necrosis and calcication, dorsally situated, were
present from the pons to the medulla, involving some cranial nerve nuclei (especially the IV, VII, and XII) that were partially or completely
depopulated of neural cells. CONCLUSIONS: The ndings suggest a circulatory mechanism to the Mobius sequence, with vascular
disruption involving the territory of the subclavian artery, occurring in a critical period of embryonic life between six to eight weeks
postconception. These cases add further evidence of the role of misoprostol as a teratogen. Birth Defects Research (Part A) 67:10021007,
2003. 2003 Wiley-Liss, Inc.

Key words: Mobius sequence; misoprostol; vascular disruption; prenatal brain stem ischemia

INTRODUCTION We present neuropathological ndings in three patients

Since the Mobius syndrome was originally described by
Mobius in 1888, when it was dened as a congenital facial
diplegia with restriction of horizontal eye movements, its
spectrum has been expanded to include palsies of other
cranial nerves, as well as craniofacial, limb, and anterior
chest abnormalities. This phenotype is currently known as
the Mobius sequence (MS). The most accepted pathogenic
mechanism is a circulatory disorder, secondary to a dis-
ruptive process in the vascular territory of the subclavian
artery, that occurs between the sixth and eighth weeks of
gestational age. Several clinical and anatomic pathological
studies corroborate this hypothesis (Lipson et al., 1989;
DCruz et al., 1993; Leong and Ashwell, 1997; Squier, per-
sonal communication).
Exposure to cocaine or to ergotamine during gestation
has been associated with MS and/or limb abnormalities
(Kankirawatana et al., 1993; Graf and Shepard, 1997). Mi-
soprostol, a PGE1 synthetic analog marketed as Cytotec,
has been used widely and illegally in Brazil as a most
popular abortifacient. Gonzalez et al. (1993, 1998) reported
two large series of Brazilian children presenting with MS
and/or other congenital abnormalities who had been ex-
posed in utero to misoprostol. Several researchers have
also reported patients with similar abnormalities who had
been exposed to that drug during the rst trimester of
pregnancy (Pastuszak et al. 1998; Nunes et al., 1999; Genest
et al., 1999; Coelho et al., 2000; Orioli and Castilla, 2000).
exposed in utero to misoprostol, in whom clastic hypoxic-
ischemic lesions of the brain stem were found. No previous
pathological studies have so clearly shown the association
of misoprostol exposure in utero with these abnormalities.
CASES
Case 1
This boy was patient 1 in the series reported by Gonzalez
et al. (1993). He was the second child of a healthy mother
who attempted to abort in the second month of pregnancy
using 600 g of misoprostol orally. She reported mild
bleeding for three days after the attempt. Otherwise, the
pregnancy was uneventful, delivery was normal and Ap-
gar scores were 7 and 10, at 1 and 5 min, respectively. He
weighed 3110 gm (50th centile), measured 46.5 cm (2 SD)
and his occipitofrontal circumference was 34.5 cm (1 SD).
On physical examination, he had an expressionless face,
strabismus, hypoplasia, and hypomotility of the tongue,
limited jaw mobility, and microretrognathism, and a poor
gag, suck, and swallow reex; otherwise he had active
Grant sponsor: Fundacao a Pesquisa do Estado de S. Paulo (FAPESP); Grant
number: 98/06808-8 (to MJMD).
*Correspondence to: Maria Joaquina Marques Dias, Av. Dr. Eneas C. de Aguiar
647, Sao Paulo, Brazil, 05403-900. E-mail: mariajmd@icr.hcnet.usp.br
DOI: 10.1002/bdra.10144

Birth Defects Research (Part A): Clinical and Molecular Teratology 67:10021007 (2003)
 MOBIUS NEUROPATHOLOGY IN MISOPROSTOL EXPOSURE
spontaneous normal movements of the limbs. In his hands
there was agenesis of distal phalanges on the ngers 2, 3
and 4, absent nails on ngers 1 and 5, complete bilateral
transverse palmar creases, and bilateral equinovarus feet.
