Published Online, 6 May 2008, www.theannals.com, DOI 10.1345/aph.1K550.
The Annals of Pharmacotherapy: Vol. 42, No. 6, pp. 888-892. DOI 10.1345/aph.1K550
© 2008 Harvey Whitney Books Company.
Möbius Syndrome in a Neonate After Mifepristone and Misoprostol Elective Abortion Failure
Marie-Andrée Bos-Thompson, PharmD PhD
Hospital Pharmacist, Department of Medical Pharmacology and Toxicology,
Lapeyronie Hospital, Montpellier, France
Dominique Hillaire-Buys, MD PhD
Lecturer in Clinical Pharmacology, Department of Medical Pharmacology and
Toxicology, Lapeyronie Hospital, Montpellier
Clarisse Roux, PharmD
Intern, Department of Medical Pharmacology and Toxicology, Lapeyronie
Hospital, Montpellier
Jean-Luc Faillie, MD
Intern, Department of Medical Pharmacology and Toxicology, Lapeyronie
Hospital, Montpellier
Daniel Amram, MD
Pediatrician, Clinical Genetics, Department of Neonatology, Centre
Hospitalier Intercommunal, Créteil, France
Reprints: Dr. Bos-Thompson, Service de Pharmacologie Médicale et
Toxicologie, Hôpital Lapeyronie, 371 avenue du Doyen Gaston Giraud,
34295 Montpellier cedex 5, France, fax 33-4-67-33-67-51,
ma-thompson{at}chu-montpellier.fr
 |
Abstract
|
|---|
OBJECTIVE: To report a case of a child born with Möbius
syndrome following exposure in utero to mifepristone and misoprostol for
elective abortion.
CASE SUMMARY: In the seventh week of pregnancy, a woman was
administered mifepristone 600 mg and, 2 days later, misoprostol 400 µg for
abortion. One month later, despite significant metrorrhagia, an ultrasound
examination showed ongoing gestation. At 33 weeks and 3 days of gestation, the
woman gave birth to a male with left facial palsy, microretrognathia, and
axial hypotonia related to Möbius syndrome.
DISCUSSION: Möbius syndrome is characterized by unilateral or
bilateral palsy of the abducens (VI) and facial (VII) cranial nerves. Other
cranial nerves (eg, the hypoglossal [XII]), craniofacial or orofacial
anomalies, and limb malformations are often associated. The etiology of the
Möbius syndrome remains largely unknown and probably involves multiple
factors. The most likely etiological hypothesis is disruption of the
developing vascular system, with transient ischemia (particularly in the
vertebral arteries) and fetal hypoxia. A teratogenic cause of Möbius
syndrome has been suggested. The critical period for the development of
Möbius syndrome following teratogen exposure appears to be 5–8
weeks of gestation. To date, mifepristone alone does not appear to have
induced Möbius syndrome. In contrast, oral or vaginal misoprostol
administration can lead to a significant increase in Doppler-measured uterine
artery resistance and may induce uterine contractions. If these occur during
the critical embryonic period, they may cause flexion in the areas of the
sixth and seventh cranial nerves and decreased blood flow.
CONCLUSIONS: Ineffective use of mifepristone and misoprostol in the
first trimester of pregnancy may be associated with a risk of Möbius
syndrome, primarily due to misoprostol activity. Women with ongoing pregnancy
after failed abortion with misoprostol administration should be informed of
this risk.