Due to difculties in sucking and swallowing, he was fed
by nasogastric tube from birth. The diagnosis was MS
(affected cranial nerves were V, VI, VII, IX, X, and XII) with
associated limb anomalies.
Fundoscopy, karyotype, TORCH, cerebral spinal uid,
electroencephalography, auditory and visual evoked po-
tentials, and abdominal ultrasonography identied no ab-
normalities. Cranial ultrasonography revealed a large third
ventricle; radiographs of the hands showed agenesis of
distal phalanges and bilateral hypoplasia of the medial
phalanges of the second, third, and fourth ngers. On the
24th day of life, he had a reversible cardio-respiratory
arrest and generalized convulsions, and needed ventilator
support for ve days; between the second and eighth
month, he had several apneic episodes, and died at eight
months of age, as a result of a further apneic episode.
Case 2
This boy was the rst child of nonconsanguineous and
healthy parents. His mother attempted to abort at the sixth
week of pregnancy, using 400 g of misoprostol; mild
bleeding and cramping occurred some hours afterward.
He was born in good condition and weighed 3300 gm (50th
centile). Due to poor sucking and swallowing, he was fed
by tube in the rst days of life. Physical examination
showed bilateral facial and abducent palsies and an equi-
novarus club foot deformity. When rst seen in our center
at one year and seven months of age, his weight was 14 kg
(75th90th centile) and the occipitofrontal circumference
was 48.5 cm (50th centile). He had a prominent forehead
with mild hirsutism, downward eye slant, bilateral epican-
thal fold, micrognathia, a long philtrum, extruded lateral
incisors, and partial syndactyly of toes 2 and 3. He had an
expressionless face, strabismus, difculties with sucking,
mild motor delay, and difculties in word articulation. On
neurological examination, he had bilateral asymmetric, fa-
cial (VII), and abducent (VI) nerve palsies, limited mouth
opening (V), and hemiatrophy of the tongue (XII). CT and
auditory evoked potentials were normal. The patient died
at age two years and three months, after receiving sedation
for a CT scan.
Case 3
This girl was the rst child of young, healthy and non-
consanguineous parents. Her mother attempted to abort in
the rst trimester, using 600 g of misoprostol by mouth.
This was followed by mild vaginal bleeding a few hours
later. Otherwise, the pregnancy was uneventful. Prenatal
ultrasonography three weeks before birth revealed poly-
hydramnios, hydrocephalus, and poor sucking. Delivery
was by cesarean section, and the child had difculty estab-
lishing respiration. Apgar scores were 1, 1, 2, and 1 at 1, 2,
5, and 10 min, respectively. Birth weight was 2980 gm
(10th25th centile) and occipitofrontal circumference was
37 cm. Physical examination revealed macrocrania, a
mask-like face, microstomia, microretrognathism, and
right equinovarus foot deformity, and it was difcult to
open her mouth. She died 40 min after birth, despite in-
tensive resuscitation attempts.
1003
NEUROPATHOLOGICAL FINDINGS
Methods
All of the brains were xed in 10% formalin for at least
21 days and then sectioned serially in the coronal axis.
Representative fragments were taken from each lobe of the
cerebral hemispheres, hippocampus, basal ganglia, thala-
mus, and cerebellum. The brain stem was sectioned seri-
ally from the rostral mesencephalon to the caudal aspect of
the medulla. All fragments were stained with hematoxylin-
eosin and cresyl violet (Nissls stain).
Case 1
The brain weighed 654 gm (normal 714 gm) and
appeared normal macroscopically. Histological examina-
tion showed lesions limited to the brainstem, which in-
cluded diffuse old reactive gliosis and necrotic calcied
foci bilaterally, next to the oor of the IVth ventricle,
around nerve nuclei VI.