Key Words: fetal ischemia, mifepristone, misoprostol, Möbius syndrome, pregnancy
Published Online, May 6, 2008. www.theannals.com, DOI 10.1345/aph.1K550
Administration of mifepristone plus misoprostol is the French protocol for
medical elective abortion. This protocol involves the administration of
mifepristone 600 mg, followed 36–48 hours later by an analog of
prostaglandin E1, oral misoprostol 400 µg (or vaginal
géméprost 1
mg).1
Mifepristone is a synthetic antiprogestin used for abortion, and misoprostol
induces uterine contractions. An ultrasonography is obligatory 14 days after
mifepristone administration to verify termination of pregnancy, because
vaginal bleeding, which may lead patients to conclude that abortion has been
successful, can occur even if pregnancy continues. In France, medical abortion
is allowed only for pregnancies less than 50 days of amenorrhea (equivalent to
36 days of gestation). The rate of complete abortion with this medical
protocol is highest (91–97%) for women who are less than 49 days
pregnant. The same protocol results in complete abortion for 88% of women who
are less than 63 days
pregnant.2 In
France, surgical abortion is authorized until the twelfth week of pregnancy
(140 days of gestation) and can be used after chemical abortion failure.
The teratogenic risk of exposure to mifepristone and misoprostol for the
fetus remains to be fully quantified. Indeed, it has not yet been documented
that mifepristone alone is related to a teratogenic process. In contrast, when
abortion fails, misoprostol has been suspected of causing teratogenic effects,
including terminal limb defects and Möbius syndrome. Most reports have
involved illegal use of the drug, such as cases reported in Brazil where
elective abortion is not
allowed.3-5
We report a case of Möbius syndrome following fetal exposure in utero to
mifepristone and misoprostol for elective abortion.
|
Case Report
|
|---|
A 28-year-old woman, with only moderate asthma treated occasionally by
albuterol, became pregnant 3 years after a miscarriage and 1 year after a
full-term pregnancy resulting in a healthy, normal child. No use of illicit
drugs was reported. She decided to terminate this pregnancy and started the
French protocol for chemical abortion at the beginning of the seventh week of
gestation (day 43). She received oral mifepristone 600 mg and, 2 days later,
misoprostol 400 µg. One month later, despite significant metrorrhagia, an
ultrasound examination showed ongoing pregnancy, with no anomalies observed in
the fetus. The patient requested genetic consultation during the fifteenth
week of pregnancy; thus, pharmacovigilance advice was solicited to counsel the
woman on teratogenic risks. A follow-up by a sonographer was started because
the woman decided to continue her pregnancy.
The woman delivered a boy at 33 weeks and 3 days of pregnancy; his
measurements were within normal parameters for his age of gestation: weight
2.28 kg, length 46 cm, and cranial perimeter 31 cm. The boy presented with
transient respiratory distress, which was corrected rapidly. Diagnosis was
immediate for left facial palsy, microretrognathia, and axial hypotonia
related to Möbius syndrome (Figure
1). Eight weeks after birth, the left facial palsy and
microretrognathia were still present. At month 4, the infant was able to suck
without help, but he was still hypotonic and unable to lift his head
completely or grasp objects.
The Naranjo probability scale indicated that the Möbius syndrome
observed in this child was possibly related to misoprostol but doubtfully
related to
mifepristone.6
However, the Naranjo scale was not specifically developed to determine the
likelihood of fetal teratogenesis from prenatal exposure to a teratogen. This
is exemplified in the fact that 5 of the 10 questions employed to construct
this scale are not applicable to this case.
|
Discussion
|
|---|
Möbius syndrome is a rare disorder first described by Von Graefe in
1880 and identified and defined in 1888 by Paul Julius Möbius, a Leipzig
neurologist, as an independent pathological
entity.7 It
consists of congenital unilateral or bilateral palsy of the abducens (VI) and
facial (VII) cranial nerves. This sequence can be associated with palsy of
other cranial nerves such as the trigeminal (V), the glossopharyngeal (IX),
and the hypoglossal (XII). Other malformations, such as craniofacial and
orofacial anomalies, face anomalies (eg, cleft palate, abnormalities of the
tongue, the ear, micrognathia), and limb malformations (eg, club foot,
syndactyly, arthrogryposis) can occur concurrently with Möbius syndrome.