The nuclei of the facial nerve (VII) were gliotic, shrunken,
and poorly populated. Gliosis was also present next to the
nuclei of nerve X and XI that could not be traced. There was
unilateral necrosis of the nucleus of nerve XII (Fig. 1).
Case 2
The brain weighed 1300 gm ( normal 1064 gm) and
was moderately edematous. Microscopically, there was a
mild neuronal loss with ischemic neurons through the
cerebral cortex, mainly in layer III and Sommer sector of
the hippocampus. Similar lesions were observed in the
quadrigeminal plate and the substantia nigra. At the pon-
tine level, there were foci of calcication symmetrically
situated in the tegmentum, next to the VI nerve nuclei
(Figs. 2 and 3). One was gliotic and almost completely
devoid of neurons. Both VII nerve nuclei were depopu-
lated, shrunken, and gliotic. There was a diffuse mild
gliosis of the tegmentum, extending from pons to medulla.
The bulbar nuclei appeared normal.
Case 3
The brain weighed 450 gm (50th centile). Except for the
fact that the insulae could still be visualized on both sides,
the external aspect of cerebral hemispheres, brainstem, and
cerebellum was normal. There was moderate dilatation of
the lateral ventricles, mainly at their posterior horns (col-
pocephaly). The corpus callosum was very thin. Microscop-
ically, the lesions were limited to the brainstem. Unfortu-
nately, for technical reasons the mesencephalon could not
be studied. There were symmetrical foci of calcication in
the lateral aspect of the tegmentum, which were observed
from the upper pons to the lower medullar level. The
nuclei of the VII nerve could not be traced. There was
severe gliosis throughout the pons, mainly in the tegmen-
tum and around the oor of the IVth ventricle. The me-
dulla was severely deformed and narrowed in the dorso-
ventral direction. The tegmentum was athrophic; the
inferior olives were malformed, poorly circumvolute, and
dorsally displaced. The pyramids were shrunken, gliotic,
and almost devoid of neurons. Around the lateral aspect of
the caudal pons and medulla, there was a rim of glioneural
ectopia formed by dysplastic nervous tissue, which lled
the arachnoidal space. An area of cerebellar micropo-
lygyria was noted beneath this ectopic tissue (Fig. 4).
Birth Defects Research (Part A) 67:10021007 (2003)
1004 MARQUES-DIAS ET AL.
DISCUSSION
The neuropathological ndings in these three cases are
characterized by symmetrical bilateral necrotic foci in dif-
ferent levels of the brain stem, with neuronal loss, gliosis,
and calcication, suggesting old hypoxic-ischemic lesions.
Similar lesions in the brainstem have been identied in
children suffering from cardiac arrest (Gilles, 1963; Damb-
ska et al., 1976; Janzer and Friede, 1980), transient circula-
tory arrest, and asphyxia (Schneider et al., 1975; Leech et
al., 1977). The intensity and distribution of the lesions
Birth Defects Research (Part A) 67:10021007 (2003)
Figure 1. Case 1. Medullaat the left, at-
rophy and gliosis of the nucleus of cranial
nerve XII.
varied. They were most evidence in the area of the cranial
nerve nuclei V, VI, and VII, as predicted by the clinical
ndings in MS. Also, diffuse gliosis was present through-
out the tegmentum of the brainstem, mainly at the pontine
level, involving reticular formation subnuclei.
Kinney et al. (1989) and Cortez and Kinney (1996) have
previously discussed central apnea in three newborns with
tegmental necrosis and olivary atrophy; Igarashi et al.
(1997) and Nunes et al. (1999) have also suggested that the
central dysfunction presented by their patients with MS
Figure 2. Case 1. A coarse calcication of
the neuropil.
 MOBIUS NEUROPATHOLOGY IN MISOPROSTOL EXPOSURE
Figure 3. Case 2. Pons bilateral symmet-
rical foci of calcication in the tegmentum.
would be the result of lesions in the proximity of respira-
tory nuclei.
We conclude that the diffuse tegmental gliosis from the
caudal pons to the medulla (where the nucleus of olivary
tract and dorsal respiratory nuclei group are located) and
near the X, XI, and XII nuclei, in all cases, and the evident
olivary atrophy in case 3, was responsible for the respira-
tory difculties and apneic spells in these patients.
Bouwess-Bavinck and Weaver (1986) reported the asso-
ciation of MS with transverse limb defects and proposed a
unifying mechanism for these abnormalities. They pro-
posed that a disruptive process in the vascular territory of
the subclavian artery, occurring between the sixth and
eighth weeks of gestational age, was the most likely patho-
genic mechanism for these disorders and suggested that
the Poland, Klippel-Feil, and Sprengel anomalies may have
a similar etiology. At that period of embryonic develop-
ment, a change in the arterial blood supply to the hind-
brain, from an exclusive carotid supply to a vertebral one,
leads to a reversal of blood ow within the basilar artery,
from a rostral caudal to a caudalrostral pattern. Any
pathogenic event that disturbs the circulation in this criti-
cal period will cause brainstem alterations or even more
widespread developmental defects, such as the failure of
segmentation of cervical vertebrae (Klippel-Feil anomaly),
absence of the muscle pectoralis major (Poland anomaly),
hypoplasia of the scapulae (Sprengel anomaly) or limb
malformations. All of these abnormalities can be features
of the Mobius syndrome.
Lipson et al. (1989), in their experimental studies of an
animal model of MS, described typical brainstem lesions
with relative sparing of cerebrum. In the three cases de-
scribed in this article, there was relative sparing of the
cerebrum when compared with the brainstem. The dyspla-
sia observed in the arachnoidal space and cerebellum of
case 3 could also be the result of a hypoxic ischemic event.
Prenatal brainstem ischemic lesions have been reported
in association with MS and, in particular, a close relation-
1005
ship between in vivo brainstem calcications seen by CT
and gliosis with calcied gliotic foci identied in neuro-
pathological sections (Thakkar et al., 1977; Govaert et al.,
1989; DCruz et al., 1993; St. Charles et al., 1993; Yoon et al.,
1997; Squier, personal communication). Leong and Ash-
well (1997) have provided further evidence for the concept
of a watershed zone in the paramedian dorsal region of the
brainstem. They show that this region, the most compro-
mised in Mobius syndrome, is especially vulnerable to
ischemia due to particularities of its vascular anatomy. The
authors showed in rats that the region is a watershed zone
due to the inability of the vessels of the paramedian region
to anastomose across the vascular midline. Moreover, Le-
ong and Ashwell (1997) also suggested that efferent motor
nuclei in this region have a high oxidative metabolic activ-
ity, which could render their constituent neurons more
susceptible to hypoxia.
Several disruptive noxious events occurring in early ges-
tation have been reported in association with Mobius syn-
drome. Lipson et al. (1989) showed that abdominal trauma,
uterine vessel clamping with handling, and hyperthermia
caused bilateral brainstem lesions in fetal rats. In a series of
15 patients with MS, noxious events, including hyperther-
mia, previous uterine surgery, electric shock, failed abor-
tion, prolonged rupture of membranes, or alcohol abuse,
occurred early during their mothers pregnancy in eight of
them.
Teratogenic causes of MS have been postulated by sev-
eral authors, including: hyperthermia during pregnancy
(Graham et al., 1988); cocaine use (Hoyme et al., 1990;
Kankirawatana et al., 1993); ergotamine use (Graf and
Shepard, 1997); thalidomide use (Newman, 1985); and cho-
rionic villus sample (CVS) (Firth et al., 1991).