Clinical examination at birth of a baby with Möbius syndrome shows
unilateral or bilateral facial palsy, with suckling problems, significant
salivation difficulties, and/or impaired facial expressions. Later in life,
the observed abnormalities include a fixed smile, difficult ocular movements,
hearing problems, dental anomalies, and speech defects.
Poland syndrome (hypoplasia of the pectoralis major muscle, syndactyly of
the hand, hypoplasia of the forearm and/or the breast, agenesis of the nipple)
and Pierre Robin syndrome (median posterior cleft palate, retrognathia,
glossoptosis) may also occur with Möbius syndrome. Mental retardation and
autism were also observed by some authors in one-third of a population of 25
patients with Möbius
syndrome.8
The etiology of Möbius syndrome is largely unknown, but the vascular
hypothesis appears to be the most plausible. The hypothesis is that transient
ischemia, particularly in the vertebral arteries, is responsible for
disruption of the developing vascular system and for fetal
ischemia.4,7,9
Obstruction or premature regression of terminal arteries of the trigeminal (V)
nerve and/or retarded formation of the basilar/vertebral system can lead to
anomalies in cranial nerve
development.10
In children with Möbius syndrome, focal brainstem necrosis with
calcifications has been reported, as well as capillary telangiectasia in the
mesencephalon and
pons.11
Dooley et
al.12
observed foci of brainstem calcification in 5 of 7 children studied and
believed it was secondary to prenatal brainstem ischemia. Subclavian artery
supply disruption sequence occurring around 6 weeks of gestation is related to
several anomalies that occur in Poland and Möbius syndromes, the same
phenomenon responsible for terminal limb defects and
arthrogryposis.9,13,14
Two factors are important in understanding the pathophysiology of
Möbius syndrome. First, cranial nerves VI and VII are primarily affected.
Second, Möbius syndrome results when the disruption occurs in a precise
period of embryonic development, between gestational weeks 5 and
8.4,15
Any pathological event that disturbs circulation during this critical period
will cause brainstem alterations or widespread developmental
defects.4 A
few cases of Möbius syndrome appear to be of familial occurrence,
sometimes associated with karyotypic
changes.8 Why
cranial nerve nuclei VI and VII are preferentially affected remains to be
fully understood.
Shepard16
postulated that the embryo is particularly vulnerable at this time of
gestation because of the position of cranial nuclei for cranial nerves VI and
VII. Both nerves are located in the ventral part of the rhomben-cephalon, near
plication, in a thin, dilated portion of the brain with relative lack of
tissue. If flexion occurs in this area, decreased blood flow will follow.
A teratogenic cause of Möbius syndrome has been suggested by many
authors.4,8,16-22
Mifepristone, the first medicine given in the French medical abortion
protocol, has not been found to be related to teratogenicity. In several case
reports, pregnancies not successfully aborted with mifepristone continued to
full term with no adverse effects on the
newborn.23
However, one case mentioned anomalies (complete lack of amniotic sac; no fetal
stomach, gallbladder, or urinary tract; sirenomelia) possibly associated with
mifepristone administration in early pregnancy (400 mg at 5 weeks'
gestation).24
In contrast, use of oral or vaginal misoprostol during the first trimester of
pregnancy significantly reduces uterine arterial blood flow. Doppler
resistance indices are significantly increased 60–90 minutes after
misoprostol administration (200 µg orally, or 200 µg intravaginally plus
200 µg orally) to pregnant
women.25,26
Based on these observations and those of our case report, we propose the
following schema for misoprostol teratogenicity
(Figure
2).2,4,7,9,14
Misoprostol induces intense uterine contractions and, thus, by a mechanical
action, may be responsible for a flexion in the area of cranial nerves VI and
VII. This flexion, along with the position of the embryo at the time of
exposure (5–8 wk gestation), could likely result in marked vulnerability
of the cranial nuclei to hemorrhage and cellular death. It may also lead to
the death of other cranial nuclei; hence, the occurrence of other
malformations as part of the Möbius syndrome. Uterine contractions also
lead to hypoperfusion, which is responsible for fetal hypoxia and ischemia,
resulting in endothelial cell injury and tissular lesions. Vascular disruption
is also suspected in limb anomalies, especially terminal limb
malformations.