Cortez et al. (1996) have proposed that some pathologies
of the caudal pons (at the level of cranial nerve VI) and the
medulla (at the level of cranial nerves IX, X, and XII) could
result from abnormal development of the respective rhom-
Birth Defects Research (Part A) 67:10021007 (2003)
1006 MARQUES-DIAS ET AL.
Figure 4. Case 3. Medullameningeal glioneural ectopia and malformation of the inferior olive.
bomeres due to a defect in the homeobox genes that reg-
ulate the development of those segments.
In mouse and frog embryos, Hox genes have been
shown to be activated after treatment with retinoic acid, a
metabolite of vitamin A, both in cultured cells and in vivo
(Boncinelli, 1999). Homeobox-containing genes EN-1 and
EN-2 have been implicated in the control of pattern forma-
tion during development of the central nervous system in
experimental animals. Expression of EN genes was dem-
onstrated in all neuronal groups of the medulla and cere-
bellum after in situ hybridization with human EN-1 and
EN-2 RNA probes in the medulla and cerebellum of hu-
man embryos (18 21 weeks gestational age) (Zec et al.,
1997).
One could speculate that misoprostol would interact,
like retinoic acid, with certain homeobox genes that act in
the pontine and medullary development of the human
fetus. However, based on the clear pathologic evidence of
old marks of hypoxic-ischemic insult in the same region,
we consider a vascular disruption mechanism as a more
plausible cause of our ndings. Specically, uterine arterial
vasoconstriction, caused by the drug, would lead to reduc-
tion in arterial blood ow to the fetus, causing the isch-
emia, hemorrhage, and tissue loss.
Misoprostol, a prostaglandin E1 analog, which has po-
tent uterotonic properties, has been used for illegal medical
termination of pregnancy in Brazil, where its use in an
uncontrolled fashion has been well reported in the litera-
Birth Defects Research (Part A) 67:10021007 (2003)
ture (Coelho et al., 1993, 1994; Faundes et al., 1996). Yip et
al. (2000) have determined signicant increase in Doppler-
resistance indices of uterine arteries 1 hr after a single oral
dose of misoprostol in women seeking legal termination of
pregnancy at 715 completed gestational weeks. Although
these changes were not associated with fetal death at that
time, the authors believe that subtherapeutic doses of mi-
soprostol could explain the congenital abnormalities by a
vascular mechanism that caused a transient ischemic-hy-
poxic insult.
Two series of infants with congenital abnormalities with
or without MS exposed in utero to misoprostol used as an
abortifacient were reported by some of us (Gonzalez et al.,
1993, 1998) in 1993 and 1998; in those two series, 25 of the
49 affected infants also had MS.
Pastuszak et al. (1998), in a cohort study, compared the
frequency of misoprostol usage during the rst trimester of
pregnancy by mothers of 96 children with MS and mothers
of 96 children with neural tube defects. The study showed
that attempted abortion with misoprostol was associated
with a signicantly increased risk of MS in infants.
Clemens et al. (1997), working with rabbits, found evi-
dence for the teratogenicity of misoprostol. They demon-
strated an increase in spina bida, caudal vertebral defects,
umbilical hernia, and gastroschisis after exposure to miso-
prostol on days 79 of gestation. In rats exposed to mater-
nal cocaine, Webster and Brown-Woodman (1990) and
 MOBIUS NEUROPATHOLOGY IN MISOPROSTOL EXPOSURE
Webster et al. (1991) reproduced brain stem lesions similar
to those found in the infants with MS we report here.
In summary, the neuropathological ndings described in
three misoprostol-exposed infants provide more evidence
that misoprostol in early pregnancy induces a vascular
disruptive episode in the brainstem of some patients, caus-
ing MS.
ACKNOWLEDGMENTS
We thank our colleagues, Chong A. Kim, Soa M.M.
Sugayama, Jose Albino da Paz, and Renata S. Mascaretti
Proenca, who helped in the clinical study. We also thank
Susan M. Huson, M.D., and Waney Squier, M.D., for their
contribution (English revision and comments).
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