Several associations between use of misoprostol and congenital
malformations with fetal ischemia have been reported, especially in countries
in which medical abortion is
illegal.3-5,17-22
Table
13-5,17,21,22
details case reports of Möbius syndrome secondary to the administration
of misoprostol. These reports all concern illegal use of the medication for
abortion (except 1 report of its use for peptic ulcer disease, a primary use
of misoprostol, alone or in combination with nonsteroidal antiinflammatory
drugs). In these reports, exposure to misoprostol varied from 400 to 16,000
µg, and no relation between dose and possible teratogenic effects is
apparent. For Möbius syndrome, Pastuszack et
al.17 and Da
Silva et
al.18
reported odds ratios of 38.8 (95% CI 9.5 to 159.4) and 25.3 (95% CI 11.1 to
57.7), respectively. In support of the vascular hypothesis for Möbius
syndrome, some cases have been described with other vasoconstrictor
medications. Puvabanditsin et
al.19
described a Poland/Möbius syndrome with brainstem calcifications that was
related to multiple use of cocaine during the first trimester of pregnancy. In
addition, the use of ergotamine 6 mg at 5 weeks and 4 days of gestation (day
39) was associated with uterine cramping within a few hours and bloody vaginal
discharge the following
day.20 The
baby girl who was exposed to ergotamine in utero was born at 37 weeks'
gestation, with talipes deformities, facial paralysis, and tongue
anomalies.
|
Conclusions
|
|---|
To our knowledge, this is the first published case report of Möbius
syndrome following fetal exposure in utero to mifepristone and misoprostol
according to the French protocol for elective medical abortion. To date,
mifepristone does not appear to be related to an augmentation of teratogenic
risk. In contrast, misoprostol can be involved in a teratogenic process.
Extreme care should be given to pregnancies that continue despite misoprostol
administration, especially when exposure occurs between weeks 5 and 8, a
period of high embryo sensitivity to the teratogenic action of this drug.
Precise ultrasonography should be performed to detect any malformations
possibly related to misoprostol exposure (eg, limb defects), although it is
almost impossible to detect Möbius syndrome before birth. Women
considering medical abortion with the combination of mifepristone and
misoprostol should be precisely counseled on the risks to their fetus if
abortion failure occurs and surgical abortion is not desirable.
|
References
|
|---|
- Vidal 2007. Le Dictionnaire. 83e édition.
Maury-Imprimeur SA, Malesherbes (France) 1er trimestre2007.
- Golberg AB, Greenberg BS, Darney PD. Misoprostol and pregnancy. N Engl J Med 2001;344:38-47.[Free Full Text]
- Gonzalez CH, Marques-Dias MJ, Kim CA, et al. Congenital
abnormalities in Brazilian children associated with misoprostol misuse in
first trimester of pregnancy. Lancet1998;351:1624-7.[CrossRef][Medline]
- Marques-Dias MJ, Gonzalez CH, Rosemberg S. Möbius sequence in
children exposed in utero to misoprostol: neuropathological study of three
cases. Birth Defects Research (Part A)2003;67:1002-7.[CrossRef]
- Sanchez O, Guerra D. Moebius syndrome due to the use of
misoprostol. Case report. Invest Clin2003;44:147-53.[Medline]
- Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the
probability of adverse drug reactions. Clin Pharmacol Ther1981;30:239-45.[Medline]
- Abramson DL, Cohen MM, Mulliken JB. Möbius syndrome:
classification and grading system. Plast Reconstr Surg1998;102:961-7.[CrossRef][Medline]
- Strömland K, Sjögreen L, Miller M, et al. Möbius
sequence—a Swedish multidiscipline study. Eur J Paediatr
Neurol 2002;6:35-45.[CrossRef][Medline]
- Issaivanan M, Virdi VS, Parmar VR. Subclavian artery supply
disruption sequence—Klippel-Feil and Möbius anomalies. Indian J Pediatr 2002;69:441-2.[Medline]
- Bavinck JN, Weaver DD. Subclavian artery supply disruption
sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and
Möbius anomalies. Am J Med Genet1986;23:903-18.[CrossRef][Medline]
- D'Cruz OF, Swisher CN, Jaradeh S, Tang T, Konkol RJ. Möbius
syndrome: evidence for a vascular etiology. J Child Neurol1993;8:260-5.[Abstract/Free Full Text]
- Dooley JM, Stewart WA, Hayden JD, Therrien A. Brainstem
calcification in Möbius syndrome. Pediatr Neurol2004;30:39-41.[CrossRef][Medline]
- St Charles S, Dimario FJ, Grunnet ML. Möbius sequence: further
in vivo support for the subclavian artery supply disruption sequence. Am J Med Genet 1993;47:289-93.[CrossRef][Medline]
- Homes LB. Teratogen-induced limb defects. Am J Med
Genet 2002;112:297-303.[CrossRef][Medline]
- Allen BM, Wert MA, Tatum SA. Congenital unilateral multiple cranial
neuropathy: an etiology shared with Möbius syndrome? Int J Pediatr
Otorhinolaryngol 2006;70:931-4.[CrossRef][Medline]
- Shepard TH. Möbius syndrome after misoprostol: a possible
teratogenic mechanism. Lancet1995;346:780.[Medline]
- Pastuszak AL, Schüler L, Speck-Martins CE, et al. Use of
misoprostol during pregnancy and Möbius' syndrome in infants. N
Eng J Med 1998;338:1881-5.[Abstract/Free Full Text]
- da Silva Dal Pizzol T, Knop FP, Mengue SS. Prenatal exposure to
misoprostol and congenital anomalies: systematic review and meta-analysis. Reprod Toxicol 2006;22:666-71.[CrossRef][Medline]
- Puvabanditsin S, Garrow E, Augustin G, Titapiwatanakul R, Kuniyoshi
K. Poland-Möbius syndrome and cocaïne abuse: a relook at vascular
etiology. Pediatr Neurol2005;32:285-7.[CrossRef][Medline]
- Graf WD, Shepard TH. Uterine contractions in the development of
Möbius syndrome. J Child Neurol1997;12:225-6.[Free Full Text]
- Gonzalez CH, Vargas FR, Alvarez Perez AB, et al. Limb deficiency
with or without Mobius sequence in seven Brazilian children associated with
misoprostol use in the first trimester of pregnancy. Am J Med
Genet 1993;47:59-64.[CrossRef][Medline]
- Vargas FR, Schuler-Faccini L, Brunoni D, et al. Prenatal exposure
to misoprostol and vascular disruption defects: a case–control study. Am J Med Genet 2000;95:302-6.[CrossRef][Medline]
- Lim BH, Lees DAR, Bjornsson S, et al. Normal development after
exposure to mifepristone in early pregnancy. Lancet1990;336:257-8.[Medline]
- Pons JC, Imbert MC, Elefant E, et al. Development after exposure to
mifepristone in early pregnancy (letter). Lancet1991;338:763.[Medline]
- Yip SK, Tse AO, Haines CJ, Chung TK. Misoprostol's effect on
uterine arterial blood flow and fetal heart rate in early pregnancy. Obstet Gynecol 2000;95:232-5.[CrossRef][Medline]
- Turan C, Koc N, Dansuk R, Cengizoglu B, Mericelli DS, Unal O.
Misoprostol administration in first-trimester pregnancies with embryonic
demise reduces uterine arterial blood flow. J Matern Fetal Neonatal
Med 2003;14:226-8.[CrossRef][Medline]
Top
Abstract
Case Report
